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Zhao Y, Liu F, Pei Y, Lian F, Lin H. Involvement of the Wnt/β-catenin signalling pathway in heterotopic ossification and ossification-related diseases. J Cell Mol Med 2024; 28:e70113. [PMID: 39320014 PMCID: PMC11423343 DOI: 10.1111/jcmm.70113] [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: 03/13/2024] [Revised: 09/05/2024] [Accepted: 09/13/2024] [Indexed: 09/26/2024] Open
Abstract
Heterotopic ossification (HO) is a pathological condition characterized by the formation of bone within soft tissues. The development of HO is a result of abnormal activation of the bone formation programs, where multiple signalling pathways, including Wnt/β-catenin, BMP and hedgehog signalling, are involved. The Wnt/β-catenin signalling pathway, a conserved pathway essential for various fundamental activities, has been found to play a significant role in pathological bone formation processes. It regulates angiogenesis, chondrocyte hypertrophy and osteoblast differentiation during the development of HO. More importantly, the crosstalk between Wnt signalling and other factors including BMP, Hedgehog signalling, YAP may contribute in a HO-favourable manner. Moreover, several miRNAs may also be involved in HO formation via the regulation of Wnt signalling. This review aims to summarize the role of Wnt/β-catenin signalling in the pathogenesis of HO, its interactions with related molecules, and potential preventive and therapeutic measures targeting Wnt/β-catenin signalling.
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Affiliation(s)
- Yike Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Queen Mary school, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Fangzhou Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Queen Mary school, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yiran Pei
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Queen Mary school, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Fengyu Lian
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
- Queen Mary school, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Hui Lin
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
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Rujeedawa T, Mowforth OD, Davies BM, Yang C, Nouri A, Francis JJ, Aarabi B, Kwon BK, Harrop J, Wilson JR, Martin AR, Rahimi-Movaghar V, Guest JD, Fehlings MG, Kotter MR. Degenerative Thoracic Myelopathy: A Scoping Review of Epidemiology, Genetics, and Pathogenesis. Global Spine J 2024; 14:1664-1677. [PMID: 38146739 PMCID: PMC11394495 DOI: 10.1177/21925682231224768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2023] Open
Abstract
STUDY DESIGN Literature Review. OBJECTIVE Myelopathy affecting the thoracic spinal cord can arise secondary to several aetiologies which have similar presentation and management. Consequently, there are many uncertainties in this area, including optimal terminology and definitions. Recent collaborative cervical spinal research has led to the proposal and subsequent community adoption of the name degenerative cervical myelopathy(DCM), which has facilitated the establishment of internationally-agreed research priorities for DCM. We put forward the case for the introduction of the term degenerative thoracic myelopathy(DTM) and degenerative spinal myelopathy(DSM) as an umbrella term for both DCM and DTM. METHODS Following PRISMA guidelines, a systematic literature search was performed to identify degenerative thoracic myelopathy literature in Embase and MEDLINE. RESULTS Conditions encompassed within DTM include thoracic spondylotic myelopathy, ossification of the posterior longitudinal ligament, ossification of the ligamentum flavum, calcification of ligaments, hypertrophy of ligaments, degenerative disc disease, thoracic osteoarthritis, intervertebral disc herniation, and posterior osteophytosis. The classic presentation includes girdle pain, gait disturbance, leg weakness, sensory disturbance, and bladder or bowel dysfunction, often with associated back pain. Surgical management is typically favoured with post-surgical outcomes dependent on many factors, including the causative pathology, and presence of additional stenosis. CONCLUSION The clinical entities encompassed by the term DTM are interrelated, can manifest concurrently, and present similarly. Building on the consensus adoption of DCM in the cervical spine and the recent proposal of degenerative cervical radiculopathy(DCR), extending this common nomenclature framework to the terms degenerative spinal myelopathy and degenerative thoracic myelopathy will help improve recognition and communication.
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Affiliation(s)
- Tanzil Rujeedawa
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Oliver D. Mowforth
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Benjamin M. Davies
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Cylene Yang
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Aria Nouri
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Department of Clinical Neurosciences, Geneva University Hospitals, Geneva, Switzerland
| | - Jibin J. Francis
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | | | - Brian K. Kwon
- Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
| | - James Harrop
- Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | | | - Allan R. Martin
- Department of Neurosurgery, University of California Davis, Sacramento, CA, USA
| | - Vafa Rahimi-Movaghar
- Department of Neurosurgery, Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - James D. Guest
- Department of Neurosurgery and The Miami Project to Cure Paralysis, The Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Michael G. Fehlings
- Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Mark R. Kotter
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
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Saito H, Yayama T, Mori K, Kumagai K, Fujikawa H, Chosei Y, Imai S. Increased Cellular Expression of Interleukin-6 in Patients With Ossification of the Posterior Longitudinal Ligament. Spine (Phila Pa 1976) 2023; 48:E78-E86. [PMID: 36729990 DOI: 10.1097/brs.0000000000004557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/24/2022] [Indexed: 02/03/2023]
Abstract
STUDY DESIGN We performed histologic, immunohistochemical, immunoblot examination and suspension array analyses of cytokine expression in cultured cells derived from human cervical ossification of the posterior longitudinal ligament (OPLL). OBJECTIVE To determine the roles of interleukin-6 (IL-6) during the maturation of osteoblasts and chondrocytes associated with the development of OPLL. SUMMARY OF BACKGROUND DATA Ectopic OPLL affects ~3% of the general population, with a higher incidence in Asian ethnic groups. Alterations in cytokine profiles may influence osteoblast differentiation, but the mechanisms and signaling pathways associated with the ossification process remain unclear. METHODS Samples were collected from 14 patients with OPLL who had undergone spinal surgery and seven with cervical spondylotic myelopathy without OPLL. Tissue sections were used for histologic and immunohistochemical studies, and primary cells from ligamentum samples were used for cytokine array and immunoblotting. A suspension array was used to measure the concentrations of 27 inflammatory cytokines or growth factors. RESULTS Suspension array and immunoblot analyses revealed significantly elevated levels of IL-6 in OPLL patients. Alterations in IL-6 concentrations were found to alter the expression of the genes Sox9 , Runx2 , and SIRT1 . In addition, immunohistochemical analysis revealed that these factors are present in mesenchymal cells within the degenerative portion of the ligament matrix that is adjacent to the ossification front. CONCLUSIONS IL-6 plays a profound role in the osteoblast differentiation process along with the induction of chondrocyte hypertrophy and cell apoptosis in the early stages of ossification in OPLL. These changes in cytokine profiles are essential factors for regulation of the ectopic ossified plaque in OPLL.
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Affiliation(s)
- Hideki Saito
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Shiga, Japan
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Zhang H, Zhang Q, Yuan Z, Dong J. Non-coding RNAs in ossification of the posterior longitudinal ligament. Front Genet 2022; 13:1069575. [PMID: 36506306 PMCID: PMC9729789 DOI: 10.3389/fgene.2022.1069575] [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] [Received: 10/14/2022] [Accepted: 11/14/2022] [Indexed: 11/25/2022] Open
Abstract
Ossification of the posterior longitudinal ligament (OPLL) is a kind of disease that involves a variety of factors leading to ectopic bone deposition of the spinal ligament. Although the detailed mechanism is not clear, genetic factors play important roles in the development of this disease. Noncoding RNA (ncRNA) refers to an RNA molecule that is not translated into a protein but participates in the regulation of gene expression. Functionally important types of ncRNA associated with OPLL include long noncoding RNA, microRNA, and circular RNA. We listed the differentially expressed ncRNAs in OPLL patients and normal controls to find the ncRNAs most relevant to the pathogenesis of the disease. The potential regulatory networks of ncRNA in OPLL cells were analyzed based on their most abundant signal transduction pathway data. The analysis of the highly connected ncRNAs in the regulatory network suggests that they play an important role in OPLL. These findings provide new directions for the study of OPLL pathogenesis and therapeutic targets. In this paper, we reviewed and analyzed the literature on ncRNAs in OPLL published in recent years, aiming to help doctors better understand and treat this disease.
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Luo H, Xie B, Xu J, Zhu Y, Sun J, Shen Y, Song X. Differential Expression of Serum Exosomal Hsa-miR-487b-3p in Progressive Vitiligo Before and After Systemic Corticosteroid Treatment. Clin Cosmet Investig Dermatol 2022; 15:1377-1386. [PMID: 35880009 PMCID: PMC9307869 DOI: 10.2147/ccid.s372112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 07/12/2022] [Indexed: 11/23/2022]
Abstract
Background Vitiligo is an acquired skin depigmentation disease. It can be misdiagnosed at an early stage and tend to relapse. Serum markers are essential to monitoring the progression of vitiligo. Exosomal miRNAs act as the communication mediator between melanocytes and immune cells. Our study aimed to use serum exosomal miRNAs as a reference for evaluating vitiligo progression. Methods The miRNAs were extracted from the serum exosomes of ten progressive vitiligo patients (before and after treatment) and ten healthy individuals. We profiled miRNAs expression by RNA sequencing and screened out potential miRNAs and plotted their receiver operating characteristic (ROC) curves to explore their sensitivity and specificity as prognostic biomarkers in vitiligo progression. We examined the correlation between miRNA expression and the lesion area. Different databases were used to predict gene targets of miRNAs, which were analyzed by gene ontology and Kyoto encyclopedia of genes and genomes (KEGG). Results Our results showed that 141 miRNAs were differentially expressed in serum exosomes of progressive vitiligo patients, and 365 miRNAs were differentially expressed in these patients after treatment compared to healthy individuals. The expression of hsa-miR-487b-3p was significantly lower in these patients compared to healthy individuals. Still, there was no difference in its levels in patients after corticosteroid treatment compared to healthy controls. ROC curve analysis (area under curve = 0.840) indicated that hsa-miR-487b-3p could serve as a biomarker for the prognosis of vitiligo progression. Its expression positively correlated with the lesion area. A total of 41 target genes of hsa-miR-487b-3p were predicted via different databases. KEGG pathways were enriched in phenylalanine metabolism, glycan degradation, and protein export. Conclusion Serum exosomal hsa-miR-487b-3p can be a biomarker to detect vitiligo progression. The predicted target genes of hsa-miR-487b-3p were enriched in catabolism. Thus, its in progressive vitiligo may accelerate catabolism in melanocytes and cause its impairment.
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Affiliation(s)
- Haixin Luo
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Bo Xie
- Department of Dermatology, Hangzhou Third People’s Hospital; Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Jinhui Xu
- Department of Dermatology, Hangzhou Third People’s Hospital; Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Yuqi Zhu
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Jiayi Sun
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Yuqing Shen
- Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Xiuzu Song
- Department of Dermatology, Hangzhou Third People’s Hospital; Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
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Ossified Ligamentum Flavum: Epidemiology, Treatment, and Outcomes. J Am Acad Orthop Surg 2022; 30:e842-e851. [PMID: 35298441 DOI: 10.5435/jaaos-d-21-01253] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/13/2022] [Indexed: 02/01/2023] Open
Abstract
Ossification of the ligamentum flavum (OLF) is an uncommon but potentially serious spinal condition which can cause progressive compression of the spinal canal with associated devastating neurologic compromise. Although debate exists regarding the exact etiology of OLF, overexpression of genes and transcription factors centered around the Notch and Wnt signaling pathways because of increased mechanical stress seems to be related. There are many clinical and radiographic presentations of OLF; however, progressive myelopathy is the most commonly encountered. Radiographic analysis may reveal isolated OLF or OLF combined with ossification of other areas of the spine, such as disk, posterior longitudinal ligament, and dura. When surgery is necessary for OLF, several surgical strategies exist including open laminectomy with excision, endoscopic decompression, Bridge Crane resection, en block resection, and combined anterior and posterior approaches. Resection may be complicated by dural adhesion or dural ossification, and postoperative neurologic deficits are not uncommon.
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Yang X, Sun C, Meng X, Chen G, Fan T, Zhang C, Chen Z. LGR5 regulates osteogenic differentiation of human thoracic ligamentum flavum cells by Wnt signalling pathway. J Cell Mol Med 2022; 26:3862-3872. [PMID: 35668632 PMCID: PMC9279595 DOI: 10.1111/jcmm.17420] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 06/02/2021] [Accepted: 06/19/2021] [Indexed: 01/13/2023] Open
Abstract
Thoracic ossification of the ligamentum flavum (TOLF) is ectopic ossification of the spinal ligaments. Histologically, the development of TOLF can be described as the process of endochondral ossification. However, the underlying aetiology has not been completely clarified. In this investigation, the gene expression profile associated with leucine‐rich repeat‐containing G‐protein‐coupled receptors (LGR) and Wnt signalling pathway in the thoracic ligamentum flavum cells (TLFCs) of different ossification stages was analysed via RNA sequencing. We further confirmed the significant differences in the related gene expression profile by Gene Ontology (GO) enrichment analysis. LGR5 was first identified in primary human TLFCs during osteogenic differentiation. To evaluate the effect of LGR5 on osteogenic differentiation, LGR5 has been knocked down and overexpressed in human TLFCs. We observed that the knockdown of LGR5 inhibited the activity of Wnt signalling and attenuated the potential osteogenic differentiation of TLFCs, while overexpression of LGR5 activated the Wnt signalling pathway and increased osteogenic differentiation. Our results provide important evidence for the potent positive mediatory effects of LGR5 on osteogenesis by enhancing the Wnt signalling pathway in TOLF.
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Affiliation(s)
- Xiaoxi Yang
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Chuiguo Sun
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Xiangyu Meng
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Guanghui Chen
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Tianqi Fan
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Chi Zhang
- Central Laboratory, Peking University International Hospital, Beijing, China
| | - Zhongqiang Chen
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
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Yayama T, Mori K, Saito H, Fujikawa H, Kitagawa M, Okumura N, Nishizawa K, Nakamura A, Kumagai K, Mimura T, Imai S. Cytokine Profile From the Ligamentum Flavum in Patients with Ossification of the Posterior Longitudinal Ligament in the Cervical Spine. Spine (Phila Pa 1976) 2022; 47:277-285. [PMID: 34919077 DOI: 10.1097/brs.0000000000004302] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Histological, immunohistochemical, and suspension array analyses of cytokine expression in human cervical ossification of the posterior longitudinal ligament (OPLL). OBJECTIVES The aim of this study was to determine whether changes in the cytokine profile reflect the maturation of chondrocytes and osteoblasts are associated with OPLL development. SUMMARY OF BACKGROUND DATA OPLL progresses gradually over a prolonged period and may lead to serious spinal cord complications. However, treatment methods only include conservative therapy for neurological symptoms or surgical decompression, whereas preventive therapy for OPLL remains nonexistent. METHODS Ligamentous samples were harvested from 24 patients with OPLL who underwent spinal surgery, and five control samples from cervical spondylotic myelo/radiculopathy patients without OPLL. Tissue sections were used for immunohistochemical studies and primary cells were cultured from the ligamentous samples for cytokine profiling. Using a suspension array system, concentrations of 27 inflammatory cytokines or growth factors were measured to generate the cytokine profiles. RESULTS Suspension array and immunoblot analysis revealed significant increments in the levels of interleukin (IL)-6, IL-1α, basic fibroblast growth factor, and RANTES in patients with OPLL. Immunohistochemical analysis further revealed that these factors were present in mesenchymal cells within the degenerative portion of the ligamentous matrix. CONCLUSION Our findings suggest that specific changes in the cytokine profile during ossification promote osteoblast differentiation, thereby providing new insights into OPLL pathogenesis. Moreover, this work supports the development of a new therapeutic method for preventing OPLL progression by regulating the cytokine profiles.Level of Evidence: 3.
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Affiliation(s)
- Takafumi Yayama
- Department of Orthopedic Surgery, Shiga University of Medical Science, Setatsukinowa, Otsu, Shiga, Japan
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Zhang B, Chen G, Chen X, Yang X, Fan T, Sun C, Chen Z. Integrating Bioinformatic Strategies with Real-World Data to Infer Distinctive Immunocyte Infiltration Landscape and Immunologically Relevant Transcriptome Fingerprints in Ossification of Ligamentum Flavum. J Inflamm Res 2021; 14:3665-3685. [PMID: 34354364 PMCID: PMC8331123 DOI: 10.2147/jir.s318009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/08/2021] [Indexed: 12/31/2022] Open
Abstract
Purpose Ossification of the ligamentum flavum (OLF) is a multifactorial disease characterized by an insidious and debilitating process of abnormal bone formation in ligamentum tissues. However, its definite pathogenesis has not been fully elucidated. Potential links between the immune system and various forms of heterotopic ossification have been discussed for many years, whereas no research investigated the immune effects on the initiation and development of OLF. Therefore, we attempt to shed light on this issue. Methods A series of bioinformatic algorithms were integrated to evaluate the immune score and the immunocyte infiltration patterns between OLF and normal samples, screen OLF-related and immune-related differentially expressed genes (OIDEGs), and analyze their biological functions. Correlation analysis inferred OIDEGs-related differentially expressed lncRNAs (OIDELs) and infiltrating immune cells (OIICs) to construct an immunoregulatory network. Results Differential immune score and immune cell infiltration were determined between two groups, and 10 OIDEGs with diverse biological function annotations were identified and verified. A lncRNA-gene-immunocyte regulatory network further revealed 10 OIDEGs, 41 OIDELs and 7 OIICs that were highly correlated. Among them, CD1E and STAT3 were predicted as hub genes whether at the expression level or interaction level. cDCs emerged as having the most prominent differences and the highest degree of connectivity. FO393414.3, AC096734.1, LINC01137 and DLX6-AS1 with the greatest number of OIDEGs were thought to be more likely to participate in immunoregulation of OLF. Conclusion This is the first research to preliminarily elucidate OLF-related immunocyte infiltration landscape and immune-associated transcriptome signatures based on bioinformatic strategies and real-world data, which may provide compelling insights into the pathogenesis and therapeutic targets of OLF.
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Affiliation(s)
- Baoliang Zhang
- Peking University Third Hospital, Department of Orthopaedics, Beijing, 100191, People's Republic of China.,Engineering Research Center of Bone and Joint Precision Medicine, Beijing, 100191, People's Republic of China.,Beijing Key Laboratory of Spinal Disease Research, Beijing, 100191, People's Republic of China
| | - Guanghui Chen
- Peking University Third Hospital, Department of Orthopaedics, Beijing, 100191, People's Republic of China.,Engineering Research Center of Bone and Joint Precision Medicine, Beijing, 100191, People's Republic of China.,Beijing Key Laboratory of Spinal Disease Research, Beijing, 100191, People's Republic of China
| | - Xi Chen
- Peking University Third Hospital, Department of Orthopaedics, Beijing, 100191, People's Republic of China.,Engineering Research Center of Bone and Joint Precision Medicine, Beijing, 100191, People's Republic of China.,Beijing Key Laboratory of Spinal Disease Research, Beijing, 100191, People's Republic of China
| | - Xiaoxi Yang
- Peking University Third Hospital, Department of Orthopaedics, Beijing, 100191, People's Republic of China.,Engineering Research Center of Bone and Joint Precision Medicine, Beijing, 100191, People's Republic of China.,Beijing Key Laboratory of Spinal Disease Research, Beijing, 100191, People's Republic of China
| | - Tianqi Fan
- Peking University Third Hospital, Department of Orthopaedics, Beijing, 100191, People's Republic of China.,Engineering Research Center of Bone and Joint Precision Medicine, Beijing, 100191, People's Republic of China.,Beijing Key Laboratory of Spinal Disease Research, Beijing, 100191, People's Republic of China
| | - Chuiguo Sun
- Peking University Third Hospital, Department of Orthopaedics, Beijing, 100191, People's Republic of China.,Engineering Research Center of Bone and Joint Precision Medicine, Beijing, 100191, People's Republic of China.,Beijing Key Laboratory of Spinal Disease Research, Beijing, 100191, People's Republic of China
| | - Zhongqiang Chen
- Peking University Third Hospital, Department of Orthopaedics, Beijing, 100191, People's Republic of China.,Engineering Research Center of Bone and Joint Precision Medicine, Beijing, 100191, People's Republic of China.,Beijing Key Laboratory of Spinal Disease Research, Beijing, 100191, People's Republic of China
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Zhang B, Chen G, Yang X, Fan T, Chen X, Chen Z. Dysregulation of MicroRNAs in Hypertrophy and Ossification of Ligamentum Flavum: New Advances, Challenges, and Potential Directions. Front Genet 2021; 12:641575. [PMID: 33912216 PMCID: PMC8075056 DOI: 10.3389/fgene.2021.641575] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Pathological changes in the ligamentum flavum (LF) can be defined as a process of chronic progressive aberrations in the nature and structure of ligamentous tissues characterized by increased thickness, reduced elasticity, local calcification, or aggravated ossification, which may cause severe myelopathy, radiculopathy, or both. Hypertrophy of ligamentum flavum (HLF) and ossification of ligamentum flavum (OLF) are clinically common entities. Though accumulated evidence has indicated both genetic and environmental factors could contribute to the initiation and progression of HLF/OLF, the definite pathogenesis remains fully unclear. MicroRNAs (miRNAs), one of the important epigenetic modifications, are short single-stranded RNA molecules that regulate protein-coding gene expression at posttranscriptional level, which can disclose the mechanism underlying diseases, identify valuable biomarkers, and explore potential therapeutic targets. Considering that miRNAs play a central role in regulating gene expression, we summarized current studies from the point of view of miRNA-related molecular regulation networks in HLF/OLF. Exploratory studies revealed a variety of miRNA expression profiles and identified a battery of upregulated and downregulated miRNAs in OLF/HLF patients through microarray datasets or transcriptome sequencing. Experimental studies validated the roles of specific miRNAs (e.g., miR-132-3p, miR-199b-5p in OLF, miR-155, and miR-21 in HLF) in regulating fibrosis or osteogenesis differentiation of LF cells and related target genes or molecular signaling pathways. Finally, we discussed the perspectives and challenges of miRNA-based molecular mechanism, diagnostic biomarkers, and therapeutic targets of HLF/OLF.
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Affiliation(s)
- Baoliang Zhang
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
| | - Guanghui Chen
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
| | - Xiaoxi Yang
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
| | - Tianqi Fan
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
| | - Xi Chen
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
| | - Zhongqiang Chen
- Orthopaedic Department, Peking University Third Hospital, Beijing, China
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Non-coding RNAs in ossification of spinal ligament. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2021; 30:801-808. [PMID: 33387048 DOI: 10.1007/s00586-020-06687-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 11/25/2020] [Accepted: 11/28/2020] [Indexed: 12/16/2022]
Abstract
PURPOSE Ossification of the spinal ligament (OSL) is a disease characterized by progressive ectopic ossification or calcification in the tissues of spinal ligament. The molecular pathogenesis of OSL has not been clearly elucidated. Recently, ncRNAs was found to functionally participate in OSL development. This review summarized current knowledge regarding the deregulation and function of ncRNAs in OSL METHODS: Relevant studies on deregulation and function of ncRNAs in OSL were retrieved from the PubMed databases. Then, studies were manually selected for inclusion based on predefined criteria. RESULT 14 studies were reviewed, with 4 studies about high throughput sequencing and microarray of ncRNAs, 8 studies relevant to the function of ncRNAs and 2 studies regarding the ncRNAs as the biomarker of OSL. CONCLUSION ncRNA play a vital role in the ossification of spinal ligament fibrocyte, including cell osteogenesis and inflammation. ncRNAs also have potential clinical utilities as therapeutic targets, risk predication and early detection in the management of OSL. LEVEL OF EVIDENCE I Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.
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Wang HF, Kuang MJ, Han SJ, Wang AB, Qiu J, Wang F, Tan BY, Wang DC. BMP2 Modified by the m 6A Demethylation Enzyme ALKBH5 in the Ossification of the Ligamentum Flavum Through the AKT Signaling Pathway. Calcif Tissue Int 2020; 106:486-493. [PMID: 31897529 DOI: 10.1007/s00223-019-00654-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 12/23/2019] [Indexed: 02/06/2023]
Abstract
Ossification of the ligamentum flavum (OLF) is characterized by a process of ectopic bone formation in the ligamentum flavum. The definitive pathophysiology of OLF still remains unclear, but the epigenetic m6A modification plays an important role in OLF. In addition, no studies have reported the function of ALKBH5 in OLF development. In this study, we investigated the function of the m6A demethylation enzyme ALKBH5 in OLF. To evaluate the function of ALKBH5, OLF tissues and normal ligamentum flavum tissues were collected. In vitro methods, including HE, IHC and western blotting assays, were used to evaluate the association of ALKBH5 with OLF. In addition, we verified the effects of ALKBH5 on osteogenesis using alizarin red and ALP staining. MeRIP q-PCR was performed to investigate the methylation level of BMP2. Moreover, the mechanism of ALKBH5-mediated regulation of the ossification of the ligamentum flavum cells through the AKT signaling pathway was also verified. The present study showed that the expression of ALKBH5 increased in OLF tissues. The overexpression of ALKBH5 increased the expression of osteogenic genes and promoted the ossification of ligamentum flavum cells. Furthermore, BMP2 was significantly enriched in the ligamentum flavum cells of the anti-m6A group compared with those of the IgG group. The overexpression of ALKBH5 led to the activation of p-AKT, and BMP2 was regulated by ALKBH5 through the AKT signaling pathway. ALKBH5 promoted the osteogenesis of the ligamentum flavum cells through BMP2 demethylation and AKT activation. ALKBH5 was shown to be an important demethylation enzyme in OLF development.
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Affiliation(s)
- Hai-Feng Wang
- Department of Orthopedics, The Provincial Hospital Affiliated To Shandong University, Shandong, 250014, China
| | - Ming-Jie Kuang
- Department of Orthopedics, The Provincial Hospital Affiliated To Shandong University, Shandong, 250014, China
| | - Shi-Jie Han
- Department of Orthopedics, The Provincial Hospital Affiliated To Shandong University, Shandong, 250014, China
| | - An-Bang Wang
- Department of Orthopedics, The Provincial Hospital Affiliated To Shandong University, Shandong, 250014, China
| | - Jie Qiu
- Department of Orthopedics, The Provincial Hospital Affiliated To Shandong University, Shandong, 250014, China
| | - Feng Wang
- Department of Orthopedics, The Provincial Hospital Affiliated To Shandong University, Shandong, 250014, China
| | - Bing-Yi Tan
- Department of Orthopedics, The Provincial Hospital Affiliated To Shandong University, Shandong, 250014, China
| | - Da-Chuan Wang
- Department of Orthopedics, The Provincial Hospital Affiliated To Shandong University, Shandong, 250014, China.
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Perna F, Geraci G, Mazzotti A, Stefanini N, Panciera A, Faldini C. Acute Presentation of Lumbar Spinal Stenosis Due to Ossified Ligamentum Flavum: The Possible Role of Spondylolisthesis: A Case Report. JBJS Case Connect 2019; 9:e0039. [PMID: 31211745 DOI: 10.2106/jbjs.cc.18.00039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
CASE A 64-year-old woman with a history of low back pain, presented with acute gait impairment and lower limbs numbness without any history of trauma. Imaging studies revealed ossification of the ligamentum flavum (OLF) at L4-L5 and concomitant spondylolisthesis. Decompression surgery with en-bloc removal including the laminae, the ossified ligamentum flavum, and the medial facet and posterior stabilization was performed resulting in complete immediate recovery. CONCLUSIONS This report is the first to describe a case of an acute nontraumatic presentation of OLF associated with spondylolisthesis. OLF pathogenesis in still unknown, although several factors have been considered. According to the literature, operative treatment has demonstrated to be effective.
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14
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Kong D, Zhao Q, Liu W, Wang F. Identification of crucial miRNAs and lncRNAs for ossification of ligamentum flavum. Mol Med Rep 2019; 20:1683-1699. [PMID: 31257472 PMCID: PMC6625436 DOI: 10.3892/mmr.2019.10377] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 04/10/2019] [Indexed: 12/20/2022] Open
Abstract
The present study aimed to screen crucial micro (mi)RNAs and long non-coding (lnc)RNAs involved in the development of ossification of ligamentum flavum (OLF) based on the miRNA-mRNA and lncRNA-miRNA-mRNA competing endogenous (ce)RNA regulatory network analyses, which are rarely reported. The differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs) and differentially expressed miRNAs (DEMs) between 4 OLF and 4 healthy controls were identified using two microarray datasets GSE106253 and GSE106256 collected from the Gene Expression Omnibus database. A protein-protein interaction (PPI) network was constructed, followed by calculation of topological characteristics and sub-module analysis in order to obtain hub DEGs. The miRNA-mRNA and lncRNA-miRNA networks that were established based on their interaction pairs, obtained from miRwalk and starBase databases, respectively, were integrated to form the ceRNA network. The underlying functions of mRNAs were predicted using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The present study screened 828 DEGs, 119 DELs and 81 DEMs between OLF and controls. PPI network and module analyses identified interleukin (IL)10, adenylate cyclase (ADCY)5, suppressor of cytokine signaling (SOCS)3, G protein subunit gamma (GNG) 4, collagen type II α 1 chain (COL2A1) and collagen type XIII α 1 chain (COL13A1) as hub genes. The miRNA-mRNA network analysis demonstrated IL10 could be regulated by miR-210-3p, while COL13A1 and COL2A1 could be modulated by miR-329-3p and miR-222-5p, respectively. lncRNA-miRNA-mRNA ceRNA network analysis identified that small nucleolar RNA host gene 16-hsa-miR-196a-5p-SOCS3, ankyrin repeat and SOCS box containing 16-AS1-hsa-miR-379-5p-GNG4, nuclear enriched abundant transcript 1-has-miR-181b-5p-ADCY5, rhophilin 1-AS1-hsa-miR-299-3p-WNT7B interaction axes may be crucial. DAVID analysis predicted IL10, ADCY5, GNG4 and SOCS3 were involved in ‘adaptive immune response’, ‘Chemokine signaling pathway’ and ‘regulation of apoptosis’ processes, while COL2A1, COL13A1 and WNT7B may be ossification related. In conclusion, the identification of these crucial miRNAs and lncRNAs may be conducive for explaining the pathogenesis of OLF and provide certain natural, endogenous and nontoxic drug targets for the treatment of OLF.
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Affiliation(s)
- Daliang Kong
- Department of Orthopedics, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Qiheng Zhao
- Department of Orthopedics, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Wenping Liu
- Department of Neurology, Second Hospital of Jilin University, Changchun, Jilin 130031, P.R. China
| | - Fei Wang
- Department of Orthopedics, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
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15
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Yang X, Chen Z, Meng X, Sun C, Li M, Shu L, Fan D, Fan T, Huang AY, Zhang C. Angiopoietin-2 promotes osteogenic differentiation of thoracic ligamentum flavum cells via modulating the Notch signaling pathway. PLoS One 2018; 13:e0209300. [PMID: 30557327 PMCID: PMC6296551 DOI: 10.1371/journal.pone.0209300] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 12/03/2018] [Indexed: 12/16/2022] Open
Abstract
Thoracic ossification of the ligamentum flavum (TOLF) is heterotopic ossification of spinal ligaments, which may cause serious thoracic spinal canal stenosis and myelopathy. However, the underlying etiology remains inadequately understood. In this study, the ossification patterns of TOLF were analyzed by micro-computer tomography (micro-CT). The expression profile of genes associated with angiogenesis was analyzed in thoracic ligamentum flavum cells at sites of different patterns of ossification using RNA sequencing. Significant differences in the expression profile of several genes were identified from Gene Ontology (GO) analysis. Angiopoietin-2 (ANGPT2) was significantly up-regulated in primary thoracic ligamentum flavum cells during osteogenic differentiation. To address the effect of ANGPT2 on Notch signaling and osteogenesis, ANGPT2 stimulation increased the expression of Notch2 and osteogenic markers of primary thoracic ligamentum flavum cells of immature ossification, while inhibition of ANGPT2 exhibited opposite effect on Notch pathway and osteogenesis of cells of mature ossification. These findings provide the first evidence for positive regulation of ANGPT2 on osteogenic differentiation in human thoracic ligamentum flavum cells via modulating the Notch signaling pathway.
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Affiliation(s)
- Xiaoxi Yang
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Zhongqiang Chen
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Xiangyu Meng
- Central Laboratory, Peking University International Hospital, Beijing, China
| | - Chuiguo Sun
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Mengtao Li
- Central Laboratory, Peking University International Hospital, Beijing, China
| | - Li Shu
- Central Laboratory, Peking University International Hospital, Beijing, China
| | - Dongwei Fan
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Tianqi Fan
- Department of Orthopedics, Peking University Third Hospital, Beijing, China
| | - Ann Y Huang
- Daobio, Inc. Dallas, Texas, United States of America
| | - Chi Zhang
- Central Laboratory, Peking University International Hospital, Beijing, China
- Department of Orthopedics, Peking University International Hospital, Beijing, China
- Bone Research Laboratory, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
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