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Song Z, Yan M, Zhang S, Hu B, Qing X, Shao Z, Chen S, Lv X, Liu H. Implications of circadian disruption on intervertebral disc degeneration: The mediating role of sympathetic nervous system. Ageing Res Rev 2025; 104:102633. [PMID: 39701186 DOI: 10.1016/j.arr.2024.102633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 12/05/2024] [Accepted: 12/05/2024] [Indexed: 12/21/2024]
Abstract
The circadian clock orchestrates a broad spectrum of physiological processes, crucially modulating human biology across an approximate 24-hour cycle. The circadian disturbances precipitated by modern lifestyle contribute to the occurrence of low back pain (LBP), mainly ascribed to intervertebral disc degeneration (IVDD). The intervertebral disc (IVD) exhibits rhythmic physiological behaviors, with fluctuations in osmotic pressure and hydration levels that synchronized with the diurnal cycle of activity and rest. Over recent decades, advanced molecular biology techniques have shed light on the association between circadian molecules and IVD homeostasis. The complex interplay between circadian rhythm disruption and IVDD is becoming increasingly evident, with the sympathetic nervous system (SNS) emerging as a potential mediator. Synchronized with circadian rhythm through suprachiasmatic nucleus, the SNS regulates diverse physiological functions and metabolic processes, profoundly influences the structural and functional integrity of the IVD. This review synthesizes the current understanding of circadian regulation and sympathetic innervation of the IVD, highlighting advancements in the comprehension of their interactions. We elucidate the impact of circadian system on the physiological functions of IVD through the SNS, advocating for the adoption of chronotherapy as a brand-new and effective strategy to ameliorate IVDD and alleviate LBP.
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Affiliation(s)
- Zongmian Song
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Miaoheng Yan
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Shuo Zhang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Binwu Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiangcheng Qing
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zengwu Shao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Songfeng Chen
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Xiao Lv
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Hongjian Liu
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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Peng BG, Li YC, Yang L. Role of neurogenic inflammation in intervertebral disc degeneration. World J Orthop 2025; 16:102120. [PMID: 39850033 PMCID: PMC11752484 DOI: 10.5312/wjo.v16.i1.102120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/29/2024] [Accepted: 12/20/2024] [Indexed: 01/13/2025] Open
Abstract
In healthy intervertebral discs (IVDs), nerves and blood vessels are present only in the outer annulus fibrosus, while in degenerative IVDs, a large amount of nerve and blood vessel tissue grows inward. Evidence supports that neurogenic inflammation produced by neuropeptides such as substance P and calcitonin gene related peptide released by the nociceptive nerve fibers innervating the IVDs plays a crucial role in the process of IVD degeneration. Recently, non-neuronal cells, including IVD cells and infiltrating immune cells, have emerged as important players in neurogenic inflammation. IVD cells and infiltrating immune cells express functional receptors for neuropeptides through which they receive signals from the nervous system. In return, IVD cells and immune cells produce neuropeptides and nerve growth factor, which stimulate nerve fibers. This communication generates a positive bidirectional feedback loop that can enhance the inflammatory response of the IVD. Recently emerging transient receptor potential channels have been recognized as contributors to neurogenic inflammation in the degenerative IVDs. These findings suggest that neurogenic inflammation involves complex pathophysiological interactions between sensory nerves and multiple cell types in the degenerative IVDs. Clarifying the mechanism of neurogenic inflammation in IVD degeneration may provide in-depth understanding of the pathology of discogenic low back pain.
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Affiliation(s)
- Bao-Gan Peng
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
| | - Yong-Chao Li
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
| | - Liang Yang
- Department of Orthopeadics, Featured Medical Center of Chinese People’s Armed Police Forces, Tianjin 300000, China
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Fukuda H, Sakuma Y, Inage K, Takahashi K, Yamaura I, Shiratsuchi H, Ohtori S. Tumor Necrosis Factor-Alpha (TNF-α) and Interleukin-6 (IL-6) Cytokines in the Injured Meniscus of Patients With Knee Subchondral Insufficiency Fractures: A Potential Association With Preoperative Pain. Cureus 2025; 17:e77734. [PMID: 39974261 PMCID: PMC11839236 DOI: 10.7759/cureus.77734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2025] [Indexed: 02/21/2025] Open
Abstract
Background The development of subchondral insufficiency fracture (SIF) of the knee following a medial meniscal posterior root tear (MMPRT) results in pain and limitations in daily activities. Pain in patients with SIF is associated with local chronic inflammation in the knee joint, involving the production of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nerve growth factor (NGF). This study aimed to quantify the levels of proinflammatory cytokines (TNF-α, IL-6, NGF) in the injured medial meniscus (IMM) tissue of patients with knee SIF and examine their potential association with preoperative pain and functional scores. Methods Meniscus samples were collected from 17 patients with knee SIF (mean age: 62.8 ± 2.6 years) who underwent total knee arthroplasty. The tissue samples were categorized into two groups based on the degree of injury: the IMM and the non-injured healthy lateral meniscus (HLM) as the control group. The levels of TNF-α, IL-6, and NGF in both groups were measured using an enzyme-linked immunosorbent assay (ELISA), and differences were evaluated with the Wilcoxon signed-rank test. The association between preoperative functional and pain scores and the levels of each inflammatory mediator was analyzed using Spearman's correlation. Results TNF-α and IL-6 were detectable in the meniscus tissues, while NGF levels were negligible. The levels of TNF-α and IL-6 were significantly higher in the IMM group compared to the HLM group (p<0.05). Furthermore, TNF-α and IL-6 levels in the IMM group were correlated with the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Conclusions This study demonstrated a significant increase in TNF-α and IL-6 cytokine levels in the IMM compared to the non-injured healthy meniscus. These findings suggest that inflammatory mediators within the IMM may be associated with preoperative pain in patients with SIF in the medial femoral condyle resulting from MMPRT.
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Affiliation(s)
- Hideaki Fukuda
- Sports Medicine and Joint Center, Inanami Spine and Joint Hospital, Tokyo, JPN
- Sports Medicine and Joint Center, Funabashi Orthopedic Hospital, Funabashi, JPN
| | - Yoshihiro Sakuma
- Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, JPN
| | - Kazuhide Inage
- Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, JPN
| | - Kenji Takahashi
- Sports Medicine and Joint Center, Funabashi Orthopedic Hospital, Funabashi, JPN
| | - Ichiro Yamaura
- Sports Medicine and Joint Center, Funabashi Orthopedic Hospital, Funabashi, JPN
| | - Hideaki Shiratsuchi
- Department of Orthopedic Surgery, Funabashi Orthopedic Hospital, Funabashi, JPN
| | - Seiji Ohtori
- Department of Orthopedics, Chiba University Hospital, Chiba, JPN
- Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, JPN
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Wu J, Chen Z, Huang H, Wang H, Wang X, Lu Z, Xu H, Ma X, Zeng F, Wang H. Custom-Made Ce-Mn Bimetallic Nanozyme for the Treatment of Intervertebral Disc Degeneration by Inhibiting Oxidative Stress and Modulating Macrophage M1/M2 Polarization. Biomater Res 2024; 28:0118. [PMID: 39717477 PMCID: PMC11665849 DOI: 10.34133/bmr.0118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 11/04/2024] [Accepted: 11/12/2024] [Indexed: 12/25/2024] Open
Abstract
Intervertebral disc degeneration (IDD)-induced lower back pain (LBP) brings heavy burden worldwide. In the degenerated intervertebral disc, there is an increase in the accumulation of reactive oxygen species (ROS) and the infiltration of M1 macrophages, which leads to abnormal local inflammatory microenvironment and exacerbates IDD. In this study, we developed a novel injectable polyethylene glycol (PEG)-capped cerium ion-manganese ion (Ce-Mn) bimetallic nanozyme (CeMn-PEG) with strong ROS scavenging and M2-type macrophage polarizing abilities to efficiently alleviate IDD. In vitro experiments demonstrated that CeMn-PEG effectively scavenged excess ROS in both nucleus pulposus (NP) and RAW264.7 cells. In addition, we found that CeMn-PEG markedly protected NP cells from H2O2-induced overproduction of inflammatory cytokines, excessive cell apoptosis and autophagy, and imbalance between extracellular matrix (ECM) degradation. Moreover, CeMn-PEG induced macrophages to transition from the M1 phenotype to the M2 phenotype and the increased M2-type macrophages could alleviate H2O2-induced ECM degradation and cell apoptosis in NP cells. In a puncture-induced mouse IDD model, CeMn-PEG treatment could effectively ameliorate the progression of disc degeneration and mitigate puncture-induced mechanical hyperalgesia. Thus, our study demonstrated the effectiveness of CeMn-PEG as a novel treatment strategy for the treatment of IDD and a range of other inflammatory diseases.
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Affiliation(s)
- Jianwei Wu
- Department of Orthopedics, Huashan Hospital,
Fudan University, Shanghai 200000, China
| | - Zhenhao Chen
- Department of Orthopedics, Huashan Hospital,
Fudan University, Shanghai 200000, China
| | - Han Huang
- Department of Orthopedics, Huashan Hospital,
Fudan University, Shanghai 200000, China
| | - Hongwei Wang
- Department of Orthopedics, Huashan Hospital,
Fudan University, Shanghai 200000, China
| | - Xianghe Wang
- Department of Orthopedics, Huashan Hospital,
Fudan University, Shanghai 200000, China
| | - Zian Lu
- Department of Orthopedics, Huashan Hospital,
Fudan University, Shanghai 200000, China
| | - Haocheng Xu
- Department of Orthopedics, Huashan Hospital,
Fudan University, Shanghai 200000, China
| | - Xiaosheng Ma
- Department of Orthopedics, Huashan Hospital,
Fudan University, Shanghai 200000, China
| | - Feng Zeng
- Artemisinin Research Center,
Guangzhou University of Chinese Medicine, Guangzhou 510450, China
| | - Hongli Wang
- Department of Orthopedics, Huashan Hospital,
Fudan University, Shanghai 200000, China
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Rudnik‐Jansen I, van Kruining Kodele S, Creemers L, Joosten B. Biomolecular therapies for chronic discogenic low back pain: A narrative review. JOR Spine 2024; 7:e1345. [PMID: 39114580 PMCID: PMC11303450 DOI: 10.1002/jsp2.1345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 02/01/2024] [Accepted: 05/01/2024] [Indexed: 08/10/2024] Open
Abstract
Chronic low back pain caused by intervertebral disc (IVD) degeneration, also termed chronic discogenic low back pain (CD-LBP), is one of the most prevalent musculoskeletal diseases. Degenerative processes in the IVD, such as inflammation and extra-cellular matrix breakdown, result in neurotrophin release. Local elevated neurotrophin levels will stimulate sprouting and innervation of sensory neurons. Furthermore, sprouted sensory nerves that are directly connected to adjacent dorsal root ganglia have shown to increase microglia activation, contributing to the maintenance and chronification of pain. Current pain treatments have shown to be insufficient or inadequate for long-term usage. Furthermore, most therapeutic approaches aimed to target the underlying pathogenesis of disc degeneration focus on repair and regeneration and neglect chronic pain. How biomolecular therapies influence the degenerative IVD environment, pain signaling cascades, and innervation and excitability of the sensory neurons often remains unclear. This review addresses the relatively underexplored area of chronic pain treatment for CD-LBP and summarizes effects of therapies aimed for CD-LBP with special emphasis on chronic pain. Approaches based on blocking pro-inflammatory mediators or neurotrophin activity have been shown to hamper neuronal ingrowth into the disc. Furthermore, the tissue regenerative and neuro inhibitory properties of extracellular matrix components or transplanted mesenchymal stem cells are potentially interesting biomolecular approaches to not only block IVD degeneration but also impede pain sensitization. At present, most biomolecular therapies are based on acute IVD degeneration models and thus do not reflect the real clinical chronic pain situation in CD-LBP patients. Future studies should aim at investigating the effects of therapeutic interventions applied in chronic degenerated discs containing established sensory nerve ingrowth. The in-depth understanding of the ramifications from biomolecular therapies on pain (chronification) pathways and pain relief in CD-LBP could help narrow the gap between the pre-clinical bench and clinical bedside for novel CD-LBP therapeutics and optimize pain treatment.
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Affiliation(s)
- Imke Rudnik‐Jansen
- Department of Anesthesiology and Pain ManagementMaastricht University Medical Center (MUMC+)Maastrichtthe Netherlands
- Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHeNs)University of MaastrichtMaastrichtthe Netherlands
| | - Sanda van Kruining Kodele
- Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHeNs)University of MaastrichtMaastrichtthe Netherlands
| | - Laura Creemers
- Department of OrthopedicsUniversity Medical Center UtrechtUtrechtthe Netherlands
| | - Bert Joosten
- Department of Anesthesiology and Pain ManagementMaastricht University Medical Center (MUMC+)Maastrichtthe Netherlands
- Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHeNs)University of MaastrichtMaastrichtthe Netherlands
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Li Y, Dai C, Wu B, Yang L, Yan X, Liu T, Chen J, Zheng Z, Peng B. Intervertebral disc injury triggers neurogenic inflammation of adjacent healthy discs. Spine J 2024; 24:1527-1537. [PMID: 38608821 DOI: 10.1016/j.spinee.2024.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 03/14/2024] [Accepted: 04/04/2024] [Indexed: 04/14/2024]
Abstract
BACKGROUND CONTEXT Intervertebral disc degeneration is common and may play an important role in low back pain, but it is not well-understood. Previous studies have shown that the outer layer of the annulus fibrosus of a healthy disc is innervated by nociceptive nerve fibers. In the process of disc degeneration, it can grow into the inner annulus fibrosus or nucleus pulposus and release neuropeptides. Disc degeneration is associated with inflammation that produces inflammatory factors and potentiates nociceptor sensitization. Subsequently neurogenic inflammation is induced by neuropeptide release from activated primary afferent terminals. Because the innervation of a lumbar disc comes from multisegmental dorsal root ganglion neurons, does neurogenic inflammation in a degenerative disc initiate neurogenic inflammation in neighboring healthy discs by antidromic activity? PURPOSE This study was based on animal experiments in Sprague-Dawley rats to investigate the role of neurogenic inflammation in adjacent healthy disc degeneration induced by disc injury. STUDY DESIGN This was an experimental study. METHODS Seventy-five 12-week-old, male Sprague-Dawley rats were allocated to 3 groups (sham group, disc injury group and disc injury+TrkA antagonist group). The disc injury group was punctured in the tail disc between the eighth and ninth coccygeal vertebrae (Co8-9) to establish an animal model of tail intervertebral disc degeneration. The sham group underwent only skin puncture and the disc injury+TrkA antagonist group was intraperitoneally injected with GW441756 two days before disc puncture. The outcome measure included quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS Disc injury induced an increase in aggrecan, NGF, TrkA, CGRP, SP, IL-1β, and IL-6 mRNA levels in the injured (Co8-9) and adjacent discs (Co7-8), which reached a peak on day 1, then gradually decreased, and returned to normal on day 14. After intraperitoneal injection of GW441756 prior to puncture, the mRNA levels of the above indicators were down-regulated in Co7-8 and Co8-9 intervertebral discs on the 1st and 7th days. The protein content of the above indicators in Co7-8 and Co8-9 intervertebral discs showed roughly the same trend as mRNA levels. CONCLUSIONS Degeneration of one disc can induce neurogenic inflammation of adjacent healthy discs in a rat model. CLINICAL SIGNIFICANCE This model supports a key role of neurogenic inflammation in disc degeneration, and may play a role in the experience of low back pain.
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Affiliation(s)
- Yongchao Li
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Chen Dai
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Bing Wu
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Liang Yang
- Department of Orthopeadics, Featured Medical Center of Chinese People's Armed Police Forces, 220 Chenglin Road, Dongli District, Tianjin, P.R. China
| | - Xiujie Yan
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China
| | - Tanghua Liu
- Algology Institute of Sino-US Zhongguancun Precision Medicine Academy, 45 Beiwa Road, Haidian District, Beijing, P.R. China
| | - Jindong Chen
- Department of Orthopaedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, 21 South Silver Spring Road, Qingyuan, P.R. China
| | - Zhaomin Zheng
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan No. 2 Road, Guangzhou, P.R. China; Pain Research Center, Sun Yat-sen University, 135 Xingang West Road, Haizhu District, Guangzhou, P.R. China.
| | - Baogan Peng
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People's Liberation Army, 69 Yongding Road, Beijing, P.R. China.
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Zhou J, Wang J, Li J, Zhu Z, He Z, Li J, Tang T, Chen H, Du Y, Li Z, Gao M, Zhou Z, Xi Y. Repetitive strikes loading organ culture model to investigate the biological and biomechanical responses of the intervertebral disc. JOR Spine 2024; 7:e1314. [PMID: 38249719 PMCID: PMC10797252 DOI: 10.1002/jsp2.1314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/14/2023] [Accepted: 12/23/2023] [Indexed: 01/23/2024] Open
Abstract
Background Disc degeneration is associated with repetitive violent injuries. This study aims to explore the impact of repetitive strikes loading on the biology and biomechanics of intervertebral discs (IVDs) using an organ culture model. Methods IVDs from the bovine tail were isolated and cultured in a bioreactor, with exposure to various loading conditions. The control group was subjected to physiological loading, while the model group was exposed to either one strike loading (compression at 38% of IVD height) or repetitive one strike loading (compression at 38% of IVD height). Disc height and dynamic compressive stiffness were measured after overnight swelling and loading. Furthermore, histological morphology, cell viability, and gene expression were analyzed on Day 32. Glycosaminoglycan (GAG) and nitric oxide (NO) release in conditioned medium were also analyzed. Results The repetitive one strike group exhibited early disc degeneration, characterized by decreased dynamic compression stiffness, the presence of annulus fibrosus clefts, and degradation of the extracellular matrix. Additionally, this group demonstrated significantly higher levels of cell death (p < 0.05) and glycosaminoglycan (GAG) release (p < 0.05) compared to the control group. Furthermore, upregulation of MMP1, MMP13, and ADAMTS5 was observed in both nucleus pulposus (NP) and annulus fibrosus (AF) tissues of the repetitive one strike group (p < 0.05). The one strike group exhibited annulus fibrosus clefts but showed no gene expression changes compared to the control group. Conclusions This study shows that repetitive violent injuries lead to the degeneration of a healthy bovine IVDs, thereby providing new insights into early-stage disc degeneration.
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Affiliation(s)
- Jiaxiang Zhou
- Department of Spinal SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Jianmin Wang
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic SurgeryThe Seventh Affiliated Hospital of Sun Yat‐sen UniversityShenzhenChina
| | - Jianfeng Li
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic SurgeryThe Seventh Affiliated Hospital of Sun Yat‐sen UniversityShenzhenChina
| | - Zhengya Zhu
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic SurgeryThe Seventh Affiliated Hospital of Sun Yat‐sen UniversityShenzhenChina
| | - Zhongyuan He
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic SurgeryThe Seventh Affiliated Hospital of Sun Yat‐sen UniversityShenzhenChina
| | - Junhong Li
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic SurgeryThe Seventh Affiliated Hospital of Sun Yat‐sen UniversityShenzhenChina
| | - Tao Tang
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic SurgeryThe Seventh Affiliated Hospital of Sun Yat‐sen UniversityShenzhenChina
| | - Hongkun Chen
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic SurgeryThe Seventh Affiliated Hospital of Sun Yat‐sen UniversityShenzhenChina
| | - Yukun Du
- Department of Spinal SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoChina
| | - Zhen Li
- AO Research Institute DavosDavosSwitzerland
| | - Manman Gao
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic SurgeryThe Seventh Affiliated Hospital of Sun Yat‐sen UniversityShenzhenChina
- Guangdong Provincial Key Laboratory of Orthopedics and TraumatologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
- Department of Sport Medicine, Inst Translat MedThe First Affiliated Hospital of Shenzhen University, Shenzhen Second People's HospitalShenzhenChina
- Shenzhen Key Laboratory of Anti‐aging and Regenerative Medicine, Department of Medical Cell Biology and Genetics, Health Sciences CenterShenzhen UniversityShenzhenChina
| | - Zhiyu Zhou
- Innovation Platform of Regeneration and Repair of Spinal Cord and Nerve Injury, Department of Orthopaedic SurgeryThe Seventh Affiliated Hospital of Sun Yat‐sen UniversityShenzhenChina
- Guangdong Provincial Key Laboratory of Orthopedics and TraumatologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Yongming Xi
- Department of Spinal SurgeryThe Affiliated Hospital of Qingdao UniversityQingdaoChina
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Xie W, Li F, Han Y, Chi X, Qin Y, Ye F, Li Z, Xiao J. Calcitonin gene-related peptide attenuated discogenic low back pain in rats possibly via inhibiting microglia activation. Heliyon 2024; 10:e25906. [PMID: 38371980 PMCID: PMC10873749 DOI: 10.1016/j.heliyon.2024.e25906] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 01/04/2024] [Accepted: 02/05/2024] [Indexed: 02/20/2024] Open
Abstract
Discogenic low back pain (DLBP) is a multifactorial disease and associated with intervertebral disc degeneration. Calcitonin gene-related protein (CGRP) plays a critical role in pain processing, while the role in DLBP remains unclear. This study aims to investigate the anti-nociceptive role and related mechanisms of CGRP in DLBP. Here we established the DLBP rat and validated the model using histology and radiography. Minocycline, a microglial inhibitor, and CGRP were intrathecally injected and the behavioral test was performed to determine hyperalgesia. Further, BV2 microglial cells and microglial activation agent lipopolysaccharide (LPS) were employed for the in vitro experiment. We observed obvious lumbar intervertebral disc degeneration and hyperalgesia at 12 weeks postoperation in DLBP group, with significantly activated microglia in the spinal cord. CGRP treatment significantly inhibited the upregulation of proinflammatory cytokines and NLRP3/caspase-1 expression induced by LPS in BV2 cells, whereas treatment with CGRP alone had little effect on BV2 cells. The intrathecal injection of CGRP into DLBP rats relieved mechanical and thermal hyperalgesia, reverted the microglial activation and decreased the expression of NLRP3/caspase-1, similar to the effects produced by minocycline. Our results provide evidence that microglial activation in the spinal cord play a key role in hyperalgesia in DLBP rats. CGRP alleviates DLBP induced hyperalgesia and inhibits microglial activation in the spinal cord. Regulation of CGRP and microglial activation may provide a new strategy for ameliorating DLBP.
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Affiliation(s)
- Weixin Xie
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
- Department of Orthopaedic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Fan Li
- Department of Orthopaedic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Yi Han
- Department of Orthopaedic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Xiaoying Chi
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Yi Qin
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Fan Ye
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Zhanchun Li
- Department of Orthopaedic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Jie Xiao
- Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
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Lai A, Iliff D, Zaheer K, Gansau J, Laudier DM, Zachariou V, Iatridis JC. Annulus Fibrosus Injury Induces Acute Neuroinflammation and Chronic Glial Response in Dorsal Root Ganglion and Spinal Cord-An In Vivo Rat Discogenic Pain Model. Int J Mol Sci 2024; 25:1762. [PMID: 38339040 PMCID: PMC10855200 DOI: 10.3390/ijms25031762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/18/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
Chronic painful intervertebral disc (IVD) degeneration (i.e., discogenic pain) is a major source of global disability needing improved knowledge on multiple-tissue interactions and how they progress in order improve treatment strategies. This study used an in vivo rat annulus fibrosus (AF) injury-driven discogenic pain model to investigate the acute and chronic changes in IVD degeneration and spinal inflammation, as well as sensitization, inflammation, and remodeling in dorsal root ganglion (DRG) and spinal cord (SC) dorsal horn. AF injury induced moderate IVD degeneration with acute and broad spinal inflammation that progressed to DRG to SC changes within days and weeks, respectively. Specifically, AF injury elevated macrophages in the spine (CD68) and DRGs (Iba1) that peaked at 3 days post-injury, and increased microglia (Iba1) in SC that peaked at 2 weeks post-injury. AF injury also triggered glial responses with elevated GFAP in DRGs and SC at least 8 weeks post-injury. Spinal CD68 and SC neuropeptide Substance P both remained elevated at 8 weeks, suggesting that slow and incomplete IVD healing provides a chronic source of inflammation with continued SC sensitization. We conclude that AF injury-driven IVD degeneration induces acute spinal, DRG, and SC inflammatory crosstalk with sustained glial responses in both DRGs and SC, leading to chronic SC sensitization and neural plasticity. The known association of these markers with neuropathic pain suggests that therapeutic strategies for discogenic pain need to target both spinal and nervous systems, with early strategies managing acute inflammatory processes, and late strategies targeting chronic IVD inflammation, SC sensitization, and remodeling.
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Affiliation(s)
- Alon Lai
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Denise Iliff
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Kashaf Zaheer
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jennifer Gansau
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Damien M Laudier
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Venetia Zachariou
- Department of Pharmacology, Physiology and Biophysics, Chobanian and Avedisian School of Medicine at Boston University, Boston, MA 02118, USA
| | - James C Iatridis
- Leni and Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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10
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Lisiewski LE, Jacobsen HE, Viola DCM, Kenawy HM, Kiridly DN, Chahine NO. Intradiscal inflammatory stimulation induces spinal pain behavior and intervertebral disc degeneration in vivo. FASEB J 2024; 38:e23364. [PMID: 38091247 PMCID: PMC10795732 DOI: 10.1096/fj.202300227r] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 10/30/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023]
Abstract
Degeneration of the intervertebral disc (IVD) results in a range of symptomatic (i.e., painful) and asymptomatic experiences. Components of the degenerative environment, including structural disruption and inflammatory cytokine production, often correlate with pain severity. However, the role of inflammation in the activation of pain and degenerative changes has been complex to delineate. The most common IVD injury model is puncture; however, it initiates structural damage that is not representative of the natural degenerative cascade. In this study, we utilized in vivo injection of lipopolysaccharide (LPS), a pro-inflammatory stimulus, into rat caudal IVDs using 33G needles to induce inflammatory activation without the physical tissue disruption caused by puncture using larger needles. LPS injection increased gene expression of pro-inflammatory cytokines (Tnfa, Il1b) and macrophage markers (Inos, Arg1), supported by immunostaining of macrophages (CD68, CCR7, Arg1) and systemic changes in blood cytokine and chemokine levels. Disruption of the IVD structural integrity after LPS injection was also evident through changes in histological grading, disc height, and ECM biochemistry. Ultimately, intradiscal inflammatory stimulation led to local mechanical hyperalgesia, demonstrating that pain can be initiated by inflammatory stimulation of the IVD. Gene expression of nociceptive markers (Ngf, Bdnf, Cgrp) and immunostaining for neuron ingrowth (PGP9.5) and sensitization (CGRP) in the IVD were also shown, suggesting a mechanism for the pain exhibited. To our knowledge, this rat IVD injury model is the first to demonstrate local pain behavior resulting from inflammatory stimulation of caudal IVDs. Future studies will examine the mechanistic contributions of inflammation in mediating pain.
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Affiliation(s)
- Lauren E. Lisiewski
- Department of Biomedical Engineering, Columbia University, New York, NY, United States
- Department of Orthopedic Surgery, Columbia University, New York, NY, United States
| | - Hayley E. Jacobsen
- Department of Orthopedic Surgery, Columbia University, New York, NY, United States
| | - Dan C. M. Viola
- Department of Orthopedic Surgery, Columbia University, New York, NY, United States
| | - Hagar M. Kenawy
- Department of Biomedical Engineering, Columbia University, New York, NY, United States
- Department of Orthopedic Surgery, Columbia University, New York, NY, United States
| | - Daniel N. Kiridly
- Department of Orthopedic Surgery, Northwell Health, Manhasset, NY, United States
| | - Nadeen O. Chahine
- Department of Biomedical Engineering, Columbia University, New York, NY, United States
- Department of Orthopedic Surgery, Columbia University, New York, NY, United States
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11
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Creighton D, Fausone D, Swanson B, Young W, Nolff S, Ruble A, Hassan N, Soley E. Myofascial and discogenic origins of lumbar pain: A critical review. J Man Manip Ther 2023; 31:435-448. [PMID: 37503571 PMCID: PMC10642329 DOI: 10.1080/10669817.2023.2237739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 07/11/2023] [Indexed: 07/29/2023] Open
Abstract
The purpose of this three-part narrative review is to examine the anatomy of, and the research which supports, either the lumbar myofascia or intervertebral disc (IVD) as principal sources of our patient's low back pain. A comprehensive understanding of anatomical lumbar pain generators in combination with the current treatment-based classification system will further improve and enhance clinical decision-making skills. Section I reviews the anatomy of the spinal myofascia, myofascial sources of lumbar pain, and imaging of myofascial tissues. Part II reviews the anatomy of the IVD, examines the IVD as a potential lumbar pain generator, and includes detailed discussion on Nerve Growth Factor, Inflammatory Cytokines, Vertebral End Plates and Modic change, Annular tears, and Discogenic instability. Part III looks at the history of myofascial pain, lab-based research and myofascial pain, and various levels of discogenic pain provocation research including animal, laboratory and human subjects. Our review concludes with author recommendations on developing a comprehensive understanding of altered stress concentrations affecting the posterior annulus fibrosis, neo-innervation of the IVD, inflammatory cytokines, discogenic instability, and how this knowledge can complement use of the Treatment-Based Classification System.
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12
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Wang D, Lai A, Gansau J, Seifert AC, Munitz J, Zaheer K, Bhadouria N, Lee Y, Nasser P, Laudier DM, Holguin N, Hecht AC, Iatridis JC. Lumbar endplate microfracture injury induces Modic-like changes, intervertebral disc degeneration and spinal cord sensitization - an in vivo rat model. Spine J 2023; 23:1375-1388. [PMID: 37086976 PMCID: PMC10524828 DOI: 10.1016/j.spinee.2023.04.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 04/05/2023] [Accepted: 04/18/2023] [Indexed: 04/24/2023]
Abstract
BACKGROUND CONTEXT Endplate (EP) injury plays critical roles in painful IVD degeneration since Modic changes (MCs) are highly associated with pain. Models of EP microfracture that progress to painful conditions are needed to better understand pathophysiological mechanisms and screen therapeutics. PURPOSE Establish in vivo rat lumbar EP microfracture model and assess crosstalk between IVD, vertebra and spinal cord. STUDY DESIGN/SETTING In vivo rat EP microfracture injury model with characterization of IVD degeneration, vertebral remodeling, spinal cord substance P (SubP), and pain-related behaviors. METHODS EP-injury was induced in 5 month-old male Sprague-Dawley rats L4-5 and L5-6 IVDs by puncturing through the cephalad vertebral body and EP into the NP of the IVDs followed by intradiscal injections of TNFα (n=7) or PBS (n=6), compared with Sham (surgery without EP-injury, n=6). The EP-injury model was assessed for IVD height, histological degeneration, pain-like behaviors (hindpaw von Frey and forepaw grip test), lumbar spine MRI and μCT, and spinal cord SubP. RESULTS Surgically-induced EP microfracture with PBS and TNFα injection induced IVD degeneration with decreased IVD height and MRI T2 signal, vertebral remodeling, and secondary damage to cartilage EP adjacent to the injury. Both EP injury groups showed MC-like changes around defects with hypointensity on T1-weighted and hyperintensity on T2-weighted MRI, suggestive of MC type 1. EP injuries caused significantly decreased paw withdrawal threshold, reduced axial grip, and increased spinal cord SubP, suggesting axial spinal discomfort and mechanical hypersensitivity and with spinal cord sensitization. CONCLUSIONS Surgically-induced EP microfracture can cause crosstalk between IVD, vertebra, and spinal cord with chronic pain-like conditions. CLINICAL SIGNIFICANCE This rat EP microfracture model was validated to induce broad spinal degenerative changes that may be useful to improve understanding of MC-like changes and for therapeutic screening.
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Affiliation(s)
- Dalin Wang
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1188, New York, NY 10029 USA; Department of Orthopaedics, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, China; Department of Orthopedic Surgery, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
| | - Alon Lai
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1188, New York, NY 10029 USA
| | - Jennifer Gansau
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1188, New York, NY 10029 USA
| | - Alan C Seifert
- Department of Radiology, Icahn School of Medicine at Mount Sinai, Leon and Norma Hess Center for Science and Medicine, 1470 Madison Avenue, 1st Floor, New York, NY 10029, USA
| | - Jazz Munitz
- Department of Radiology, Icahn School of Medicine at Mount Sinai, Leon and Norma Hess Center for Science and Medicine, 1470 Madison Avenue, 1st Floor, New York, NY 10029, USA
| | - Kashaf Zaheer
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1188, New York, NY 10029 USA
| | - Neharika Bhadouria
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1188, New York, NY 10029 USA; School of Mechanical Engineering, Purdue University, 610 Purdue Mall, West Lafayette, IN 47907, USA
| | - Yunsoo Lee
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1188, New York, NY 10029 USA
| | - Philip Nasser
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1188, New York, NY 10029 USA
| | - Damien M Laudier
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1188, New York, NY 10029 USA
| | - Nilsson Holguin
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1188, New York, NY 10029 USA
| | - Andrew C Hecht
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1188, New York, NY 10029 USA
| | - James C Iatridis
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1188, New York, NY 10029 USA.
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13
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Wu Q, Cui X, Guan LC, Zhang C, Liu J, Ford NC, He S, Chen X, Cao X, Zang L, Guan Y. Chronic pain after spine surgery: Insights into pathogenesis, new treatment, and preventive therapy. J Orthop Translat 2023; 42:147-159. [PMID: 37823035 PMCID: PMC10562770 DOI: 10.1016/j.jot.2023.07.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 10/13/2023] Open
Abstract
Chronic pain after spine surgery (CPSS) is often characterized by intractable low back pain and/or radiating leg pain, and has been reported in 8-40% of patients that received lumbar spine surgery. We conducted a literature search of PubMed, MEDLINE/OVID with a focus on studies about the etiology and treatments of CPSS and low back pain. Our aim was to provide a narrative review that would help us better understand the pathogenesis and current treatment options for CPSS. This knowledge will aid in the development of optimal strategies for managing postoperative pain symptoms and potentially curing the underlying etiologies. Firstly, we reviewed recent advances in the mechanistic study of CPSS, illustrated both structural (e.g., fibrosis and scaring) and non-structural factors (e.g., inflammation, neuronal sensitization, glial activation, psychological factor) causing CPSS, and highlighted those having not been given sufficient attention as the etiology of CPSS. Secondly, we summarized clinical evidence and therapeutic perspectives of CPSS. We also presented new insights about the treatments and etiology of CPSS, in order to raise awareness of medical staff in the identification and management of this complex painful disease. Finally, we discussed potential new targets for clinical interventions of CPSS and future perspectives of mechanistic and translational research. CPSS patients often have a mixed etiology. By reviewing recent findings, the authors advocate that clinicians shall comprehensively evaluate each case to formulate a patient-specific and multi-modal pain treatment, and importantly, consider an early intraoperative intervention that may decrease the risk or even prevent the onset of CPSS. Translational potential statement CPSS remains difficult to treat. This review broadens our understanding of clinical therapies and underlying mechanisms of CPSS, and provides new insights which will aid in the development of novel mechanism-based therapies for not only managing the established pain symptoms but also preventing the development of CPSS.
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Affiliation(s)
- Qichao Wu
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA
- Department of Orthopedics, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100149, China
| | - Xiang Cui
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA
| | - Leo C. Guan
- McDonogh School, Owing Mills, Maryland, 21117, USA
| | - Chi Zhang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA
| | - Jing Liu
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA
| | - Neil C. Ford
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA
| | - Shaoqiu He
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA
| | - Xueming Chen
- Department of Orthopedics, Beijing Luhe Hospital, Capital Medical University, Beijing, 100149, China
| | - Xu Cao
- Department of Orthopedics, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA
| | - Lei Zang
- Department of Orthopedics, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100149, China
| | - Yun Guan
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA
- Department of Neurological Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA
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14
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Diwan AD, Melrose J. Intervertebral disc degeneration and how it leads to low back pain. JOR Spine 2023; 6:e1231. [PMID: 36994466 PMCID: PMC10041390 DOI: 10.1002/jsp2.1231] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 09/23/2022] [Accepted: 10/21/2022] [Indexed: 11/16/2022] Open
Abstract
The purpose of this review was to evaluate data generated by animal models of intervertebral disc (IVD) degeneration published in the last decade and show how this has made invaluable contributions to the identification of molecular events occurring in and contributing to pain generation. IVD degeneration and associated spinal pain is a complex multifactorial process, its complexity poses difficulties in the selection of the most appropriate therapeutic target to focus on of many potential candidates in the formulation of strategies to alleviate pain perception and to effect disc repair and regeneration and the prevention of associated neuropathic and nociceptive pain. Nerve ingrowth and increased numbers of nociceptors and mechanoreceptors in the degenerate IVD are mechanically stimulated in the biomechanically incompetent abnormally loaded degenerate IVD leading to increased generation of low back pain. Maintenance of a healthy IVD is, thus, an important preventative measure that warrants further investigation to preclude the generation of low back pain. Recent studies with growth and differentiation factor 6 in IVD puncture and multi-level IVD degeneration models and a rat xenograft radiculopathy pain model have shown it has considerable potential in the prevention of further deterioration in degenerate IVDs, has regenerative properties that promote recovery of normal IVD architectural functional organization and inhibits the generation of inflammatory mediators that lead to disc degeneration and the generation of low back pain. Human clinical trials are warranted and eagerly anticipated with this compound to assess its efficacy in the treatment of IVD degeneration and the prevention of the generation of low back pain.
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Affiliation(s)
- Ashish D. Diwan
- Spine Service, Department of Orthopaedic Surgery, St. George & Sutherland Clinical SchoolUniversity of New South WalesSydneyNew South WalesAustralia
| | - James Melrose
- Raymond Purves Bone and Joint Research LaboratoryKolling Institute, Sydney University Faculty of Medicine and Health, Northern Sydney Area Health District, Royal North Shore HospitalSydneyNew South WalesAustralia
- Graduate School of Biomedical EngineeringThe University of New South WalesSydneyNew South WalesAustralia
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15
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Lai A, Iliff D, Zaheer K, Wang D, Gansau J, Laudier DM, Zachariou V, Iatridis JC. Spinal Cord Sensitization and Spinal Inflammation from an In Vivo Rat Endplate Injury Associated with Painful Intervertebral Disc Degeneration. Int J Mol Sci 2023; 24:3425. [PMID: 36834838 PMCID: PMC9964286 DOI: 10.3390/ijms24043425] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 02/11/2023] Open
Abstract
Intervertebral disc (IVD) degeneration with Modic-like changes is strongly associated with pain. Lack of effective disease-modifying treatments for IVDs with endplate (EP) defects means there is a need for an animal model to improve understanding of how EP-driven IVD degeneration can lead to spinal cord sensitization. This rat in vivo study determined whether EP injury results in spinal dorsal horn sensitization (substance P, SubP), microglia (Iba1) and astrocytes (GFAP), and evaluated their relationship with pain-related behaviors, IVD degeneration, and spinal macrophages (CD68). Fifteen male Sprague Dawley rats were assigned into sham or EP injury groups. At chronic time points, 8 weeks after injury, lumbar spines and spinal cords were isolated for immunohistochemical analyses of SubP, Iba1, GFAP, and CD68. EP injury most significantly increased SubP, demonstrating spinal cord sensitization. Spinal cord SubP-, Iba1- and GFAP-immunoreactivity were positively correlated with pain-related behaviors, indicating spinal cord sensitization and neuroinflammation play roles in pain responses. EP injury increased CD68 macrophages in the EP and vertebrae, and spinal cord SubP-, Iba1- and GFAP-ir were positively correlated with IVD degeneration and CD68-ir EP and vertebrae. We conclude that EP injuries result in broad spinal inflammation with crosstalk between spinal cord, vertebrae and IVD, suggesting that therapies must address neural pathologies, IVD degeneration, and chronic spinal inflammation.
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Affiliation(s)
- Alon Lai
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Denise Iliff
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Kashaf Zaheer
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Dalin Wang
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Orthopaedics, Nanjing First Hospital, Nanjing Medical University, Nanjing 211166, China
- Department of Orthopedic Surgery, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
| | - Jennifer Gansau
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Damien M. Laudier
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Venetia Zachariou
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - James C. Iatridis
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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16
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Bhujel B, Yang SS, Kim HR, Kim SB, Min BH, Choi BH, Han I. An Injectable Engineered Cartilage Gel Improves Intervertebral Disc Repair in a Rat Nucleotomy Model. Int J Mol Sci 2023; 24:3146. [PMID: 36834559 PMCID: PMC9966384 DOI: 10.3390/ijms24043146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/19/2023] [Accepted: 02/03/2023] [Indexed: 02/09/2023] Open
Abstract
Lower back pain is a major problem caused by intervertebral disc degeneration. A common surgical procedure is lumbar partial discectomy (excision of the herniated disc causing nerve root compression), which results in further disc degeneration, severe lower back pain, and disability after discectomy. Thus, the development of disc regenerative therapies for patients who require lumbar partial discectomy is crucial. Here, we investigated the effectiveness of an engineered cartilage gel utilizing human fetal cartilage-derived progenitor cells (hFCPCs) on intervertebral disc repair in a rat tail nucleotomy model. Eight-week-old female Sprague-Dawley rats were randomized into three groups to undergo intradiscal injection of (1) cartilage gel, (2) hFCPCs, or (3) decellularized extracellular matrix (ECM) (n = 10/each group). The treatment materials were injected immediately after nucleotomy of the coccygeal discs. The coccygeal discs were removed six weeks after implantation for radiologic and histological analysis. Implantation of the cartilage gel promoted degenerative disc repair compared to hFCPCs or hFCPC-derived ECM by increasing the cellularity and matrix integrity, promoting reconstruction of nucleus pulposus, restoring disc hydration, and downregulating inflammatory cytokines and pain. Our results demonstrate that cartilage gel has higher therapeutic potential than its cellular or ECM component alone, and support further translation to large animal models and human subjects.
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Affiliation(s)
- Basanta Bhujel
- Department of Biomedical Science, College of Life Sciences, CHA University, Seongnam 13496, Republic of Korea
| | | | | | - Sung Bum Kim
- Department of Neurosurgery, Kyung Hee University, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Byoung-Hyun Min
- ATEMs Inc., Seoul 02447, Republic of Korea
- Wake Forest Institute of Regenerative Medicine, School of Medicine, Wake Forest University, Winston Salem, NC 27101, USA
| | - Byung Hyune Choi
- ATEMs Inc., Seoul 02447, Republic of Korea
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon 22212, Republic of Korea
| | - Inbo Han
- Department of Neurosurgery, CHA Bundang Medical Center, School of Medicine, CHA University, Seongnam 13496, Republic of Korea
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17
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Wang D, Lai A, Gansau J, Seifert AC, Munitz J, Zaheer K, Bhadouria N, Lee Y, Nasser P, Laudier DM, Holguin N, Hecht AC, Iatridis JC. Lumbar endplate microfracture injury induces Modic-like changes, intervertebral disc degeneration and spinal cord sensitization - An In Vivo Rat Model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.27.525924. [PMID: 36778423 PMCID: PMC9915494 DOI: 10.1101/2023.01.27.525924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND CONTEXT : Endplate (EP) injury plays critical roles in painful IVD degeneration since Modic changes (MCs) are highly associated with pain. Models of EP microfracture that progress to painful conditions are needed to better understand pathophysiological mechanisms and screen therapeutics. PURPOSE : Establish in vivo rat lumbar EP microfracture model with painful phenotype. STUDY DESIGN/SETTING : In vivo rat study to characterize EP-injury model with characterization of IVD degeneration, vertebral bone marrow remodeling, spinal cord sensitization, and pain-related behaviors. METHODS : EP-driven degeneration was induced in 5-month-old male Sprague-Dawley rats L4-5 and L5-6 IVDs through the proximal vertebral body injury with intradiscal injections of TNFα (n=7) or PBS (n=6), compared to Sham (surgery without EP-injury, n=6). The EP-driven model was assessed for IVD height, histological degeneration, pain-like behaviors (hindpaw von Frey and forepaw grip test), lumbar spine MRI and μCT analyses, and spinal cord substance P (SubP). RESULTS : EP injuries induced IVD degeneration with decreased IVD height and MRI T2 values. EP injury with PBS and TNFα both showed MC type1-like changes on T1 and T2-weighted MRI, trabecular bone remodeling on μCT, and damage in cartilage EP adjacent to the injury. EP injuries caused significantly decreased paw withdrawal threshold and reduced grip forces, suggesting increased pain sensitivity and axial spinal discomfort. Spinal cord dorsal horn SubP was significantly increased, indicating spinal cord sensitization. CONCLUSIONS : EP microfracture can induce crosstalk between vertebral bone marrow, IVD and spinal cord with chronic pain-like conditions. CLINICAL SIGNIFICANCE : This rat EP microfracture model of IVD degeneration was validated to induce MC-like changes and pain-like behaviors that we hope will be useful to screen therapies and improve treatment for EP-drive pain.
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Affiliation(s)
- Dalin Wang
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
- Department of Orthopaedics, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Orthopedic Surgery, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, USA 66160
| | - Alon Lai
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jennifer Gansau
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Alan C. Seifert
- Biomedical Engineering and Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jazz Munitz
- Biomedical Engineering and Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Kashaf Zaheer
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Neharika Bhadouria
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
- School of Mechanical Engineering, Purdue University, West Lafayette, IN
| | - Yunsoo Lee
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Philip Nasser
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Damien M. Laudier
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Nilsson Holguin
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Andrew C. Hecht
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - James C. Iatridis
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY
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18
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Sun K, Jiang J, Wang Y, Sun X, Zhu J, Xu X, Sun J, Shi J. The role of nerve fibers and their neurotransmitters in regulating intervertebral disc degeneration. Ageing Res Rev 2022; 81:101733. [PMID: 36113765 DOI: 10.1016/j.arr.2022.101733] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/11/2022] [Accepted: 09/11/2022] [Indexed: 01/31/2023]
Abstract
Intervertebral disc degeneration (IVDD) has been the major contributor to chronic lower back pain (LBP). Abnormal apoptosis, senescence, and pyroptosis of IVD cells, extracellular matrix (ECM) degradation, and infiltration of immune cells are the major molecular alternations during IVDD. Changes at tissue level frequently occur at advanced IVD tissue. Ectopic ingrowth of nerves within inner annulus fibrosus (AF) and nucleus pulposus (NP) tissue has been considered as the primary cause for LBP. Innervation at IVD tissue mainly included sensory and sympathetic nerves, and many markers for these two types of nerves have been detected since 1940. In fact, in osteoarthritis (OA), beyond pain transmission, the direct regulation of neuropeptides on functions of chondrocytes have attracted researchers' great attention recently. Many physical and pathological similarities between joint and IVD have shed us the light on the neurogenic mechanism involved in IVDD. Here, an overview of the advances in the nervous system within IVD tissue will be performed, with a discussion on in the role of nerve fibers and their neurotransmitters in regulating IVDD. We hope this review can attract more research interest to address neuromodulation and IVDD itself, which will enhance our understanding of the contribution of neuromodulation to the structural changes within IVD tissue and inflammatory responses and will help identify novel therapeutic targets and enable the effective treatment of IVDD disease.
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Affiliation(s)
- Kaiqiang Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China; Department of Orthopedics, Naval Medical Center of PLA, China
| | - Jialin Jiang
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Yuan Wang
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Xiaofei Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Jian Zhu
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Ximing Xu
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China
| | - Jingchuan Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China.
| | - Jiangang Shi
- Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, No.415 Fengyang Road, Shanghai 200003, China.
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A High Body Mass Index and the Vacuum Phenomenon Upregulate Pain-Related Molecules in Human Degenerated Intervertebral Discs. Int J Mol Sci 2022; 23:ijms23062973. [PMID: 35328395 PMCID: PMC8953228 DOI: 10.3390/ijms23062973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/05/2022] [Accepted: 03/09/2022] [Indexed: 01/02/2023] Open
Abstract
Animal studies suggest that pain-related-molecule upregulation in degenerated intervertebral discs (IVDs) potentially leads to low back pain (LBP). We hypothesized that IVD mechanical stress and axial loading contribute to discogenic LBP’s pathomechanism. This study aimed to elucidate the relationships among the clinical findings, radiographical findings, and pain-related-molecule expression in human degenerated IVDs. We harvested degenerated-IVD samples from 35 patients during spinal interbody fusion surgery. Pain-related molecules including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, calcitonin gene-related peptide (CGRP), microsomal prostaglandin E synthase-1 (mPGES1), and nerve growth factor (NGF) were determined. We also recorded preoperative clinical findings including body mass index (BMI), Oswestry Disability Index (ODI), and radiographical findings including the vacuum phenomenon (VP) and spinal instability. Furthermore, we compared pain-related-molecule expression between the VP (−) and (+) groups. BMI was significantly correlated with the ODI, CGRP, and mPGES-1 levels. In the VP (+) group, mPGES-1 levels were significantly higher than in the VP (−) group. Additionally, CGRP and mPGES-1 were significantly correlated. Axial loading and mechanical stress correlated with CGRP and mPGES-1 expression and not with inflammatory cytokine or NGF expression. Therefore, axial loading and mechanical stress upregulate CGRP and mPGES-1 in human degenerated IVDs, potentially leading to chronic discogenic LBP.
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20
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Yamamoto Y, Kokubo Y, Nakajima H, Honjoh K, Watanabe S, Matsumine A. Distribution and Polarization of Hematogenous Macrophages Associated with the Progression of Intervertebral Disc Degeneration. Spine (Phila Pa 1976) 2022; 47:E149-E158. [PMID: 34545043 DOI: 10.1097/brs.0000000000004222] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN In vivo study using immunostaining and immunoblot analysis. OBJECTIVE To determine the distribution of bone marrow-derived macrophages (BMDMs), macrophage polarization and cytokine expression in the process of intervertebral disc (IVD) degeneration. SUMMARY OF BACKGROUND DATA Knowledge of the detailed distribution of exogeneous macrophages in the disc degeneration process is important for understanding the pathomechanisms and establishing novel therapeutic targets. METHODS To distinguish BMDMs, GFP-labeled bone marrow chimeric rats (n = 12) were generated. The degenerative process of the intervertebral disc was reproduced in a rat caudal disc puncture model (n = 49). Immunofluorescence staining was performed to observe the distribution of BMDMs, Iba-1 and GFP double-positive cells, and Iba-1 and iNOS (M1 macrophage) or arginase-1 (M2 macrophage) double-positive cells. Immunoblot analysis was used to evaluate differences in cytokines (TNF-α, IL-1β, IL-6, TGF-β, IL-4, and IL-10) depending on the distribution of BMDMs. RESULTS BMDMs infiltrated into the outer annulus fibrosus and endplate, while increasing tissue-resident macrophage was observed inside the annulus fibrosus/nucleus pulposus. The ratio of BMDMs and the polarity change differed among the regions. Especially in the endplate, BMDMs increased gradually and the macrophage phenotype was M2 dominant. Expression of IL-1β decreased gradually at endplate, and that of IL-4 increased early after disc puncture at inside of the annulus fibrosus. CONCLUSION During the disc degeneration process, BMDMs were observed mainly around the endplate and outside area of the annulus fibrosus, with few in the inside area of annulus fibrosus and nucleus pulposus. Compared to other IVD area, macrophage polarity and cytokine expression is concomitantly M2-dominant in endplate. Increased hematogenous M2-phenotype macrophages in endplate with progression of IVD degeneration could enhance our understanding of the underlying mechanisms of disc degeneration.Level of Evidence: N/A.
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Affiliation(s)
- Yusuke Yamamoto
- Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Yoshida-gun, Fukui, Japan
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21
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Miyagi M, Uchida K, Takano S, Nakawaki M, Sekiguchi H, Nakazawa T, Imura T, Saito W, Shirasawa E, Kawakubo A, Akazawa T, Inoue G, Takaso M. Role of CD14-positive cells in inflammatory cytokine and pain-related molecule expression in human degenerated intervertebral discs. J Orthop Res 2021; 39:1755-1762. [PMID: 32856747 DOI: 10.1002/jor.24839] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 07/13/2020] [Accepted: 08/18/2020] [Indexed: 02/04/2023]
Abstract
Multiple human and animal studies suggest that the upregulation of inflammatory cytokines and other pain-related molecules in degenerated or injured intervertebral discs (IVDs) may cause discogenic low back pain (LBP). We previously reported that macrophages in injured IVD in mice produced inflammatory cytokines, but not other pain-related molecules. CD14 is a monocyte marker expressed mainly by macrophages. The aim of the current study was to evaluate the role of CD14-positive cells in inflammatory cytokine and pain-related molecule expression in human degenerated IVD. IVD samples were harvested from 14 patients, including 10 with lumbar spinal stenosis, four with adult spinal deformity, and one with lumbar disc herniation during spinal interbody fusion surgery. Harvested IVD-derived mononuclear cells were obtained and CD14-positive (+) and CD14-negative (-) cells were separated using CD14 antibody and streptavidin-labeled magnetic beads. Inflammatory cytokines messenger RNA (mRNA) in the CD14(+) and CD14(-) cells, including tumor necrosis factor ɑ (TNFA), in, terleukin-1β (IL1B) and IL6, were determined using quantitative polymerase chain reaction (qPCR) and their expression levels were compared. To evaluate factors controlling the regulation of pain-related molecules mRNA expression, cultured CD14(-) and CD14(+) cells from IVDs were stimulated with recombinant human TNF-ɑ and IL-1β and levels of pain-related molecules, including calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) were determined using qPCR. Levels of TNFA, IL1B, IL6, and NGF in CD14(+) cells were significantly increased compared with those in CD14(-) cells (TNFA, p = 0.006; IL1B, p = .017; IL6, p = .010; NGF, p = .027). Following TNFA stimulation, NGF levels were significantly increased in CD14(-) and CD14(+) cells (CD14(-), p = .003; CD14(+), p < .001) and CGRP was significantly increased in CD14(-) IVD cells (p = .040). Following IL1B stimulation, NGF levels were significantly increased in CD14(-) cells (p = .004). CD14(+) cells had higher TNFA, IL1B, IL6, and NGF expressions than CD14(-) cells in human degenerated IVDs. Additionally, TNFA stimulation promoted the upregulation of NGF and CGRP in CD14(-) cells. These findings suggested that CD14(+) cells directly and indirectly contributed to inflammatory cytokine and pain-related molecule expression in human degenerated IVD. CD14(+) cells might be important in the pathological mechanism of chronic discogenic LBP in humans.
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Affiliation(s)
- Masayuki Miyagi
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - Kentaro Uchida
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - Shotaro Takano
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - Mitsufumi Nakawaki
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - Hiroyuki Sekiguchi
- Shonan University of Medical Sciences Research Institute, Chigasaki City, Kanagawa, Japan
| | - Toshiyuki Nakazawa
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - Takayuki Imura
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - Wataru Saito
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - Eiki Shirasawa
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - Ayumu Kawakubo
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - Tsutomu Akazawa
- Department of Orthopaedic Surgery, St. Marianna University School of Medicine, Kawasaki City, Kanagawa, Japan
| | - Gen Inoue
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
| | - Masashi Takaso
- Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa, Japan
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22
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Navone SE, Campanella R, Guarnaccia L, Ouellet JA, Locatelli M, Cordiglieri C, Gualtierotti R, Gaudino C, Ciniglio Appiani G, Luzzi S, Borsa S, Rampini P, Pluderi M, Haglund L, Riboni L, Alini M, Marfia G. Inflammatory interactions between degenerated intervertebral discs and microglia: Implication of sphingosine-1-phosphate signaling. J Orthop Res 2021; 39:1479-1495. [PMID: 32779775 DOI: 10.1002/jor.24827] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 05/08/2020] [Accepted: 07/27/2020] [Indexed: 02/04/2023]
Abstract
The etiology of intervertebral disc degeneration is largely unknown, but local neuroinflammation may exert a crucial role through activation of cells as microglia and pro-inflammatory cytokines production. We aimed to compare the effect of degenerated and normal intervertebral disc microenvironment on microglial cells and the potential role of sphingosine-1-phosphate, a pro-inflammatory sphingolipid, in their crosstalk. Human degenerated intervertebral discs (Pfirrmann grade IV) were obtained at surgery for spondylolisthesis. Normal intervertebral discs were collected from cadaveric normal lumbar spines. Normal and degenerated-intervertebral discs were kept in culture to obtain media conditioning. Then, microglial cells were cocultured with conditioned media and viability, proliferation, migration, chemotaxis, and inflammatory gene expression were evaluated. The results demonstrate that conditioned media from degenerated intervertebral discs activate microglial cells, increasing chemotaxis, migration, and pro-inflammatory mediators release to a great extent than normal discs. In addition, we show that the administration of sphingosine-1-phosphate to normal intervertebral disc/microglia coculture mimicked degenerative effects. Interestingly, sphingosine-1-phosphate content in conditioned media from degenerated discs was significantly higher than that from normal ones. In addition, FTY720, a functional antagonist of sphingosine-1-phosphate, potently inhibited the effect of degenerated intervertebral discs on microglial inflammatory factor transcription and migration. Our data report, for the first time, that sphingosine-1-phosphate is involved as signal in the microenvironment of human degenerated intervertebral discs. Sphingosine-1-phosphate signaling modulation by FTY720 may induce beneficial effects in counteracting microglial activation during intervertebral disc degeneration.
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Affiliation(s)
- Stefania E Navone
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,"Aldo Ravelli" Research Center, Milan, Italy
| | - Rolando Campanella
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Laura Guarnaccia
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Jean A Ouellet
- McGill Scoliosis and Spine Group, Department of Surgery, McGill University, Montreal, QC, Canada
| | - Marco Locatelli
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,"Aldo Ravelli" Research Center, Milan, Italy
| | - Chiara Cordiglieri
- Imaging Facility, National Institute for Molecular Genetics (INGM), Milan, Italy
| | - Roberta Gualtierotti
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Chiara Gaudino
- Department of Neuroradiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Sabino Luzzi
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.,Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Stefano Borsa
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paolo Rampini
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Mauro Pluderi
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Lisbet Haglund
- McGill Scoliosis and Spine Group, Department of Surgery, McGill University, Montreal, QC, Canada
| | - Laura Riboni
- Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, Milan, Italy
| | - Mauro Alini
- AO Research Institute Davos, Davos, Switzerland
| | - Giovanni Marfia
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,"Aldo Ravelli" Research Center, Milan, Italy.,Clinical Pathology Unit, Istituto di Medicina Aerospaziale "A. Mosso", Aeronautica Militare, Milano
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23
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Park TSW, Khan N, Kuo A, Nicholson JR, Corradini L, Smith MT. Characterisation of a rat model of mechanical low back pain at an advanced stage using immunohistochemical methods. Clin Exp Pharmacol Physiol 2021; 48:96-106. [PMID: 32888350 DOI: 10.1111/1440-1681.13402] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 07/25/2020] [Accepted: 08/25/2020] [Indexed: 01/23/2023]
Abstract
Chronic low back pain (LBP) has high prevalence in the adult population which is associated with enormous disability. Hence, our aim was to further characterise our LBP rat model by using immunohistological and immunohistochemical methods at an advanced stage (day 49) of the model. Male Sprague-Dawley rats were anaesthetised and their lumbar L4/L5 and L5/L6 intervertebral discs (IVDs) were punctured (0.5 mm outer diameter, 2 mm-deep) 10 times per disc. Sham-rats underwent similar surgery, but no discs were punctured. For LBP- but not sham-rats, noxious pressure hyperalgesia was fully developed in the lumbar axial deep tissues on day 21 post-surgery, which was maintained until at least day 49. In the lumbar (L4-L6) dorsal root ganglia (DRGs), somatostatin (SRIF) and the somatostatin receptor type 4 (SST4 receptor) were co-localised with substance P and IB4, markers of small diameter unmyelinated peptidergic and non-peptidergic C-fibres respectively as well as with NF200, a marker of medium to large diameter neurons. On day 49, there was increased expression of SRIF but not the somatostatin receptor type 4 (SST4 receptor) in the lumbar DRGs and the spinal dorsal horns. There were increased DRG expression levels of the putative pro-nociceptive mediators: phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) and phosphorylated p44/p42 MAPK (pp44/pp42 MAPK) as well as pp38 MAPK expression levels in the lumbar spinal cord. Taken together, the increased expression of SRIF in the lumbar DRGs and spinal cord and its co-localisation with nociceptive fibres in DRG sections suggest a potential role of SRIF in modulating chronic mechanical LBP.
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Affiliation(s)
- Thomas S W Park
- Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
- Department of Neurophysiology, Mannheim Centre for Translational Neuroscience, Heidelberg University, Mannheim, Germany
| | - Nemat Khan
- Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Andy Kuo
- Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | | | - Laura Corradini
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Maree T Smith
- Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
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24
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Zhou Z, Cui S, Du J, Richards RG, Alini M, Grad S, Li Z. One strike loading organ culture model to investigate the post-traumatic disc degenerative condition. J Orthop Translat 2020; 26:141-150. [PMID: 33437633 PMCID: PMC7773974 DOI: 10.1016/j.jot.2020.08.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 07/01/2020] [Accepted: 08/09/2020] [Indexed: 02/06/2023] Open
Abstract
Background Acute trauma on intervertebral discs (IVDs) is thought to be one of the risk factors for IVD degeneration. The pathophysiology of IVD degeneration induced by single high impact mechanical injury is not very well understood. The aim of this study was using a post-traumatic IVD model in a whole organ culture system to analyze the biological and biomechanical consequences of the single high-impact loading event on the cultured IVDs. Methods Isolated healthy bovine IVDs were loaded with a physiological loading protocol in the control group or with injurious loading (compression at 50% of IVD height) in the one strike loading (OSL) group. After another 1 day (short term) or 8 days (long term) of whole organ culture within a bioreactor, the samples were collected to analyze the cell viability, histological morphology and gene expression. The conditioned medium was collected daily to analyze the release of glycosaminoglycan (GAG) and nitric oxide (NO). Results The OSL IVD injury group showed signs of early degeneration including reduction of dynamic compressive stiffness, annulus fibrosus (AF) fissures and extracellular matrix degradation. Compared to the control group, the OSL model group showed more severe cell death (P < 0.01) and higher GAG release in the culture medium (P < 0.05). The MMP and ADAMTS families were up-regulated in both nucleus pulposus (NP) and AF tissues from the OSL model group (P < 0.05). The OSL injury model induced a traumatic degenerative cascade in the whole organ cultured IVD. Conclusions The present study shows a single hyperphysiological mechanical compression applied to healthy bovine IVDs caused significant drop of cell viability, altered the mRNA expression in the IVD, and increased ECM degradation. The OSL IVD model could provide new insights into the mechanism of mechanical injury induced early IVD degeneration. The translational potential of this article This model has a high potential for investigation of the degeneration mechanism in post-traumatic IVD disease, identification of novel biomarkers and therapeutic targets, as well as screening of treatment therapies.
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Affiliation(s)
- Zhiyu Zhou
- The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,AO Research Institute Davos, Davos, Switzerland.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shangbin Cui
- AO Research Institute Davos, Davos, Switzerland.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jie Du
- AO Research Institute Davos, Davos, Switzerland
| | - R Geoff Richards
- AO Research Institute Davos, Davos, Switzerland.,Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Mauro Alini
- AO Research Institute Davos, Davos, Switzerland
| | | | - Zhen Li
- AO Research Institute Davos, Davos, Switzerland
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25
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Swanson BT, Creighton D. The degenerative lumbar disc: not a disease, but still an important consideration for OMPT practice: a review of the history and science of discogenic instability. J Man Manip Ther 2020; 28:191-200. [PMID: 32364465 PMCID: PMC8550621 DOI: 10.1080/10669817.2020.1758520] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND A recent AAOMPT position paper was published that opposed the use of the term 'degenerative disc disease' (DDD), in large part because it appears to be a common age-related finding. While common, there are significant physiologic and biomechanical changes that occur as a result of discogenic degeneration, which are relevant to consider during the practice of manual therapy. METHODS A narrative review provides an overview of these considerations, including a historical perspective of discogenic instability, the role of the disc as a pain generator, the basic science of a combined biomechanical and physiologic cycle of degeneration and subsequent discogenic instability, the influence of rotation on the degenerative segment, the implications of these factors for manual therapy practice, and a perspective on an evidence-based treatment approach to patients with concurrent low back pain and discogenic degeneration. CONCLUSIONS As we consider the role of imaging findings such as DDD, we pose the following question: Do our manual interventions reflect the scientifically proven biomechanical aspects of DDD, or have we chosen to ignore the helpful science as we discard the harmful diagnostic label?
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Affiliation(s)
- Brian T. Swanson
- Department of Rehabilitation Sciences, University of Hartford, West Hartford, CT, USA
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26
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Reed WR, Little JW, Lima CR, Sorge RE, Yarar-Fisher C, Eraslan M, Hurt CP, Ness TJ, Gu JG, Martins DF, Li P. Spinal Mobilization Prevents NGF-Induced Trunk Mechanical Hyperalgesia and Attenuates Expression of CGRP. Front Neurosci 2020; 14:385. [PMID: 32425750 PMCID: PMC7204433 DOI: 10.3389/fnins.2020.00385] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 03/30/2020] [Indexed: 12/15/2022] Open
Abstract
Introduction Low back pain (LBP) is a complex and growing global health problem in need of more effective pain management strategies. Spinal mobilization (SM) is a non-pharmacological approach recommended by most clinical guidelines for LBP, but greater utilization and treatment optimization are hampered by a lack of mechanistic knowledge underlying its hypoalgesic clinical effects. Methods Groups of female Sprague-Dawley rats received unilateral trunk (L5 vertebral level) injections (50 μl) of either vehicle (phosphate-buffer solution, PBS; VEH) or nerve growth factor (NGF; 0.8 μM) on Days 0 and 5 with or without daily L5 SM (VEH, NGF, VEH + SM, VEH + SM). Daily passive SM (10 min) was delivered by a feedback motor (1.2 Hz, 0.9N) from Days 1 to 12. Changes in pain assays were determined for mechanical and thermal reflexive behavior, exploratory behavior (open field events) and spontaneous pain behavior (rat grimace scale). On Day 12, lumbar (L1–L6) dorsal root ganglia (DRG) were harvested bilaterally and calcitonin gene-related peptide (CGRP) positive immunoreactive neurons were quantified from 3 animals (1 DRG tissue section per segmental level) per experimental group. Results NGF induced bilateral trunk (left P = 0.006, right P = 0.001) mechanical hyperalgesia and unilateral hindpaw allodynia (P = 0.006) compared to the vehicle group by Day 12. Additionally, we found for the first time that NGF animals demonstrated decreased exploratory behaviors (total distance traveled) and increased grimace scale scoring compared to the VEH group. Passive SM prevented this development of local (trunk) mechanical hyperalgesia and distant (hindpaw) allodynia, and normalized grimace scale scores. NGF increased CGRP positive immunoreactive neurons in ipsilateral lumbar DRGs compared to the VEH group ([L1]P = 0.02; [L2]P = 0.007) and SM effectively negated this increase in pain-related neuropeptide CGRP expression. Conclusion SM prevents the development of local (trunk) NGF-induced mechanical hyperalgesia and distant (hindpaw) allodynia, in part, through attenuation of CGRP expression in lumbar DRG sensory neurons. NGF decreases rat exploratory behavior and increases spontaneous pain for which passive SM acts to mitigate these pain-related behavioral changes. These initial study findings suggest that beginning daily SM soon after injury onset might act to minimize or prevent the development of LBP by reducing production of pain-related neuropeptides.
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Affiliation(s)
- William R Reed
- Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, United States.,Rehabilitation Sciences Program, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Joshua W Little
- Department of Surgery, Center for Anatomical Science and Education, Saint Louis University School of Medicine, St. Louis, MO, United States
| | - Carla R Lima
- Rehabilitation Sciences Program, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Robert E Sorge
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Ceren Yarar-Fisher
- Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Mualla Eraslan
- Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Christopher P Hurt
- Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, United States.,Rehabilitation Sciences Program, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Timothy J Ness
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jianguo G Gu
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Daniel F Martins
- Postgraduate Program in Health Sciences, Experimental Neuroscience Laboratory (LaNEx), University of Southern Santa Catarina, Palhoça, Brazil
| | - Peng Li
- School of Nursing, University of Alabama at Birmingham, Birmingham, AL, United States
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27
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Cannata F, Vadalà G, Ambrosio L, Fallucca S, Napoli N, Papalia R, Pozzilli P, Denaro V. Intervertebral disc degeneration: A focus on obesity and type 2 diabetes. Diabetes Metab Res Rev 2020; 36:e3224. [PMID: 31646738 DOI: 10.1002/dmrr.3224] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 06/16/2019] [Accepted: 09/25/2019] [Indexed: 02/05/2023]
Abstract
Obesity (OB) and type 2 diabetes (T2D) are among the most prevalent metabolic diseases. They currently affect a substantial part of the world population and are characterized by several systemic co-morbidities, including cardiovascular diseases, stroke, cancer, liver steatosis, and musculoskeletal disorders, by increasing the risk of developing osteoarthritis and intervertebral disc degeneration (IVDD). IVDD is a chronic, progressive process whose main features are disc dehydration, loss of disc height, and changes of load distribution across the spine, resulting in disc structure disruption and leading to low back pain onset. Given the high prevalence of these metabolic disorders and their association with IVDD, several studies have been conducted in order to investigate the causative role of biological and biomechanical characteristics proper to these conditions in the development of IVDD. This review aims to analyse the role of OB and T2D on IVDD, in order to clarify the pathophysiological drivers of the degenerative process and to delineate possible targets to which appropriate treatments may be addressed in the near future.
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Affiliation(s)
- Francesca Cannata
- Department of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, Rome, Italy
| | - Gianluca Vadalà
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Luca Ambrosio
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Sara Fallucca
- Department of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, Rome, Italy
| | - Nicola Napoli
- Department of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, Rome, Italy
| | - Rocco Papalia
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Paolo Pozzilli
- Department of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, Rome, Italy
| | - Vincenzo Denaro
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
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Lai A, Ho L, Evashwick-Rogler TW, Watanabe H, Salandra J, Winkelstein BA, Laudier D, Hecht AC, Pasinetti GM, Iatridis JC. Dietary polyphenols as a safe and novel intervention for modulating pain associated with intervertebral disc degeneration in an in-vivo rat model. PLoS One 2019; 14:e0223435. [PMID: 31577822 PMCID: PMC6774529 DOI: 10.1371/journal.pone.0223435] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 09/21/2019] [Indexed: 01/08/2023] Open
Abstract
Developing effective therapies for back pain associated with intervertebral disc (IVD) degeneration is a research priority since it is a major socioeconomic burden and current conservative and surgical treatments have limited success. Polyphenols are naturally occurring compounds in plant-derived foods and beverages, and evidence suggests dietary supplementation with select polyphenol preparations can modulate diverse neurological and painful disorders. This study tested whether supplementation with a select standardized Bioactive-Dietary-Polyphenol-Preparation (BDPP) may alleviate pain symptoms associated with IVD degeneration. Painful IVD degeneration was surgically induced in skeletally-mature rats by intradiscal saline injection into three consecutive lumbar IVDs. Injured rats were given normal or BDPP-supplemented drinking water. In-vivo hindpaw mechanical allodynia and IVD height were assessed weekly for 6 weeks following injury. Spinal column, dorsal-root-ganglion (DRG) and serum were collected at 1 and 6 weeks post-operative (post-op) for analyses of IVD-related mechanical and biological pathogenic processes. Dietary BDPP significantly alleviated the typical behavioral sensitivity associated with surgical procedures and IVD degeneration, but did not modulate IVD degeneration nor changes of pro-inflammatory cytokine levels in IVD. Gene expression analyses suggested BDPP might have an immunomodulatory effect in attenuating the expression of pro-inflammatory cytokines in DRGs. This study supports the idea that dietary supplementation with BDPP has potential to alleviate IVD degeneration-related pain, and further investigations are warranted to identify the mechanisms of action of dietary BDPP.
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Affiliation(s)
- Alon Lai
- Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Lap Ho
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- James J. Peters Veterans Affairs Medical Center, Bronx, New York, United States of America
| | - Thomas W. Evashwick-Rogler
- Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | | | - Jonathan Salandra
- Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, United States of America
| | - Beth A. Winkelstein
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Damien Laudier
- Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Andrew C. Hecht
- Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Giulio M. Pasinetti
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- James J. Peters Veterans Affairs Medical Center, Bronx, New York, United States of America
| | - James C. Iatridis
- Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
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Behavioral Compensations and Neuronal Remodeling in a Rodent Model of Chronic Intervertebral Disc Degeneration. Sci Rep 2019; 9:3759. [PMID: 30842475 PMCID: PMC6403208 DOI: 10.1038/s41598-019-39657-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 01/29/2019] [Indexed: 12/25/2022] Open
Abstract
Low back pain is associated with degeneration of the intervertebral disc, but specific mechanisms of pain generation in this pathology remain unknown. Sensory afferent nerve fiber growth into the intervertebral disc after injury-induced inflammation may contribute to discogenic pain. We describe a clinically relevant behavioral phenotype in a rodent model of chronic intervertebral disc degeneration which provides a means to map sensory neuron changes to a single affected lumbar intervertebral disc. Unilateral disc puncture of one lumbar intervertebral disc revealed a bilateral behavioral phenotype characterized by gait changes and decreased activity. Moreover, neurons extracted from the dorsal root ganglia in animals with intervertebral disc injury demonstrated altered TRPV1 activation in vitro independent of exogenous NGF administration. Finally, neuronal nuclear hypertrophy and elevated expression of p75NTR provide evidence of active adaptation of innervating sensory neurons in chronic intervertebral disc degeneration. Therefore, this model and findings provide the template for future studies to establish specific mechanisms of nociceptive pain in chronic intervertebral disc degeneration.
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30
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Abstract
CGRP has long been suspected as a mediator of arthritis pain, although evidence that CGRP directly mediates human musculoskeletal pain remains circumstantial. This chapter describes in depth the evidence surrounding CGRP's association with pain in musculoskeletal disorders and also summarises evidence for CGRP being a direct cause of pain in other conditions. CGRP-immunoreactive nerves are present in musculoskeletal tissues, and CGRP expression is altered in musculoskeletal pain. CGRP modulates musculoskeletal pain through actions both in the periphery and central nervous system. Human observational studies, research on animal arthritis models and the few reported randomised controlled trials in humans of treatments that target CGRP provide the context of CGRP as a possible pain biomarker or mediator in conditions other than migraine.
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Affiliation(s)
- David A Walsh
- Pain Centre Versus Arthritis, NIHR Nottingham Biomedical Research Centre and Division of ROD, University of Nottingham, Nottingham, UK.
- Rheumatology, Sherwood Forest Hospitals NHS Foundation Trust, Nottinghamshire, UK.
| | - Daniel F McWilliams
- Pain Centre Versus Arthritis, NIHR Nottingham Biomedical Research Centre and Division of ROD, University of Nottingham, Nottingham, UK
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Abstract
Cervical intervertebral disc has long been considered a common source of neck pain. However, the pain caused by the disc itself has not been clearly defined so far, and its diagnosis and treatment has always been controversial. Degenerative cervical disc has a rich supply of nerve fibers, is prone to inflammatory reactions, and is susceptible to pain that can be provoked by disc stimulation or distention, and can be eliminated by block. Overwhelming clinical evidence demonstrates that neck pain in patients with degenerative cervical radiculopathy or myelopathy can be subsided rapidly by anterior cervical surgery, further indicating that this neck pain stems from the pathology of cervical disc itself. Cervical discography is advocated as the only test that connects disease to symptoms, but the procedure remains controversial. If strict criteria and technique are maintained, discography can discriminate painful, symptomatic discs from nonpainful, asymptomatic discs. Discogenic neck pain alone without cervical disc herniation or cervical spondylosis accounts for a large proportion of chronic neck pain. For these patients who continue to have refractory neck pain and fail to respond to conservative treatment, anterior cervical fusion surgery or artificial cervical disc replacement may be a better choice, and preoperative cervical discography can guarantee the excellent surgical results. Existing basic and clinical studies have scientifically shown that cervical intervertebral disc degeneration can lead to neck pain.
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Affiliation(s)
- Baogan Peng
- Department of Spinal Surgery, General Hospital of Armed Police Force, Beijing 100039, People's Republic of China,
| | - Michael J DePalma
- Interventional Spine and Musculoskeletal Care, Virginia iSpine Physicians, PC Virginia Spine Research Institute, Inc Richmond, VA, USA
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Yang G, Liao W, Shen M, Mei H. Insight into neural mechanisms underlying discogenic back pain. J Int Med Res 2018; 46:4427-4436. [PMID: 30270809 PMCID: PMC6259376 DOI: 10.1177/0300060518799902] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 08/20/2018] [Indexed: 12/17/2022] Open
Abstract
Back pain is a common clinical symptom. Degeneration of intervertebral discs is one of the most important factors leading to back pain, namely, discogenic back pain. However, at present, the understanding of lumbar intervertebral discs causing back pain is confined to biomechanical and histological studies. The neuropathological mechanism related to discogenic back pain is still not well understood. Many studies have found that as an intervertebral disc degenerates, the peripheral nerve tissues have corresponding structural reorganization, and a series of nerve cells become involved in progression of discogenic back pain. Therefore, study of neural mechanisms that are involved in progression of discogenic back pain will provide additional assistance for treatment of its symptoms. We review the anatomical structure of intervertebral discs and the related neural mechanisms involved in discogenic back pain. We also discuss the current view of neural mechanisms underlying discogenic back pain.
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Affiliation(s)
- Ge Yang
- Orthopaedic Department, Hunan Children’s Hospital, The Pediatric
Academy of University of South China, Changsha, Hunan Province, China
- Orthopaedic Department, the First Hospital of Medical College of
Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Wenyu Liao
- Hunan Provincial Key Laboratory for Biology and Control of Plant
Diseases and Insect Pests, Hunan Agricultural University, Changsha, Hunan
Province, China
| | - Miaoda Shen
- Orthopaedic Department, the First Hospital of Medical College of
Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Haibo Mei
- Orthopaedic Department, Hunan Children’s Hospital, The Pediatric
Academy of University of South China, Changsha, Hunan Province, China
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Yang G, Chen L, Gao Z, Wang Y. Implication of microglia activation and CSF-1/CSF-1Rpathway in lumbar disc degeneration-related back pain. Mol Pain 2018; 14:1744806918811238. [PMID: 30326776 PMCID: PMC6243401 DOI: 10.1177/1744806918811238] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Back pain is common and costly. Although lumbar disc degeneration has long been regarded as a major contributor to back pain, how disc degeneration leads to back pain remains unclear. Recent studies observed microglia activation in the spinal cord after disc degeneration, suggesting activated microglia may be involved in discogenic back pain. To determine whether microglia activation participates in disc degeneration-induced back pain, we used a modified disc puncture-induced degeneration-related back pain mouse model to examine the changes in spinal microglia and investigate the potential link between microglia activation and discogenic back pain. In this study, 46 CX3CR1GFP/+ male mice were used in experimental and sham groups. A modified posterolateral retroperitoneal approach was used to expose the L3/L4 disc to induce the needle puncture in the experimental group. Behavioral tests, including grip force and physical function, were used to measure back pain at pre- and postsurgery. The L3 dorsal root ganglions and lumbar spinal cord were obtained at postoperative weeks 1 to 4 followed by immunofluorescence with different antibodies. Micrographs were obtained by confocal microscopy, and morphometric measurements of microglia were analyzed using Imaris. The punctured disc underwent progressive degeneration and mice with disc degeneration showed impaired grip force and physical function. Compared to the control mice, the number of microglia in the lumbar spinal cord was significantly increased in the disc-punctured animals. Moreover, accumulated microglia exhibited larger soma size and lesser ramification in the disc-injured mice. Immunofluorescence demonstrated colony-stimulating factor 1, a cytokine that promotes microglia repopulation, was significantly increased in L3 dorsal root ganglions, whereas its receptor colony-stimulating factor 1 receptor was upregulated on microglia in the disc-injured mice. In summary, lumbar disc puncture caused progressive disc degeneration which induced microglia activation and back pain in mice. Increased colony-stimulating factor 1/colony-stimulating factor 1 receptor signaling is involved in the disc degeneration-induced microglia activation and back pain.
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Affiliation(s)
- Ge Yang
- 1 Spine Lab, Department of Orthopedic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lunhao Chen
- 1 Spine Lab, Department of Orthopedic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhihua Gao
- 2 Department of Neurobiology, Institute of Neuroscience, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Yue Wang
- 1 Spine Lab, Department of Orthopedic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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34
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Shi C, Das V, Li X, Kc R, Qiu S, O-Sullivan I, Ripper RL, Kroin JS, Mwale F, Wallace AA, Zhu B, Zhao L, van Wijnen AJ, Ji M, Lu J, Votta-Velis G, Yuan W, Im HJ. Development of an in vivo mouse model of discogenic low back pain. J Cell Physiol 2018; 233:6589-6602. [PMID: 29150945 DOI: 10.1002/jcp.26280] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 11/14/2017] [Indexed: 11/09/2022]
Abstract
Discogenic low back pain (DLBP) is extremely common and costly. Effective treatments are lacking due to DLBP's unknown pathogenesis. Currently, there are no in vivo mouse models of DLBP, which restricts research in this field. The aim of this study was to establish a reliable DLBP model in mouse that captures the pathological changes in the disc and allows longitudinal pain testing. The model was generated by puncturing the mouse lumbar discs (L4/5, L5/6, and L6/S1) and removing the nucleus pulposus using a microscalpel under the microscope. Histology, molecular pathways, and pain-related behaviors were examined. Over 12 weeks post-surgery, animals displayed the mechanical, heat, and cold hyperalgesia along with decreased burrowing and rearing. Histology showed progressive disc degeneration with loss of disc height, nucleus pulposus reduction, proteoglycan depletion, and annular fibrotic disorganization. Immunohistochemistry revealed a substantial increase in inflammatory mediators at 2 and 4 weeks. Nerve growth factor was upregulated from 2 weeks to the end of the experiment. Nerve fiber ingrowth was induced in the injured discs after 4 weeks. Disc-puncture also produced an upregulation of neuropeptides in dorsal root ganglia neurons and an activation of glial cells in the spinal cord dorsal horn. These findings indicate that the cellular and structural changes in discs, as well as peripheral and central nervous system plasticity, paralleled persistent, and robust behavioral pain responses. Therefore, this mouse DLBP model could be used to investigate mechanisms underlying discogenic pain, thereby facilitating effective drug screening and development of treatments for DLBP.
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Affiliation(s)
- Changgui Shi
- Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
- Department of Biochemistry, Rush University Medical Center, Chicago, Illinois
| | - Vaskar Das
- Department of Biochemistry, Rush University Medical Center, Chicago, Illinois
| | - Xin Li
- Department of Biochemistry, Rush University Medical Center, Chicago, Illinois
| | - Ranjan Kc
- Department of Biochemistry, Rush University Medical Center, Chicago, Illinois
| | - Sujun Qiu
- Department of Biochemistry, Rush University Medical Center, Chicago, Illinois
- Department of Orthopedic Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - InSug O-Sullivan
- Department of Internal Medicine, The University of Illinois at Chicago (UIC), Chicago, Illinois
| | - Richard L Ripper
- Department of Anesthesiology, The University of Illinois at Chicago (UIC), Chicago, Illinois
| | - Jeffrey S Kroin
- Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois
| | - Fackson Mwale
- Department of Surgery, McGill University and Orthopaedic Research Laboratory, Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, Canada
| | - Atiyayein A Wallace
- Department of Biochemistry, Rush University Medical Center, Chicago, Illinois
| | - Bingqian Zhu
- Department of Biobehavioral Health Science, The University of Illinois at Chicago (UIC), Chicago, Illinois
| | - Lan Zhao
- Department of Biochemistry, Rush University Medical Center, Chicago, Illinois
| | | | - Mingliang Ji
- Department of Orthopaedic Surgery, Southeast University Zhongda Hospital, Nanjing, China
| | - Jun Lu
- Department of Orthopaedic Surgery, Southeast University Zhongda Hospital, Nanjing, China
| | - Gina Votta-Velis
- Department of Anesthesiology, The University of Illinois at Chicago (UIC), Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center (JBVAMC), Chicago, Illinois
| | - Wen Yuan
- Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Hee-Jeong Im
- Department of Biochemistry, Rush University Medical Center, Chicago, Illinois
- Jesse Brown Veterans Affairs Medical Center (JBVAMC), Chicago, Illinois
- Department of Bioengineering, The University of Illinois at Chicago (UIC), Chicago, Illinois
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35
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Navone SE, Peroglio M, Guarnaccia L, Beretta M, Grad S, Paroni M, Cordiglieri C, Locatelli M, Pluderi M, Rampini P, Campanella R, Alini M, Marfia G. Mechanical loading of intervertebral disc modulates microglia proliferation, activation, and chemotaxis. Osteoarthritis Cartilage 2018; 26:978-987. [PMID: 29723636 DOI: 10.1016/j.joca.2018.04.013] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 04/10/2018] [Accepted: 04/20/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVE The aim of the study is to assess the effects of the neuroinflammatory microenvironment of a mechanically-induced degenerating intervertebral disc (IVD) on neuroinflammatory like cells such as microglia, in order to comprehend the role of microglial cells in degenerative disc disease. METHODS Bovine caudal IVDs were kept in culture in an ex vivo bioreactor under high frequency loading and limited nutrition or in free swelling conditions as control samples. Conditioned media (CM) were collected, analysed for cytokine and neurotrophin content and applied to microglial cells for neuroinflammatory activation assessment. RESULTS Degenerative conditioned medium (D-CM) induced a higher production of interleukin (IL)-8, nerve growth factor (NGF), interferon (IFN)-γ, IL-17 from IVD cells than unloaded control conditioned medium (U-CM). Upon 48 h of co-incubation with microglia, D-CM stimulated microglia proliferation, activation, with increased expression of ionized calcium binding adaptor molecule 1 (IBA1) and CD68, and chemotaxis. Moreover, an increment of nitrite production was observed. Interestingly, D-CM caused an upregulation of IL-1β, IL-6, tumour necrosis factor α (TNFα), inducible NO synthase (iNOS), IBA1, and vascular endothelial growth factor (VEGF) genes in microglia. Similar results were obtained when microglia were treated with the combination of the measured cytokines. CONCLUSIONS Our findings show that in IVD degenerative microenvironment, IL-8, NGF, IFN-γ, IL-17 drive activation of microglia in the spinal cord and increase upregulation of neuroinflammatory markers. This, in turn, enhances the inflammatory milieu within IVD tissues and in the peridiscal space, aggravating the cascade of degenerative events. This study provides evidence for an important role of microglia in maintaining IVD neuroinflammatory microenvironment and probably inducing low back pain.
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Affiliation(s)
- S E Navone
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - M Peroglio
- AO Research Institute Davos, Davos, Switzerland
| | - L Guarnaccia
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - M Beretta
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - S Grad
- AO Research Institute Davos, Davos, Switzerland
| | - M Paroni
- Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milan, Italy
| | - C Cordiglieri
- Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi," Milan, Italy
| | - M Locatelli
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - M Pluderi
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - P Rampini
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - R Campanella
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - M Alini
- AO Research Institute Davos, Davos, Switzerland
| | - G Marfia
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
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36
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Evashwick-Rogler TW, Lai A, Watanabe H, Salandra JM, Winkelstein BA, Cho SK, Hecht AC, Iatridis JC. Inhibiting tumor necrosis factor-alpha at time of induced intervertebral disc injury limits long-term pain and degeneration in a rat model. JOR Spine 2018; 1. [PMID: 29963655 PMCID: PMC6022768 DOI: 10.1002/jsp2.1014] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background Painful intervertebral disc (IVD) degeneration has tremendous societal costs and few effective therapies. Intradiscal tumor necrosis factor‐alpha (TNFα) is commonly associated with low back pain, but the direct relationship remains unclear. Purpose Treatment strategies for low back pain require improved understanding of the complex relationships between pain, intradiscal pro‐inflammatory cytokines, and structural IVD degeneration. A rat in vivo lumbar IVD puncture model was used to 1) determine the role of TNFα in initiating painful IVD degeneration, and 2) identify statistical relationships between painful behavior, IVD degeneration, and intradiscal pro‐inflammatory cytokine expression. Methods Lumbar IVDs were punctured anteriorly and injected with TNFα, anti‐TNFα, or saline and compared with sham and naive controls. Hindpaw mechanical hyperalgesia was assayed weekly to determine pain over time. 6‐weeks post‐surgery, animals were sacrificed, and IVD degeneration, IVD height, and intradiscal TNFα and interleukin‐1 beta (IL‐1β) expressions were assayed. Results Intradiscal TNFα injection increased pain and IVD degeneration whereas anti‐TNFα alleviated pain to sham level. Multivariate step‐wise linear regression identified pain threshold was predicted by IVD degeneration and intradiscal TNFα expression. Pain threshold was also linearly associated with IVD height loss and IL‐1β. Discussion The significant associations between IVD degeneration, height loss, inflammation, and painful behavior highlight the multifactorial nature of painful IVD degeneration and the challenges to diagnose and treat a specific underlying factor. We concluded that TNFα is an initiator of painful IVD degeneration and its early inhibition can mitigate pain and degeneration. Intradiscal TNFα inhibition following IVD injury may warrant investigation for its potential to alter downstream painful IVD degeneration processes.
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Affiliation(s)
- Thomas W Evashwick-Rogler
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Alon Lai
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Hironobu Watanabe
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York.,Keiyu Spine Center, Keiyu Orthopedic Hospital, Tatebayashi, Japan
| | - Jonathan M Salandra
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Beth A Winkelstein
- Departments of Bioengineering and Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Samuel K Cho
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Andrew C Hecht
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - James C Iatridis
- Leni and Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York
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37
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Park TSW, Kuo A, Smith MT. Chronic low back pain: a mini-review on pharmacological management and pathophysiological insights from clinical and pre-clinical data. Inflammopharmacology 2018; 26:10.1007/s10787-018-0493-x. [PMID: 29754321 DOI: 10.1007/s10787-018-0493-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 05/01/2018] [Indexed: 12/19/2022]
Abstract
Globally, low back pain (LBP) is one of the most common health problems affecting humans. The lifetime prevalence of non-specific LBP is approximately 84%, with the chronic prevalence at about 23%. Chronic LBP in humans is defined as LBP that persists for more than 12 weeks without a significant pain improvement. Although there are numerous evidence-based guidelines on the management of acute LBP, this is not the case for chronic LBP, which is regarded as particularly difficult to treat. Research aimed at discovering new drug treatments for alleviation of chronic mechanical LBP is lacking due to the paucity of knowledge on the pathobiology of this condition, despite its high morbidity in the affected adult population. For a debilitating condition such as chronic LBP, it is necessary to assess the sustained effects of pharmacotherapy of various agents spanning months to years. Although many rodent models of mechanical LBP have been developed to mimic the human condition, some of the major shortcomings of many of these models are (1) the presence of a concurrent neuropathic component that develops secondary to posterior intervertebral disc puncture, (2) severe model phenotype, and/or (3) use of behavioural endpoints that have yet to be validated for pain. Hence, there is a great, unmet need for research aimed at discovering new biological targets in rodent models of chronic mechanical LBP for use in drug discovery programs as a means to potentially produce new highly effective and well-tolerated analgesic agents to improve relief of chronic LBP. On a cautionary note, it must be borne in mind that because humans and rats display orthograde and pronograde postures, respectively, the different mechanical forces on their spines add to the difficulty in translation of promising rodent data to humans.
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Affiliation(s)
- Thomas S W Park
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia
- UQ Centre for Clinical Research, Faculty of Medicine, Steele Building, St Lucia Campus, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Andy Kuo
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Maree T Smith
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia.
- School of Pharmacy, Pharmacy Australia Centre of Excellence, Faculty of Health and Rehabilitation Sciences, The University of Queensland, Brisbane, QLD, 4102, Australia.
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Miyagi M, Uchida K, Takano S, Fujimaki H, Aikawa J, Sekiguchi H, Nagura N, Ohtori S, Inoue G, Takaso M. Macrophage-derived inflammatory cytokines regulate growth factors and pain-related molecules in mice with intervertebral disc injury. J Orthop Res 2018; 36:2274-2279. [PMID: 29508435 DOI: 10.1002/jor.23888] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 02/22/2018] [Indexed: 02/04/2023]
Abstract
Upregulation of inflammatory cytokines and various growth factors is a significant contributor to discogenic low back pain. The aim of this study was to investigate possible regulation of pain-related molecules by macrophages and the role of macrophage-derived molecules in injured intervertebral disc (IVD)s. C57BL/6J mice were used in this study. We characterized the expression profiles of genes for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) in both intact and injured IVDs. We examined whether macrophage depletion, induced by systemic injection of clodronate-laden liposomes, affected the expression of these molecules in injured IVDs. The effect of TNF-alpha on cultured F4/80-CD11b-cells in injured IVDs was investigated. Expression of TNF-alpha and IL-1beta was significantly increased in injured IVDs, but decreased by macrophage depletion. Expression of NGF and VEGF was also significantly increased, but by contrast was not decreased by macrophage depletion. TNF-alpha treatment of F4/80-cells from injured IVDs upregulated NGF, VEGF, cyclooxygenase (COX)-2, and microsomal prostaglandin E synthase-1 (mPGES1). IVD injury upregulated inflammatory cytokines and various growth factors. Macrophages in the injured IVDs produced inflammatory cytokines, but not growth factors. Macrophage-derived inflammatory cytokines regulate growth factors and pain-related molecules. These findings demonstrate further complexity in the pathogenesis of discogenic pain. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
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Affiliation(s)
- Masayuki Miyagi
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Kentaro Uchida
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Shotaro Takano
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Hisako Fujimaki
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Jun Aikawa
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Hiroyuki Sekiguchi
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Naoshige Nagura
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Seiji Ohtori
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Gen Inoue
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
| | - Masashi Takaso
- Department of Orthopedic Surgery, Kitasato University School of Medicine, 1-15-1 Minami-ku Kitasato, Sagamihara City, Kanagawa, 252-0374, Japan
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Arendt‐Nielsen L, Morlion B, Perrot S, Dahan A, Dickenson A, Kress H, Wells C, Bouhassira D, Drewes AM. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain 2018; 22:216-241. [DOI: 10.1002/ejp.1140] [Citation(s) in RCA: 435] [Impact Index Per Article: 62.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
AbstractDifferent neuroplastic processes can occur along the nociceptive pathways and may be important in the transition from acute to chronic pain and for diagnosis and development of optimal management strategies. The neuroplastic processes may result in gain (sensitisation) or loss (desensitisation) of function in relation to the incoming nociceptive signals. Such processes play important roles in chronic pain, and although the clinical manifestations differ across condition processes, they share some common mechanistic features. The fundamental understanding and quantitative assessment of particularly some of the central sensitisation mechanisms can be translated from preclinical studies into the clinic. The clinical perspectives are implementation of such novel information into diagnostics, mechanistic phenotyping, prevention, personalised treatment, and drug development. The aims of this paper are to introduce and discuss (1) some common fundamental central pain mechanisms, (2) how they may translate into the clinical signs and symptoms across different chronic pain conditions, (3) how to evaluate gain and loss of function using quantitative pain assessment tools, and (4) the implications for optimising prevention and management of pain. The chronic pain conditions selected for the paper are neuropathic pain in general, musculoskeletal pain (chronic low back pain and osteoarthritic pain in particular), and visceral pain (irritable bowel syndrome in particular). The translational mechanisms addressed are local and widespread sensitisation, central summation, and descending pain modulation.SignificanceCentral sensitisation is an important manifestation involved in many different chronic pain conditions. Central sensitisation can be different to assess and evaluate as the manifestations vary from pain condition to pain condition. Understanding central sensitisation may promote better profiling and diagnosis of pain patients and development of new regimes for mechanism based therapy. Some of the mechanisms underlying central sensitisation can be translated from animals to humans providing new options in development of therapies and profiling drugs under development.
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Affiliation(s)
| | - B. Morlion
- The Leuven Centre for Algology University Hospitals Leuven University of Leuven Belgium
| | - S. Perrot
- INSERM U987 Pain Center Cochin Hospital Paris Descartes University Paris France
| | - A. Dahan
- Department of Anesthesiology Leiden University Medical Center Leiden The Netherlands
| | - A. Dickenson
- Neuroscience Physiology & Pharmacology University College London UK
| | - H.G. Kress
- Department of Special Anaesthesia and Pain Therapy Medizinische Universität/AKH Wien Vienna Austria
| | | | - D. Bouhassira
- INSERM U987 Centre d'Evaluation et de Traitement de la Douleur Hôpital Ambroise Paré Boulogne Billancourt France
| | - A. Mohr Drewes
- Mech‐Sense Department of Gastroenterology and Hepatology Clinical Institute Aalborg University Hospital Aalborg Denmark
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Sato J, Inage K, Miyagi M, Sakuma Y, Yamauchi K, Suzuki M, Koda M, Furuya T, Nakamura J, Eguchi Y, Suzuki M, Kubota G, Oikawa Y, Sainoh T, Fujimoto K, Shiga Y, Abe K, Kanamoto H, Inoue M, Kinoshita H, Norimoto M, Umimura T, Takahashi K, Ohtori S, Orita S. Vascular endothelial growth factor in degenerating intervertebral discs of rat caudal vertebrae. Spine Surg Relat Res 2018; 2:42-47. [PMID: 31440645 PMCID: PMC6698553 DOI: 10.22603/ssrr.2017-0026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 06/27/2017] [Indexed: 11/27/2022] Open
Abstract
Introduction Discogenic back pain remains poorly understood with respect to etiopathogenesis, despite being a considerable burden. We sought to examine the expression of vascular endothelial growth factor in injured intervertebral discs in rat caudal vertebrae. Methods Forty-eight male Sprague Dawley rats were assigned to 2 groups according to disc puncture injury: puncture (n = 32) or non-puncture (n = 16). Disc puncture was performed percutaneously such that the incision would be in the primary plane of motion for the coccygeal discs 5-6, 6-7, and 7-8. A 26-gauge needle was used to puncture each disc 10 times. Punctured discs were examined histologically by hematoxylin and eosin staining at 1, 7, 14, and 28 days post-injury. Results Vascular endothelial growth factor was localized immunohistochemically, and determined quantitatively using an enzyme-linked immunosorbent assay. Peak inflammation occurred on the 7th day post-injury, but tissue degeneration continued until day 28. Local expression of vascular endothelial growth factor tended to be highest in the annulus fibrosus on the 7th and 14th days after puncture injury. The level of vascular endothelial growth factor was highest 1-day post-injury, and then gradually decreased thereafter. Furthermore, vascular endothelial growth factor levels in the puncture group were significantly higher than those in the non-puncture control group (p < 0.05). Conclusions We found increased expression of the inflammatory cytokine vascular endothelial growth factor in injured intervertebral discs, suggesting that vascular endothelial growth factor may be clinically important in discogenic back pain.
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Affiliation(s)
- Jun Sato
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.,Department of Orthopaedic Surgery, Chiba Aoba Municipal Hospital, Chiba, Japan
| | - Kazuhide Inage
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masayuki Miyagi
- Department of Orthopaedic Surgery, Kitasato University Hospital, Kanagawa, Japan
| | - Yoshihiro Sakuma
- Department of Orthopaedic Surgery, National Hospital Organization Chiba Medical Center, Chiba, Japan
| | - Kazuyo Yamauchi
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masahiko Suzuki
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masao Koda
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takeo Furuya
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Junichi Nakamura
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yawara Eguchi
- Department of Orthopaedic Surgery, National Hospital Organization Shimoshizu National Hospital, Chiba, Japan
| | - Miyako Suzuki
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Go Kubota
- Department of Orthopaedic Surgery, Eastern Chiba Medical Center, Chiba, Japan
| | - Yasuhiro Oikawa
- Department of Orthopaedic Surgery, Chiba Children's Hospital, Chiba, Japan
| | - Takeshi Sainoh
- Department of Orthopaedic Surgery, Sainou Hospital, Toyama, Japan
| | - Kazuki Fujimoto
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yasuhiro Shiga
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Koki Abe
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hirohito Kanamoto
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masahiro Inoue
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hideyuki Kinoshita
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masaki Norimoto
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Tomotaka Umimura
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kazuhisa Takahashi
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Seiji Ohtori
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Sumihisa Orita
- Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
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Ohtori S, Miyagi M, Inoue G. Sensory nerve ingrowth, cytokines, and instability of discogenic low back pain: A review. Spine Surg Relat Res 2018; 2:11-17. [PMID: 31440640 PMCID: PMC6698542 DOI: 10.22603/ssrr.2016-0018] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/30/2017] [Indexed: 01/07/2023] Open
Abstract
Introduction Many patients suffer from discogenic low back pain. However, the mechanisms, diagnosistic strategy, and treatment of discogenic low back pain all remain controversial. The purpose of this paper was to review the pathological mechanisms of discogenic low back pain. Methods Many authors have investigated the pathological mechanisms of discogenic low back pain using animal models and examining human patients. Central to most investigations is understanding the innervation and instabilities of diseased intervertebral discs and the role of inflammatory mediators. We discuss three pathological mechanisms of discogenic low back pain: innervation, inflammation, and mechanical hypermobility of the intervertebral disc. Results Sensory nerve fibers include C-fibers and A delta-fibers, which relay pain signals from the innervated outer layers of the intervertebral disc under normal conditions. However, ingrowth of these sensory nerve fibers into the inner layers of intervertebral disc occurs under disease conditions. Levels of neurotrophic factors and some cytokines are significantly higher in diseased discs than in normal discs. Stablization of the segmental hypermobility, which can be induced by intervertebral disc degeneration, suppresses inflammation and prevents sensitization of sensory nerve fibers innervating the disc. Conclusions Pathological mechanisms of discogenic low back pain include sensory nerve ingrowth into inner layers of the intervertebral disc, upregulation of neurotrophic factors and cytokines, and instability. Inhibition of these mechanisms is important in the treatment of discogenic low back pain.
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Affiliation(s)
- Seiji Ohtori
- Department of Orthopaedic Surgery, Graduate School of Medicine Chiba University, Chiba, Japan
| | - Masayuki Miyagi
- Department of Orthopaedic Surgery, Kitasato University, School of Medicine, Kanagawa, Japan
| | - Gen Inoue
- Department of Orthopaedic Surgery, Kitasato University, School of Medicine, Kanagawa, Japan
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Hu MH, Yang KC, Chen YJ, Sun YH, Lin FH, Yang SH. Optimization of puncture injury to rat caudal disc for mimicking early degeneration of intervertebral disc. J Orthop Res 2018; 36:202-211. [PMID: 28594131 DOI: 10.1002/jor.23628] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 06/05/2017] [Indexed: 02/04/2023]
Abstract
The caudal discs of rats have been proposed as a puncture model in which intervertebral disc (IVD) degeneration can be induced and novel therapies can be tested. For biological repair, treatments for ongoing IVD degeneration are ideally administered during the earlier stages. The purpose of this study was to elucidate the optimal puncture needle size for creating a model that mimicked the earlier stages of IVD degeneration. According to the disc height index, histologic score, and MRI grading, a puncture needle sized 21G or larger induced rapid degenerative processes in rat caudal discs during the initial 2-4 weeks. The degenerative changes were severe and continued deteriorating after 4 weeks. Conversely, puncture injury induced by needles sized 25G or smaller also produced degenerative changes in rat caudal discs during initial 2-4 weeks; however, the changes were less severe. Furthermore, the degenerative process became stabilized and showed no further deterioration or spontaneous recovery after 4 weeks. In the discs punctured by 25G needles, the expression of collagen I was increased at 2-4 weeks with a gradually fibrotic transformation thereafter. The expressions of collagen II and SOX9 were enhanced initially but returned to pre-injury levels at 4-8 weeks. The above-mentioned findings were more compatible with earlier degeneration in discs punctured by needles sized 25G or smaller than by needles sized 21G or larger, and the appropriate timing for intradiscal administration of proposed therapeutic agents would be 4 weeks or longer after puncture. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:202-211, 2018.
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Affiliation(s)
- Ming-Hsiao Hu
- Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.,Department of Orthopedics, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Chiang Yang
- Department of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yeong-Jang Chen
- Department of Orthopedics, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Yuan-Hui Sun
- Department of Orthopedics, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Feng-Huei Lin
- Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.,Institute of Biomedical Engineering & Nanomedicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan
| | - Shu-Hua Yang
- Department of Orthopedics, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
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Miyagi M, Ishikawa T, Kamoda H, Suzuki M, Inoue G, Sakuma Y, Oikawa Y, Orita S, Uchida K, Takahashi K, Takaso M, Ohtori S. Efficacy of nerve growth factor antibody in a knee osteoarthritis pain model in mice. BMC Musculoskelet Disord 2017; 18:428. [PMID: 29100502 PMCID: PMC5670727 DOI: 10.1186/s12891-017-1792-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 10/30/2017] [Indexed: 01/06/2023] Open
Abstract
Background Nerve growth factor (NGF) is not only an important factor in nerve growth but also a major contributor to the production of inflammation. It has been reported that inhibiting NGF could reduce several types of pain in several animal models. Here, we aimed to clarify the efficacy of NGF antibody in a knee osteoarthritis (OA) pain model in mice. Method Six-week-old male C57BR/J mice were used (n = 30). Ten mice comprised the control group, which received saline injection into the right knee joints; the other 20 mice comprised the experimental group, which received monoiodoacetate (MIA) injection into the right knee joints. Three weeks after surgery, the 20 experimental mice were randomly placed into treatment groups which received either sterile saline (non-treat group: 10 mg/kg, i.p.) or an anti-NGF antibody (anti-NGF group: 10 mg/kg, i.p.). Simultaneously, all mice received fluorogold (FG) retrograde neurotracer injection into their right joints. In a behavioral study, we evaluated gait using the CatWalk quantitative gait analysis system before surgery, 3 weeks after surgery (before treatment), 4 weeks after surgery (one week after surgery), and 5 weeks after surgery (2 weeks after surgery). In immunohistochemical analysis, the right dorsal root ganglia (DRGs) from the L4–L6 levels were resected 5 weeks after surgery (2 weeks after surgery). They were immunostained for calcitonin gene-related peptide (CGRP), and the number of FG-labeled or CGRP-immunoreactive (IR) DRG neurons was counted. Results On gait analysis using the CatWalk system, duty cycle, swing speed, and print area were decreased in non-treat group compared with those in control group and improved in the anti-NGF group compared with those in non-treat group. CGRP expression in DRGs was up-regulated in non-treat group compared with that in control group and suppressed in the anti-NGF group compared with that in non-treat group (both p < 0.05). Conclusions MIA injection into the knee joint induced gait impairment and the up-regulation of CGRP in DRG neurons in a knee OA pain model in mice. Intraperitoneal injection of anti-NGF antibody suppressed this impairment of gait and up-regulation of CGRP in DRG neurons. These finding suggest that anti-NGF therapy might be valuable in the treatment of OA pain in the knee.
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Affiliation(s)
- Masayuki Miyagi
- Department of Orthopaedic Surgery, Kitasato University, School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara city, Kanagawa, 252-0374, Japan.
| | - Tetsuhiro Ishikawa
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroto Kamoda
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Miyako Suzuki
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Gen Inoue
- Department of Orthopaedic Surgery, Kitasato University, School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara city, Kanagawa, 252-0374, Japan
| | - Yoshihiro Sakuma
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yasuhiro Oikawa
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sumihisa Orita
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kentaro Uchida
- Department of Orthopaedic Surgery, Kitasato University, School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara city, Kanagawa, 252-0374, Japan
| | - Kazuhisa Takahashi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masashi Takaso
- Department of Orthopaedic Surgery, Kitasato University, School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara city, Kanagawa, 252-0374, Japan
| | - Seiji Ohtori
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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Yin J, Huang Y, Gao G, Nong L, Xu N, Zhou D. Changes and significance of inflammatory cytokines in a rat model of cervical spondylosis. Exp Ther Med 2017; 15:400-406. [PMID: 29387194 DOI: 10.3892/etm.2017.5418] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 04/10/2017] [Indexed: 12/15/2022] Open
Abstract
The aim of the present study was to dynamically observe and discuss the significance of inflammatory cytokines in cervical degenerative disease induced by unbalanced dynamic and static forces in rats. A total of 60 Sprague Dawley rats were randomized into test (n=45) and control (n=15) groups, which were randomly subdivided into three groups corresponding to assessment at one, three and six months post-operation. The test group included 10, 15 and 20 rats at the corresponding post-operative stage and the control group had five rats at each time-point. By excising cervicodorsal muscles and ligaments, an unbalanced dynamic and static rat model was established in the test group. At one, three and six-months post-operation, venous serum of test and control group rats was collected and inflammatory cytokines in the serum of all rats were quantitatively determined by ELISA. The results revealed that compared with the control group, the interleukin (IL)-1β, IL-10 and tumor necrosis factor-α levels in the test group were significantly increased at one and three months (P<0.05, <0.01 or <0.001), and that IL-12 was significantly increased at three months (P<0.05). However, transforming growth factor-β1 increased at one month but was significantly decreased at three months (P<0.01). IL-6 did not change significantly throughout the observation period (P>0.05). In conclusion, cervical vertebral stability may be accompanied with changes of inflammatory cytokines.
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Affiliation(s)
- Jianjian Yin
- Department of Orthopedics, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China
| | - Yongjing Huang
- Department of Orthopedics, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China
| | - Gongming Gao
- Department of Orthopedics, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China
| | - Luming Nong
- Department of Orthopedics, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China
| | - Nanwei Xu
- Department of Orthopedics, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China
| | - Dong Zhou
- Department of Orthopedics, Changzhou Second People's Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China
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Inhibiting Vascular Endothelial Growth Factor in Injured Intervertebral Discs Attenuates Pain-Related Neuropeptide Expression in Dorsal Root Ganglia in Rats. Asian Spine J 2017; 11:556-561. [PMID: 28874973 PMCID: PMC5573849 DOI: 10.4184/asj.2017.11.4.556] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 12/26/2016] [Accepted: 01/26/2017] [Indexed: 12/22/2022] Open
Abstract
STUDY DESIGN An experimental animal study. PURPOSE To evaluate effects of anti-vascular endothelial growth factor (VEGF) on the content and distribution of the calcitonin gene-related peptide (CGRP) in the dorsal ganglia in a rat model. OVERVIEW OF LITERATURE Increased expression of VEGF in degenerative disc disease increases the levels of inflammatory cytokines and nerve ingrowth into the damaged discs. In animal models, increased levels of VEGF can persist for up to 2 weeks after an injury. METHODS Through abdominal surgery, the dorsal root ganglia (DRG) innervating L5/L6 intervertebral disc were labeled (FluoroGold neurotracer) in 24, 8-week old Sprague Dawley rats. The rats were randomly allocated to three groups of eight rats each. The anti-VEGF group underwent L5/6 intervertebral disc puncture using a 26-gauge needle, intradiscal injection of 33.3 µg of the pegaptanib sodium, a VEGF165 aptamer. The control-puncture group underwent disc puncture and intradiscal injection of 10 µL saline solution, and the sham-surgery group underwent labeling but no disc puncture. Two rats in each group were sacrificed on postoperative days 1, 7, 14, and 28 after surgery. L1-L6 DRGs were harvested, sectioned, and immunostained to detect the content and distribution of CGRP. RESULTS Compared with the control, the percentage of CGRP-positive cells was lower in the anti-VEGF group (p<0.05; 40.6% and 58.1% on postoperative day 1, 44.3% and 55.4% on day 7, and 42.4% and 59.3% on day 14). The percentage was higher in the control group compared with that of the sham group (p<0.05; sham group, 34.1%, 40.7%, and 33.7% on postoperative days 1, 7, and 14, respectively). CONCLUSIONS Decreasing CGRP-positive cells using anti-VEGF therapy provides fundamental evidence for a possible therapeutic role of anti-VEGF in patients with discogenic lower back pain.
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Lim TKY, Anderson KM, Hari P, Di Falco M, Reihsen TE, Wilcox GL, Belani KG, LaBoissiere S, Pinto MR, Beebe DS, Kehl LJ, Stone LS. Evidence for a Role of Nerve Injury in Painful Intervertebral Disc Degeneration: A Cross-Sectional Proteomic Analysis of Human Cerebrospinal Fluid. THE JOURNAL OF PAIN 2017; 18:1253-1269. [PMID: 28652204 DOI: 10.1016/j.jpain.2017.06.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 06/08/2017] [Accepted: 06/08/2017] [Indexed: 12/18/2022]
Abstract
Intervertebral disc degeneration (DD) is a cause of low back pain (LBP) in some individuals. However, although >30% of adults have DD, LBP only develops in a subset of individuals. To gain insight into the mechanisms underlying nonpainful versus painful DD, human cerebrospinal fluid (CSF) was examined using differential expression shotgun proteomic techniques comparing healthy control participants, subjects with nonpainful DD, and patients with painful DD scheduled for spinal fusion surgery. Eighty-eight proteins were detected, 27 of which were differentially expressed. Proteins associated with DD tended to be related to inflammation (eg, cystatin C) regardless of pain status. In contrast, most differentially expressed proteins in DD-associated chronic LBP patients were linked to nerve injury (eg, hemopexin). Cystatin C and hemopexin were selected for further examination using enzyme-linked immunosorbent assay in a larger cohort. While cystatin C correlated with DD severity but not pain or disability, hemopexin correlated with pain intensity, physical disability, and DD severity. This study shows that CSF can be used to study mechanisms underlying painful DD in humans, and suggests that while painful DD is associated with nerve injury, inflammation itself is not sufficient to develop LBP. PERSPECTIVE CSF was examined for differential protein expression in healthy control participants, pain-free adults with asymptomatic intervertebral DD, and LBP patients with painful intervertebral DD. While DD was related to inflammation regardless of pain status, painful degeneration was associated with markers linked to nerve injury.
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Affiliation(s)
- Tony K Y Lim
- Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, Montreal, McGill University, Quebec, Canada
| | - Kathleen M Anderson
- Program in Physical Therapy, Department of Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, Minnesota
| | - Pawan Hari
- Department of Epidemiology, University of Minnesota, Minneapolis, Minnesota
| | - Marcos Di Falco
- Genome Quebec, McGill University Innovation Centre, Montreal, Quebec, Canada
| | - Troy E Reihsen
- Department of Anesthesiology, University of Minnesota, Minneapolis, Minnesota
| | - George L Wilcox
- Department of Anesthesiology, University of Minnesota, Minneapolis, Minnesota; Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
| | - Kumar G Belani
- Department of Anesthesiology, University of Minnesota, Minneapolis, Minnesota
| | - Sylvie LaBoissiere
- Genome Quebec, McGill University Innovation Centre, Montreal, Quebec, Canada
| | | | - David S Beebe
- Department of Anesthesiology, University of Minnesota, Minneapolis, Minnesota
| | - Lois J Kehl
- Department of Anesthesiology, University of Minnesota, Minneapolis, Minnesota; Minnesota Head & Neck Pain Clinic, St. Paul, Minnesota
| | - Laura S Stone
- Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Faculty of Dentistry, McGill University, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
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Jin L, Balian G, Li XJ. Animal models for disc degeneration-an update. Histol Histopathol 2017; 33:543-554. [PMID: 28580566 DOI: 10.14670/hh-11-910] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Intervertebral disc degeneration is considered a major cause of back pain that places a heavy burden on society, both because of its effect on the physiology of individuals and its consequences on the world economy. During the past few decades, research findings in the pre-clinical setting have led to a significant increase in the understanding of intervertebral disc degeneration, although many aspects of the disease remain unclear. The goal of this review is to summarize existing animal models for disc degeneration studies and the difficulties that are associated with the use of such models. A firm understanding of the cellular and molecular events that ensue as a result of injuries, as well as environmental factors, could be instrumental in the development of targeted therapies for the treatment of intervertebral disc degeneration.
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Affiliation(s)
- Li Jin
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA, USA
| | - Gary Balian
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA, USA
| | - Xudong Joshua Li
- Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA, USA.
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Evaluation of Histological Changes in Back Muscle Injuries in Rats over Time. Asian Spine J 2017; 11:88-92. [PMID: 28243375 PMCID: PMC5326738 DOI: 10.4184/asj.2017.11.1.88] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 06/20/2016] [Accepted: 06/21/2016] [Indexed: 11/08/2022] Open
Abstract
STUDY DESIGN Animal model study. PURPOSE The purpose of this study was to evaluate the histological variation in the injured muscle and production of calcitonin gene-related peptide in rats over time. OVERVIEW OF LITERATURE Vertebral surgery has been reported to cause atrophy of the back muscles, which may result in pain. However, few reports have described the time series histological variation in the injured muscle and changes in the dominant nerve. METHODS We used 30 male, 8-week-old Sprague-Dawley rats. The right and left sides of the paravertebral muscle were considered as the injured and uninjured sides, respectively. A 115 g weight was dropped from a height of 1 m on the right paravertebral muscle. Hematoxylin and eosin (H&E) staining of the muscle was performed 1-3 weeks after injury for histological evaluation. Fluoro-Gold (FG) was injected into the paravertebral muscle. The L2 dorsal root ganglia on both sides were resected 1, 2, and 3 weeks after injury, and immunohistochemical staining for calcitonin gene-related peptide was performed. RESULTS H&E staining of the paravertebral muscle showed infiltration of inflammatory cells and the presence of granulation tissue in the injured part on the ipsilateral side 1 week after injury. Muscle atrophy occurred 3 weeks after injury, but was repaired via spontaneous replacement of muscle cells/fibers. In contrast, compared with the uninjured side, the percentage of cells double-labeled with FG and calcitonin gene-related peptide in FG-positive cells in the dorsal root ganglia of the injured side was significantly increased at each time point throughout the study period. CONCLUSIONS These results suggest that sensitization of the dominant nerve in the dorsal root ganglia, which may be caused by cicatrix formation, can protract injured muscle pain. This information may be helpful in elucidating the underlying mechanism of persistent pain after back muscle injury.
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Sainoh T, Orita S, Miyagi M, Inoue G, Kamoda H, Ishikawa T, Yamauchi K, Suzuki M, Sakuma Y, Kubota G, Oikawa Y, Inage K, Sato J, Nakata Y, Nakamura J, Aoki Y, Toyone T, Takahashi K, Ohtori S. Single Intradiscal Administration of the Tumor Necrosis Factor-Alpha Inhibitor, Etanercept, for Patients with Discogenic Low Back Pain. PAIN MEDICINE 2016; 17:40-5. [PMID: 26243249 DOI: 10.1111/pme.12892] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVE To examine the analgesic effect of intradiscal administration of a tumor necrosis factor-αα (TNF-α) inhibitor in patients with discogenic low back pain (LBP). DESIGN Prospective, randomized study. SETTING Department of Orthopaedic Surgery, Chiba (Japan) University Hospital. SUBJECTS Seventy-seven patients diagnosed with discogenic LBP. METHODS Discogenic LBP patients were randomly assigned to the etanercept (n = 38; bupivacaine [2 mL] with etanercept [10 mg]) or control (n = 39; bupivacaine [2 mL]) groups. Patients received a single intradiscal injection. Numerical rating scale (NRS) scores for LBP at baseline, 1 day, and 1, 2, 4, and 8 weeks after the injection were recorded. The Oswestry disability index (ODI) scores at baseline and at 4 and 8 weeks after injection were evaluated. Postinjection complications were recorded and evaluated. RESULTS In the etanercept group, the NRS scores were significantly lower than in the control group at every time point after the injection for 8 weeks (P < 0.05). Similarly, 4 weeks after the injection, the ODI score was lower in the etanercept group than in the control group (P < 0.05). However, the ODI scores were not significantly different at 8 weeks. Complications were not observed. CONCLUSIONS Single intradiscal administration of a TNF-α inhibitor can alleviate intractable discogenic LBP for up to 8 weeks. TNF-α may be involved in discogenic pain pathogenesis. This procedure is a novel potential treatment; longer-term effectiveness trials are required in the future.
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50
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Ogura T, Suzuki M, Sakuma Y, Yamauchi K, Orita S, Miyagi M, Ishikawa T, Kamoda H, Oikawa Y, Kanisawa I, Takahashi K, Sakai H, Nagamine T, Fukuda H, Takahashi K, Ohtori S, Tsuchiya A. Differences in levels of inflammatory mediators in meniscal and synovial tissue of patients with meniscal lesions. J Exp Orthop 2016; 3:7. [PMID: 26915007 PMCID: PMC4740471 DOI: 10.1186/s40634-016-0041-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 01/25/2016] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Meniscal injuries are a risk factor for osteoarthritis (OA). While a mechanical pathway between meniscal injury and OA has been described, the biological effects of inflammation on this pathway have yet to be clarified. The aim of our study was to compare levels of specific inflammatory mediators, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nerve growth factor (NGF), in injured and uninjured meniscal tissue and related knee joint synovium. METHODS Tissue samples were obtained from 19 patients, 31.1 ± 13.6 years old, who underwent arthroscopic partial meniscectomy. For analysis, tissue samples were categorized into the following groups: injured meniscal site (IM), non-injured meniscal site (NIM), synovium 'nearest' the lesion (NS), and synovium from the opposite knee compartment, 'farthest' synovium (FS). Levels of inflammatory mediators were determined using enzyme-linked immunosorbent assay and between-group differences (IM and NIM; NS and FS) were evaluated using the Wilcoxon signed-rank test. The association between pre-operative pain score and the level of each inflammatory mediator was evaluated using Spearman's correlation. RESULTS Higher levels of TNF-α and IL-6 were identified in the IM tissue, compared to NIM (p <0.05). IL-6 levels were also higher in the NS compared to the FS (p <0.05). There was no correlation between pre-operative pain score and level of each inflammatory mediator. CONCLUSIONS Our outcomes confirm a local increase in inflammatory mediator levels, in both meniscal and synovial tissue, which could contribute to development of OA. Management of these biological effects of meniscal injury might be warranted.
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Affiliation(s)
- Takahiro Ogura
- Funabashi Orthopaedic Hospital Sports Medicine Center, Funabashi, Chiba, Japan.
| | - Miyako Suzuki
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Yoshihiro Sakuma
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Kazuyo Yamauchi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Sumihisa Orita
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Masayuki Miyagi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Tetsuhiro Ishikawa
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Hiroto Kamoda
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Yasuhiro Oikawa
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Izumi Kanisawa
- Funabashi Orthopaedic Hospital Sports Medicine Center, Funabashi, Chiba, Japan.
| | - Kenji Takahashi
- Funabashi Orthopaedic Hospital Sports Medicine Center, Funabashi, Chiba, Japan.
| | - Hiroki Sakai
- Funabashi Orthopaedic Hospital Sports Medicine Center, Funabashi, Chiba, Japan.
| | - Tomonori Nagamine
- Funabashi Orthopaedic Hospital Sports Medicine Center, Funabashi, Chiba, Japan.
| | - Hideaki Fukuda
- Funabashi Orthopaedic Hospital Sports Medicine Center, Funabashi, Chiba, Japan.
| | - Kazuhisa Takahashi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Seiji Ohtori
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Akihiro Tsuchiya
- Funabashi Orthopaedic Hospital Sports Medicine Center, Funabashi, Chiba, Japan.
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