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1
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Wu J, Wu P, Wang S, Guan Y, Wang J. Revealing the Landscape Crosstalk Between Reproductive System and Organs Aging. FASEB J 2025; 39:e70572. [PMID: 40289595 DOI: 10.1096/fj.202403410r] [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: 12/29/2024] [Revised: 03/30/2025] [Accepted: 04/16/2025] [Indexed: 04/30/2025]
Abstract
The reproductive system is a vital component of the human body. In modern society, due to various socio-economic reasons, an increasing number of couples are choosing to postpone childbearing. Research into the impact of aging on the reproductive system is becoming increasingly important. As people age, there is a decline in the reproductive system across various levels, from the testes in males to spermatogonia cells, and from the ovaries in females to oocytes. The aging of the reproductive system not only affects the system itself but also has implications for other organs and systems in the body. Conversely, the aging of other organs and systems can also damage the reproductive system. This review organizes the changes that occur within the reproductive system as a result of aging and focuses on the interactions between the reproductive system and other systems. Additionally, this review summarizes current therapies aimed at delaying aging, which may provide insights for future interventions targeting the aging of the reproductive system and other systems.
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Affiliation(s)
- Jiahong Wu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, P.R. China
| | - Peng Wu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, P.R. China
| | - Sicheng Wang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, P.R. China
| | - Yupeng Guan
- School of Medicine, Sun Yat-sen University, Shenzhen, P.R. China
| | - Jiancheng Wang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, P.R. China
- School of Medicine, Sun Yat-sen University, Shenzhen, P.R. China
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Dabeer S, Tripathi AK, Weiss D, Vikulina T, Ofotokun I, Weitzmann MN. Combined Sequential Antiretroviral Therapy-Induced Immune Reconstitution Bone Loss and Estrogen Deficiency Bone Loss Are Cumulative in Mice Models. J Infect Dis 2025; 231:967-980. [PMID: 39726127 PMCID: PMC11998558 DOI: 10.1093/infdis/jiae643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 12/13/2024] [Accepted: 12/24/2024] [Indexed: 12/28/2024] Open
Abstract
BACKGROUND Antiretroviral therapy causes osteoporosis and bone fractures, increasing morbidity and mortality in people with HIV (PWH). Antiretroviral therapy induces immune reconstitution bone loss (IRBL), an inflammatory reaction associated with immune system reactivation. Women represent >50% of PWH, and many are now undergoing menopause, a major cause of postmenopausal osteoporosis that also increases fracture risk. However, the interactions between IRBL and postmenopausal bone loss are poorly understood and were investigated in this study. METHODS We used a mouse model of IRBL, which was applied simultaneously or sequentially with surgical ovariectomy (Ovx) as a mouse model of postmenopausal osteoporosis. Cortical and trabecular bone in vertebrae and femurs was assessed with micro-computed tomography, and bone turnover was quantified by serum markers of bone resorption and formation via enzyme-linked immunosorbent assay. T-cell production of osteoclastogenic cytokines was analyzed by flow cytometry. RESULTS Although simultaneous Ovx and IRBL did not have additive effects, sequential Ovx and IRBL caused cumulative bone loss. Vertebral bone loss from combined Ovx and IRBL (Δ = -42.6 vs control, P < .01) was blunted by the anti-inflammatory agent abatacept (Δ = -13.9 vs control, not significant) and the probiotic Lactobacillus rhamnosus GG (Δ = -8.6 vs control, not significant). Both treatments reduced bone resorption, stimulated formation, and suppressed CD4+ T-cell production of the osteoclastogenic cytokines TNF-α and IL-17A. CONCLUSIONS Sequential IRBL and postmenopausal bone loss appear to be cumulative. If validated in humans, early screening and prophylaxis could reduce fracture risk in postmenopausal women with HIV. Probiotic therapy may provide a beneficial alternative to pharmacotherapy.
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Affiliation(s)
- Sadaf Dabeer
- Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine
- Research Service Line, Joseph Maxwell Cleland Atlanta VA Health Care System
| | - Ashish Kumar Tripathi
- Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine
| | - Daiana Weiss
- Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine
| | - Tatyana Vikulina
- Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine
- Research Service Line, Joseph Maxwell Cleland Atlanta VA Health Care System
| | - Ighovwerha Ofotokun
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine
- Infectious Disease Program, Grady Healthcare System, Atlanta, Georgia
| | - M Neale Weitzmann
- Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine
- Research Service Line, Joseph Maxwell Cleland Atlanta VA Health Care System
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Kverka M, Stepan JJ. Associations Among Estrogens, the Gut Microbiome and Osteoporosis. Curr Osteoporos Rep 2024; 23:2. [PMID: 39585466 PMCID: PMC11588883 DOI: 10.1007/s11914-024-00896-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/25/2024] [Indexed: 11/26/2024]
Abstract
PURPOSE OF THE REVIEW The purpose of this Review was to summarize the evidence on the associations among estrogen status, cellular senescence, the gut microbiome and osteoporosis. RECENT FINDINGS Indicate that osteoporosis is a global public health problem that impacts individuals and society. In postmenopausal women, a decrease in estrogen levels is associated with a decrease in gut microbial diversity and richness, as well as increased permeability of the gut barrier, which allows for low-grade inflammation. The direct effects of estrogen status on the association between bone and the gut microbiome were observed in untreated and treated ovariectomized women. In addition to the direct effects of estrogens on bone remodeling, estrogen therapy could reduce the risk of postmenopausal osteoporosis by preventing increased gut epithelial permeability, bacterial translocation and inflammaging. However, in studies comparing the gut microbiota of older women, there were no changes at the phylum level, suggesting that age-related comorbidities may have a greater impact on changes in the gut microbiota than menopausal status does. Estrogens modify bone health not only by directly influencing bone remodeling, but also indirectly by influencing the gut microbiota, gut barrier function and the resulting changes in immune system reactivity.
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Affiliation(s)
- Miloslav Kverka
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology, Czech Academy of Sciences, Prague, Czechia
| | - Jan J Stepan
- Institute of Rheumatology, Prague, Czechia.
- Department of Rheumatology, First Faculty of Medicine, Charles University, Kateřinská 32, Praha 2, 121 08, Czech Republic.
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Long L, Luo H, Wang Y, Gu J, Xiong J, Tang X, Lv H, Zhou F, Cao K, Lin S. Kurarinone, a flavonoid from Radix Sophorae Flavescentis, inhibits RANKL-induced osteoclastogenesis in mouse bone marrow-derived monocyte/macrophages. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:7071-7087. [PMID: 38643449 DOI: 10.1007/s00210-024-03100-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/11/2024] [Indexed: 04/22/2024]
Abstract
Inflammation-induced osteoclast proliferation is a crucial contributor to impaired bone metabolism. Kurarinone (KR), a flavonoid extracted from the Radix Sophorae Flavescentis, exhibits notable anti-inflammatory properties. Nevertheless, the precise influence of KR on osteoclast formation remains unclear. This study's objective was to assess the impact of KR on osteoclast activity in vitro and unravel its underlying mechanism. Initially, a target network for KR-osteoclastogenesis-osteoporosis was constructed using network pharmacology. Subsequently, the intersecting targets were identified through the Venny platform and a PPI network was created using Cytoscape 3.9.1. Key targets within the network were identified employing topological algorithms. GO enrichment and KEGG pathway analysis were then performed on these targets to explore their specific functions and pathways. Additionally, molecular docking of potential core targets of KR was conducted, and the results were validated through cell experiments. A total of 83 target genes overlapped between KR and osteoclastogenesis-osteoporosis targets. Enrichment analysis revealed their role in inflammatory response, protein tyrosine kinase activity, osteoclast differentiation, and MAPK and NF-κB signaling pathways. PPI analysis and molecular docking demonstrate that key targets MAPK14 and MAPK8 exhibit more stable binding with KR compared to other proteins. In vitro experiments demonstrate that KR effectively inhibits osteoclast differentiation and bone resorption without cellular toxicity. It suppresses key osteoclast genes (NFATc1, c-Fos, TRAP, MMP9, Ctsk, Atp6v2), hinders IκB-α degradation, and inhibits ERK and JNK phosphorylation, while not affecting p38 phosphorylation. The results indicate that KR may inhibit osteoclast maturation and bone resorption by blocking NF-κB and MAPK signaling pathways, suggesting its potential as a natural therapeutic agent for osteoporosis.
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Affiliation(s)
- Ling Long
- Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, 332000, Jiangxi, China
| | - Hao Luo
- Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, 332000, Jiangxi, China
| | - Yi Wang
- Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, 332000, Jiangxi, China
| | - Jiaxiang Gu
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China
| | - Jiachao Xiong
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China
| | - Xiaokai Tang
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China
| | - Hao Lv
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China
| | - Faxin Zhou
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China
| | - Kai Cao
- Orthopedic Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330209, Jiangxi, China.
| | - Sijian Lin
- Rehabilitation Medicine Department, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
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Chen H, Lin H, Dai J. Causal associations of interleukins and osteoporosis: A genetic correlation study. Medicine (Baltimore) 2024; 103:e39036. [PMID: 39121248 PMCID: PMC11315551 DOI: 10.1097/md.0000000000039036] [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: 10/19/2023] [Accepted: 07/01/2024] [Indexed: 08/11/2024] Open
Abstract
The association between interleukins and osteoporosis has attracted much attention these days. However, the causal relationship between them is uncertain. Hence, this study performed a Mendelian randomization (MR) analysis to investigate the causal effects of interleukins on osteoporosis. The summary data for interleukins and osteoporosis came from 4 different genome-wide association studies. Significant and independent (P < 5 × 10-6; r2 < 0.001, 10,000 kbp) single-nucleotide polymorphisms were extracted for MR analysis. The inverse-variance weighted and other methods were used for MR analysis, while sensitivity analyses were conducted to test the reliability and stability. The positive causal effects of interleukin-7 on osteoporosis (odds ratio = 1.084; 95% confidence interval: 1.010-1.163; P = .025) were observed. No causal relationship was found between other interleukins and osteoporosis. In the sensitivity analysis, the results did not show the presence of pleiotropy and heterogeneity. Therefore, the results were robust for the MR analysis. This study revealed that interleukin-7 was positively related to osteoporosis and that other interleukins were not related to osteoporosis.
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Affiliation(s)
- Huihuang Chen
- Emergency Department, The Affiliated Hospital of Putian University, Putian, Fujian Province, China
| | - Haibin Lin
- Department of Orthopedics, The Affiliated Hospital of Putian University, Putian, Fujian Province, China
| | - Jianhui Dai
- Department of Orthopedics, The Affiliated Hospital of Putian University, Putian, Fujian Province, China
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Amroodi MN, Maghsoudloo M, Amiri S, Mokhtari K, Mohseni P, Pourmarjani A, Jamali B, Khosroshahi EM, Asadi S, Tabrizian P, Entezari M, Hashemi M, Wan R. Unraveling the molecular and immunological landscape: Exploring signaling pathways in osteoporosis. Biomed Pharmacother 2024; 177:116954. [PMID: 38906027 DOI: 10.1016/j.biopha.2024.116954] [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: 04/19/2024] [Revised: 06/05/2024] [Accepted: 06/15/2024] [Indexed: 06/23/2024] Open
Abstract
Osteoporosis, characterized by compromised bone density and microarchitecture, represents a significant global health challenge, particularly in aging populations. This comprehensive review delves into the intricate signaling pathways implicated in the pathogenesis of osteoporosis, providing valuable insights into the pivotal role of signal transduction in maintaining bone homeostasis. The exploration encompasses cellular signaling pathways such as Wnt, Notch, JAK/STAT, NF-κB, and TGF-β, all of which play crucial roles in bone remodeling. The dysregulation of these pathways is a contributing factor to osteoporosis, necessitating a profound understanding of their complexities to unveil the molecular mechanisms underlying bone loss. The review highlights the pathological significance of disrupted signaling in osteoporosis, emphasizing how these deviations impact the functionality of osteoblasts and osteoclasts, ultimately resulting in heightened bone resorption and compromised bone formation. A nuanced analysis of the intricate crosstalk between these pathways is provided to underscore their relevance in the pathophysiology of osteoporosis. Furthermore, the study addresses some of the most crucial long non-coding RNAs (lncRNAs) associated with osteoporosis, adding an additional layer of academic depth to the exploration of immune system involvement in various types of osteoporosis. Finally, we propose that SKP1 can serve as a potential biomarker in osteoporosis.
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Affiliation(s)
- Morteza Nakhaei Amroodi
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, department of orthopedic, school of medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mazaher Maghsoudloo
- Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Shayan Amiri
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, department of orthopedic, school of medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Khatere Mokhtari
- Department of Cellular and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Parnaz Mohseni
- Department of Pediatrics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Azadeh Pourmarjani
- Department of Pediatrics, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Behdokht Jamali
- Department of microbiology and genetics, kherad Institute of higher education, Busheher, lran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Pouria Tabrizian
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, department of orthopedic, school of medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Runlan Wan
- Department of Oncology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China; Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China.
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7
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Li S, Liu G, Hu S. Osteoporosis: interferon-gamma-mediated bone remodeling in osteoimmunology. Front Immunol 2024; 15:1396122. [PMID: 38817601 PMCID: PMC11137183 DOI: 10.3389/fimmu.2024.1396122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/26/2024] [Indexed: 06/01/2024] Open
Abstract
As the world population ages, osteoporosis, the most common disease of bone metabolism, affects more than 200 million people worldwide. The etiology is an imbalance in bone remodeling process resulting in more significant bone resorption than bone remodeling. With the advent of the osteoimmunology field, the immune system's role in skeletal pathologies is gradually being discovered. The cytokine interferon-gamma (IFN-γ), a member of the interferon family, is an important factor in the etiology and treatment of osteoporosis because it mediates bone remodeling. This review starts with bone remodeling process and includes the cellular and key signaling pathways of bone remodeling. The effects of IFN-γ on osteoblasts, osteoclasts, and bone mass are discussed separately, while the overall effects of IFN-γ on primary and secondary osteoporosis are summarized. The net effect of IFN-γ on bone appears to be highly dependent on the environment, dose, concentration, and stage of cellular differentiation. This review focuses on the mechanisms of bone remodeling and bone immunology, with a comprehensive discussion of the relationship between IFN-γ and osteoporosis. Finding the paradoxical balance of IFN-γ in bone immunology and exploring the potential of its clinical application provide new ideas for the clinical treatment of osteoporosis and drug development.
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Affiliation(s)
- Siying Li
- The Orthopaedic Center, The First People’s Hospital of Wenling, Taizhou University Affiliated Wenling Hospital, Wenling, Zhejiang, China
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, China
| | - Gang Liu
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, China
| | - Siwang Hu
- The Orthopaedic Center, The First People’s Hospital of Wenling, Taizhou University Affiliated Wenling Hospital, Wenling, Zhejiang, China
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8
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Chen S, Lei J, Mou H, Zhang W, Jin L, Lu S, Yinwang E, Xue Y, Shao Z, Chen T, Wang F, Zhao S, Chai X, Wang Z, Zhang J, Zhang Z, Ye Z, Li B. Multiple influence of immune cells in the bone metastatic cancer microenvironment on tumors. Front Immunol 2024; 15:1335366. [PMID: 38464516 PMCID: PMC10920345 DOI: 10.3389/fimmu.2024.1335366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/07/2024] [Indexed: 03/12/2024] Open
Abstract
Bone is a common organ for solid tumor metastasis. Malignant bone tumor becomes insensitive to systemic therapy after colonization, followed by poor prognosis and high relapse rate. Immune and bone cells in situ constitute a unique immune microenvironment, which plays a crucial role in the context of bone metastasis. This review firstly focuses on lymphatic cells in bone metastatic cancer, including their function in tumor dissemination, invasion, growth and possible cytotoxicity-induced eradication. Subsequently, we examine myeloid cells, namely macrophages, myeloid-derived suppressor cells, dendritic cells, and megakaryocytes, evaluating their interaction with cytotoxic T lymphocytes and contribution to bone metastasis. As important components of skeletal tissue, osteoclasts and osteoblasts derived from bone marrow stromal cells, engaging in 'vicious cycle' accelerate osteolytic bone metastasis. We also explain the concept tumor dormancy and investigate underlying role of immune microenvironment on it. Additionally, a thorough review of emerging treatments for bone metastatic malignancy in clinical research, especially immunotherapy, is presented, indicating current challenges and opportunities in research and development of bone metastasis therapies.
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Affiliation(s)
- Shixin Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jiangchu Lei
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Haochen Mou
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Wenkan Zhang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Lingxiao Jin
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Senxu Lu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Eloy Yinwang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yucheng Xue
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhenxuan Shao
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Tao Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Fangqian Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Shenzhi Zhao
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xupeng Chai
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zenan Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jiahao Zhang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zengjie Zhang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhaoming Ye
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Binghao Li
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China
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9
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Yun SJ, Sang H, Park SY, Chin SO. Effect of Hyperprolactinemia on Bone Metabolism: Focusing on Osteopenia/Osteoporosis. Int J Mol Sci 2024; 25:1474. [PMID: 38338751 PMCID: PMC10855748 DOI: 10.3390/ijms25031474] [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: 12/20/2023] [Revised: 01/19/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Prolactin is a hormone secreted from lactotroph cells in the anterior pituitary gland to induce lactation after birth. Hyperprolactinemia unrelated to lactation is a common cause of amenorrhea in women of a childbearing age, and a consequent decrease in the gonadotropin-releasing hormone (GnRH) by a high prolactin level can result in decreased bone mineral density. Osteoporosis is a common skeletal disorder characterized by decreased bone mineral density (BMD) and quality, which results in decreased bone strength. In patients with hyperprolactinemia, changes in BMD can be induced indirectly by the inhibition of the GnRH-gonadal axis due to increased prolactin levels or by the direct action of prolactin on osteoblasts and, possibly, osteoclast cells. This review highlights the recent work on bone remodeling and discusses our knowledge of how prolactin modulates these interactions, with a brief literature review on the relationship between prolactin and bone metabolism and suggestions for new possibilities.
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Affiliation(s)
| | | | | | - Sang Ouk Chin
- Department of Endocrinology and Metabolism, Kyung Hee University College of Medicine, Kyung Hee University Hospital, Seoul 02447, Republic of Korea; (S.J.Y.); (H.S.); (S.Y.P.)
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10
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Zhou X, Chen Y, Zhang Z, Miao J, Chen G, Qian Z. Identification of differentially expressed genes, signaling pathways and immune infiltration in postmenopausal osteoporosis by integrated bioinformatics analysis. Heliyon 2024; 10:e23794. [PMID: 38205281 PMCID: PMC10777010 DOI: 10.1016/j.heliyon.2023.e23794] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 12/12/2023] [Accepted: 12/13/2023] [Indexed: 01/12/2024] Open
Abstract
Background Postmenopausal osteoporosis is a systemic metabolic disorder typified by an imbalance in bone turnover, where bone resorption supersedes bone formation. This imbalance primarily arises from a decline in bone mass induced by estrogen deficiency, and an elevated risk of fractures resulting from degradation of bone microstructure. Despite recognizing these changes, the precise causative factors and potential molecular pathways remain elusive. In this study, we aimed to identify differentially expressed genes (DEGs), associated pathways, and the role of immune infiltration in osteoporosis, leveraging an integrated bioinformatics approach to shed light on potential underlying molecular mechanisms. Methods We retrieved the expression profiles of GSE230665 from the Gene Expression Omnibus database, comprising 15 femur samples, including 12 postmenopausal osteoporosis samples and 3 normal controls. From the aggregated microarray datasets, we derived differentially expressed genes (DEGs) for further bioinformatics analysis. We used WGCNA, analyzed DEGs, PPI, and conducted GO analysis to identify pivotal genes. We then used the CIBERSORT method to explore the degree of immune cell infiltration within femur specimens affected by postmenopausal osteoporosis. To probe into the relationship between pivotal genes and infiltrating immune cells, we conducted correlation analysis. Results We identified a total of 12,204 DEGs. Among these, 12,157 were up-regulated, and 47 were down-regulated. GO and KEGG pathway analyses indicated that these DEGs predominantly targeted cellular protein localization activity and associated signaling pathways. The protein-protein interaction network highlighted four central hub-genes: RPL31, RPL34, EEF1G, and BPTF. Principal component analysis indicated a positive correlation between the expression of these genes and resting NK cells (as per CIBERSORT). In contrast, the expression of RPL31, RPL34, and EEF1G showed a negative correlation with T cells (gamma delta per CIBERSORT). Conclusions Immune infiltration plays a role in the development of osteoporosis.
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Affiliation(s)
- Xiaoli Zhou
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin 300211, China
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
| | - Yang Chen
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin 300211, China
| | - Zepei Zhang
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin 300211, China
| | - Jun Miao
- Department of Spine Surgery, Tianjin Hospital, Tianjin University, Tianjin 300211, China
| | - Guangdong Chen
- Department of Orthopaedics, Cangzhou Central Hospital, Hebei 061001, China
| | - Zhiyong Qian
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China
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11
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Xu J, Yu L, Liu F, Wan L, Deng Z. The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review. Front Immunol 2023; 14:1222129. [PMID: 37475866 PMCID: PMC10355373 DOI: 10.3389/fimmu.2023.1222129] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 06/12/2023] [Indexed: 07/22/2023] Open
Abstract
The complicated connections and cross talk between the skeletal system and the immune system are attracting more attention, which is developing into the field of Osteoimmunology. In this field, cytokines that are among osteoblasts and osteoclasts play a critical role in bone remodeling, which is a pathological process in the pathogenesis and development of osteoporosis. Those cytokines include the tumor necrosis factor (TNF) family, the interleukin (IL) family, interferon (IFN), chemokines, and so on, most of which influence the bone microenvironment, osteoblasts, and osteoclasts. This review summarizes the effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis, aiming to providing the latest reference to the role of immunology in osteoporosis.
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Affiliation(s)
- Jie Xu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Linxin Yu
- Renmin Hospital of Wuhan University, Wuhan, China
| | - Feng Liu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Longbiao Wan
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhenhua Deng
- Hubei Provincial Hospital of Traditional Chinese Medicine (TCM), Wuhan, China
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12
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Huang H, He YM, Lin MM, Wang Y, Zhang X, Liang L, He X. P2X7Rs: new therapeutic targets for osteoporosis. Purinergic Signal 2023; 19:207-219. [PMID: 35106736 PMCID: PMC9984661 DOI: 10.1007/s11302-021-09836-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/17/2021] [Indexed: 02/05/2023] Open
Abstract
Increasing evidence suggests that both the occurrence and progression of osteoporosis are associated with inflammation, especially in primary osteoporosis. The maintenance of skeletal homeostasis is dependent on the complex regulation of bone metabolism. Numerous evidence suggested that purinoceptor networks are essential for bone homeostasis. In this review, the relationship between inflammation and the development of osteoporosis and the role of P2X7 receptor (P2X7R) in regulating the dynamic regulation of bone reconstruction were covered. We also discussed how P2X7R regulates the balance between resorption and bone formation by osteoblasts and reviewed the relevance of P2X7R polymorphisms in skeletal physiology. Finally, we analyzed potential targets of P2X7R for osteoporosis.
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Affiliation(s)
- Haoyun Huang
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Yu-Mei He
- School of Sports Medicine and Health, Chengdu Sports University, Chengdu, 610041, China
| | - Miao-Miao Lin
- School of Sports Medicine and Health, Chengdu Sports University, Chengdu, 610041, China
| | - Yanchao Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaomei Zhang
- Laboratory Animal Center of Sichuan University, Chengdu, 610041, China
| | - Li Liang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Xueling He
- Laboratory Animal Center of Sichuan University, Chengdu, 610041, China.
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13
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Huifang L, Jie G, Yi F. Neuro-immune-endocrine mechanisms with poor adherence to aromatase inhibitor therapy in breast cancer. Front Oncol 2022; 12:1054086. [PMID: 36578931 PMCID: PMC9791186 DOI: 10.3389/fonc.2022.1054086] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 11/16/2022] [Indexed: 12/14/2022] Open
Abstract
As the most commonly used endocrine therapy regimen for patients with hormone receptor-positive (HR+) breast cancer (BC) at present, aromatase inhibitors (AIs) reduce the risk of localized and distant recurrence, contralateral BC and secondary cancer, and prolong disease-free survival. Clinical data show that poor adherence during AI treatment is mainly attributed to muscle and joint pain, fatigue, anxiety, depression and sleep disturbances during treatment. The rapid decline of estrogen caused by AIs in a short period of time enhances sympathetic activity, activates T cells in the body, produces inflammatory factors such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin (IL)-17A, and promotes the occurrence of inflammation and bone loss. This article reviewed the mechanism of poor dependence on AIs in BC patients from the neuro-immuno-endocrine (NIE) perspective and provided clues for clinical intervention against poor adherence.
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Affiliation(s)
- Li Huifang
- Department of Anesthesiology, Peking University People’s Hospital, Beijing, China
| | - Gao Jie
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Feng Yi
- Department of Anesthesiology, Peking University People’s Hospital, Beijing, China,*Correspondence: Feng Yi,
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14
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Effects of Soy–Whey Protein Nutritional Supplementation on Hematopoiesis and Immune Reconstitution in an Allogeneic Transplanted Mice. Nutrients 2022; 14:nu14153014. [PMID: 35893870 PMCID: PMC9332233 DOI: 10.3390/nu14153014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/13/2022] [Accepted: 07/20/2022] [Indexed: 12/07/2022] Open
Abstract
Profound malnutrition and immunodeficiency are serious negative effects of radiotherapy and bone marrow transplantation for hematologic malignancy patients. This study aimed to evaluate the effects of nutritional supplementation with a soy–whey protein mixture on hematopoietic and immune reconstitution in an allogeneic transplant mouse model. Male BALB/c (H-2Kd) mice, 6–8 weeks-old, were divided randomly into five groups and then provided with different protein nutrition support. After 28 days, blood samples, bone marrow, spleen, and thymus were harvested to measure the effects. The results showed that soy–whey blended protein supplements promoted hematopoietic stem cell engraftment, body weight recovery, and the recovery of white blood cells, lymphocytes, and neutrophils; triggered the expansion of hematopoietic stem cells and progenitor cell pools by increasing the numbers of the c-kit+ progenitor, Lin-Sca1+c-kit+, short-term hematopoietic stem cells, and multipotent progenitors; enhanced thymus re-establishment and splenic subset recovery in both organ index and absolute number; improved overall nutritional status by increasing total serum protein, albumin, and globulin; protected the liver from radiation-induced injury, and increased antioxidant capacity as indicated by lower concentrations of alanine aminotransferase, aspartate aminotransferase, malondialdehyde, and 4-hydroxynonenal. This study indicated that soy–whey blended protein as important nutrients, from both plant and animal sources, had a greater positive effect on patients with hematological malignancies to accelerate hematopoiesis and immune reconstitution after bone marrow transplantation.
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15
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Zhang W, Gao R, Rong X, Zhu S, Cui Y, Liu H, Li M. Immunoporosis: Role of immune system in the pathophysiology of different types of osteoporosis. Front Endocrinol (Lausanne) 2022; 13:965258. [PMID: 36147571 PMCID: PMC9487180 DOI: 10.3389/fendo.2022.965258] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Osteoporosis is a skeletal system disease characterized by low bone mass and altered bone microarchitecture, with an increased risk of fractures. Classical theories hold that osteoporosis is essentially a bone remodeling disorder caused by estrogen deficiency/aging (primary osteoporosis) or secondary to diseases/drugs (secondary osteoporosis). However, with the in-depth understanding of the intricate nexus between both bone and the immune system in recent decades, the novel field of "Immunoporosis" was proposed by Srivastava et al. (2018, 2022), which delineated and characterized the growing importance of immune cells in osteoporosis. This review aimed to summarize the response of the immune system (immune cells and inflammatory factors) in different types of osteoporosis. In postmenopausal osteoporosis, estrogen deficiency-mediated alteration of immune cells stimulates the activation of osteoclasts in varying degrees. In senile osteoporosis, aging contributes to continuous activation of the immune system at a low level which breaks immune balance, ultimately resulting in bone loss. Further in diabetic osteoporosis, insulin deficiency or resistance-induced hyperglycemia could lead to abnormal regulation of the immune cells, with excessive production of proinflammatory factors, resulting in osteoporosis. Thus, we reviewed the pathophysiology of osteoporosis from a novel insight-immunoporosis, which is expected to provide a specific therapeutic target for different types of osteoporosis.
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Affiliation(s)
- Weidong Zhang
- Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
| | - Ruihan Gao
- Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
| | - Xing Rong
- Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
| | - Siqi Zhu
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
- Affiliated Hospital 2, Jinzhou Medical University, Jinzhou, China
| | - Yajun Cui
- Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
| | - Hongrui Liu
- Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
- *Correspondence: Minqi Li, ; Hongrui Liu,
| | - Minqi Li
- Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
- Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, China
- *Correspondence: Minqi Li, ; Hongrui Liu,
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16
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Hong W, Tang L, Ge R, Li W, Shen X, Hong L, Xu X. Persistent Abnormal Immunocytes Induced Systemic Bone Loss in Locally Irradiated Rats. Calcif Tissue Int 2021; 109:706-718. [PMID: 34191050 DOI: 10.1007/s00223-021-00883-8] [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: 01/27/2021] [Accepted: 06/19/2021] [Indexed: 11/30/2022]
Abstract
Chronic and systemic bone complications frequently occur in patients who undergo radiotherapy; however, the pathological mechanisms underlying these complications remain unclear. This study aimed to observe persistent and systemic changes in locally irradiated rats and to determine the systemic pathological changes that persistently affect bone metabolism. We examined the inflammatory and oxidative stress responses that occurred after local irradiation using enzyme immunoassays and biochemical analyses. Lymphocytes obtained from the blood, spleen, thymus, and bone marrow were evaluated using flow cytometry. The proliferation and apoptosis characteristics of co-cultured bone marrow-derived mesenchymal stem cells (BMSCs) were detected by MTT assay and PI/Annexin V-FITC staining, respectively, and the differentiation of BMSCs was measured according to alkaline phosphatase (ALP) staining, alizarin red staining, and Oil Red O staining and by evaluating the mRNA expression of ALP, osteocalcin (OCN), osteopontin (OPN), collagen I, Runx2, and PPARγ. Our results revealed that no significant or continuous differences were present in the inflammatory response or the oxidative stress response throughout the body after local irradiation. B lymphocyte levels increased continuously in the blood, spleen, and bone marrow after local irradiation. T lymphocyte levels were decreased at 2 weeks after local irradiation, and CD8+T lymphocyte levels were increased in the blood, thymus, and bone marrow at 12 weeks after local irradiation. The ratio of CD4+/CD8+T lymphocytes began to decrease during the early phase after local irradiation and became significantly decreased at 12 weeks after local irradiation. Normal BMSCs co-cultured with lymphocytes derived from irradiated rats exhibited decreased proliferation and increased apoptosis, and the ALP staining intensity, alizarin red staining intensity, and mRNA expression of related genes were all also decreased. Oil Red O staining intensity and mRNA expression of PPARγ were both increased. Lymphocyte levels contribute to chronic and systemic bone complications after radiotherapy by inhibiting the proliferation and osteoblastogenesis of BMSCs.
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Affiliation(s)
- Wei Hong
- Department of Geriatrics and Gerontology, Huadong Hospital, Fudan University, 221 West Yan'an Road, Shanghai, 200040, China.
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, 221 West Yan'an Road, Shanghai, 200040, China.
| | - Lichen Tang
- Department of Breast Surgery, Shanghai Cancer Hospital, Fudan University, 270 Dongan Road, Shanghai, 200032, China
| | - Rui Ge
- Department of General Surgery, Huadong Hospital, Fudan University, 221 West Yan'an Road, Shanghai, 200040, China
| | - Weiping Li
- Department of General Surgery, Huadong Hospital, Fudan University, 221 West Yan'an Road, Shanghai, 200040, China
| | - Xiaoyong Shen
- Department of Thoracic Surgery, Huadong Hospital, Fudan University, 221 West Yan'an Road, Shanghai, 200040, China
| | - Lixia Hong
- Department of General Surgery, Huadong Hospital, Fudan University, 221 West Yan'an Road, Shanghai, 200040, China
| | - Xiaoya Xu
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, 2094 Xietu Road, Shanghai, 200032, China.
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17
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Uehara IA, Soldi LR, Silva MJB. Current perspectives of osteoclastogenesis through estrogen modulated immune cell cytokines. Life Sci 2020; 256:117921. [DOI: 10.1016/j.lfs.2020.117921] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/02/2020] [Accepted: 06/04/2020] [Indexed: 12/12/2022]
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18
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Brunetti G, Storlino G, Oranger A, Colaianni G, Faienza MF, Ingravallo G, Di Comite M, Reseland JE, Celi M, Tarantino U, Passeri G, Ware CF, Grano M, Colucci S. LIGHT/TNFSF14 regulates estrogen deficiency-induced bone loss. J Pathol 2020; 250:440-451. [PMID: 31990039 DOI: 10.1002/path.5385] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 12/24/2019] [Accepted: 01/15/2020] [Indexed: 12/30/2022]
Abstract
Bone loss induced by ovariectomy is due to the direct activity on bone cells and mesenchymal cells and to the dysregulated activity of bone marrow cells, including immune cells and stromal cells, but the underlying mechanisms are not completely known. Here, we demonstrate that ovariectomy induces the T-cell co-stimulatory cytokine LIGHT, which stimulates both osteoblastogenesis and osteoclastogenesis by modulating osteoclastogenic cytokine expression, including TNF, osteoprotegerin, and the receptor activator of nuclear factor-κB ligand (RANKL). Predictably, LIGHT-deficient (Tnfsf14-/- ) mice are protected from ovariectomy-dependent bone loss, whereas trabecular bone mass increases in mice deficient in both LIGHT and T and B lymphocytes (Rag -/- Tnfsf14 -/- ) and is associated with an inversion of the TNF and RANKL/OPG ratio. Furthermore, women with postmenopausal osteoporosis display high levels of LIGHT in circulating T cells and monocytes. Taken together, these results indicate that LIGHT mediates bone loss induced by ovariectomy, suggesting that patients with postmenopausal osteoporosis may benefit from LIGHT antagonism. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Giacomina Brunetti
- Department of Basic and Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy
| | - Giuseppina Storlino
- Department of Emergency and Organ Transplantation, Section of Human Anatomy and Histology, University of Bari, Bari, Italy
| | - Angela Oranger
- Department of Emergency and Organ Transplantation, Section of Human Anatomy and Histology, University of Bari, Bari, Italy
| | - Graziana Colaianni
- Department of Emergency and Organ Transplantation, Section of Human Anatomy and Histology, University of Bari, Bari, Italy
| | - Maria F Faienza
- Department of Biomedical Science and Human Oncology, Paediatric Unit, University of Bari, Bari, Italy
| | - Giuseppe Ingravallo
- Department of Emergency and Organ Transplantation, Pathology Section, University of Bari, Bari, Italy
| | - Mariasevera Di Comite
- Department of Basic and Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy
| | - Janne E Reseland
- Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, Blindern, Oslo, Norway
| | - Monica Celi
- Department of Orthopedics and Traumatology, Tor Vergata University of Rome, Rome, Italy
| | - Umberto Tarantino
- Department of Orthopedics and Traumatology, Tor Vergata University of Rome, Rome, Italy
| | - Giovanni Passeri
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | - Carl F Ware
- Laboratory of Molecular Immunology, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - Maria Grano
- Department of Emergency and Organ Transplantation, Section of Human Anatomy and Histology, University of Bari, Bari, Italy
| | - Silvia Colucci
- Department of Basic and Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy
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Abstract
Cytokines and hematopoietic growth factors have traditionally been thought of as regulators of the development and function of immune and blood cells. However, an ever-expanding number of these factors have been discovered to have major effects on bone cells and the development of the skeleton in health and disease (Table 1). In addition, several cytokines have been directly linked to the development of osteoporosis in both animal models and in patients. In order to understand the mechanisms regulating bone cells and how this may be dysregulated in disease states, it is necessary to appreciate the diverse effects that cytokines and inflammation have on osteoblasts, osteoclasts, and bone mass. This chapter provides a broad overview of this topic with extensive references so that, if desired, readers can access specific references to delve into individual topics in greater detail.
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Affiliation(s)
- Joseph Lorenzo
- Departments of Medicine and Orthopaedic Surgery, UConn Health, Farmington, CT, USA.
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Activated B Lymphocyte Inhibited the Osteoblastogenesis of Bone Mesenchymal Stem Cells by Notch Signaling. Stem Cells Int 2019; 2019:8150123. [PMID: 31281386 PMCID: PMC6589309 DOI: 10.1155/2019/8150123] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 04/17/2019] [Accepted: 05/06/2019] [Indexed: 11/23/2022] Open
Abstract
Estrogen is very important to the differentiation of B lymphocytes; B lymphopoiesis induced by OVX was supposedly involved in osteoporosis. But the effects of B lymphocytes on the osteogenic differentiation of bone mesenchymal stem cells (BMSCs) are not clear. In this study, we detected bone quality and bone loss in a trabecular bone by electronic universal material testing machine and microcomputed tomography (micro-CT) in OVX and splenectomized-ovariectomy (SPX-OVX) rats. Additionally, changes in lymphocytes (B lymphocyte, CD4+ and CD8+ T lymphocytes, and macrophages) in the bone marrow were analyzed by flow cytometry. The osteogenesis of BMSCs cocultured with normal and LPS-pretreated B lymphocytes was detected by BCIP/NBT and Alizarin red S staining. Measurement of the Notch2, Notch4, Hey1, Hey2, Hes1, and runt-related transcription factor 2 (Runx2) expression in BMSCs cocultured with B lymphocytes was done using real-time PCR. The effects of dexamethasone and DAPT (inhibitor of Notch signaling) on osteogenesis of BMSCs were detected by BCIP/NBT, Alizarin red S staining, and real-time PCR. Osteoporosis happened in OVX rats, more serious in SPX-OVX rats, B lymphocytes increased in OVX rats, and sharply higher in SPX-OVX rats. Osteoporosis did not happen in SPX rats which is still companied with a high increase of B lymphocytes. LPS-pretreated B lymphocytes suppressed the osteogenesis of BMSCs, but the normal B lymphocytes could not. The LPS-pretreated B lymphocytes upregulated the expression of Notch4, Hes1, and Hey2 and downregulated the expression of Runx2 in BMSCs. Dexamethasone and DAPT could downregulate the high expression of Notch4, Hes1, Hey2 and upregulate the low expression of Runx2 in BMSCs which cocultured with LPS treated B lymphocytes, the inhibited ALP and Alizarin red staining in BMSCs which cocultured with LPS treated B lymphocytes also partly restored.
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Lombardi G, Ziemann E, Banfi G. Physical Activity and Bone Health: What Is the Role of Immune System? A Narrative Review of the Third Way. Front Endocrinol (Lausanne) 2019; 10:60. [PMID: 30792697 PMCID: PMC6374307 DOI: 10.3389/fendo.2019.00060] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 01/22/2019] [Indexed: 12/12/2022] Open
Abstract
Bone tissue can be seen as a physiological hub of several stimuli of different origin (e.g., dietary, endocrine, nervous, immune, skeletal muscle traction, biomechanical load). Their integration, at the bone level, results in: (i) changes in mineral and protein composition and microarchitecture and, consequently, in shape and strength; (ii) modulation of calcium and phosphorous release into the bloodstream, (iii) expression and release of hormones and mediators able to communicate the current bone status to the rest of the body. Different stimuli are able to act on either one or, as usual, more levels. Physical activity is the key stimulus for bone metabolism acting in two ways: through the biomechanical load which resolves into a direct stimulation of the segment(s) involved and through an indirect load mediated by muscle traction onto the bone, which is the main physiological stimulus for bone formation, and the endocrine stimulation which causes homeostatic adaptation. The third way, in which physical activity is able to modify bone functions, passes through the immune system. It is known that immune function is modulated by physical activity; however, two recent insights have shed new light on this modulation. The first relies on the discovery of inflammasomes, receptors/sensors of the innate immunity that regulate caspase-1 activation and are, hence, the tissue triggers of inflammation in response to infections and/or stressors. The second relies on the ability of certain tissues, and particularly skeletal muscle and adipose tissue, to synthesize and secrete mediators (namely, myokines and adipokines) able to affect, profoundly, the immune function. Physical activity is known to act on both these mechanisms and, hence, its effects on bone are also mediated by the immune system activation. Indeed, that immune system and bone are tightly connected and inflammation is pivotal in determining the bone metabolic status is well-known. The aim of this narrative review is to give a complete view of the exercise-dependent immune system-mediated effects on bone metabolism and function.
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Affiliation(s)
- Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Department of Physiology and Pharmacology, Faculty of Rehabilitation and Kinesiology, Gdansk University of Physical Education and Sport, Gdansk, Poland
- *Correspondence: Giovanni Lombardi
| | - Ewa Ziemann
- Department of Physiology and Pharmacology, Faculty of Rehabilitation and Kinesiology, Gdansk University of Physical Education and Sport, Gdansk, Poland
| | - Giuseppe Banfi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
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Yoon JR, Ha GC, Ko KJ, Kang SJ. Effects of exercise type on estrogen, tumor markers, immune function, antioxidant function, and physical fitness in postmenopausal obese women. J Exerc Rehabil 2018; 14:1032-1040. [PMID: 30656166 PMCID: PMC6323343 DOI: 10.12965/jer.1836446.223] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 11/02/2018] [Indexed: 12/17/2022] Open
Abstract
This study aims to identify the effects of exercise type on estrogen, tumor markers, immune function, antioxidant function, and physical fitness in postmenopausal obese women. The subjects were 30 post-menopausal obese women with body fat percentage higher than 30%. Participants were divided into aerobic exercise group (n=10; age, 53.70±3.37 years), resistance exercise group (n=10; age, 52.20±2.15 years), and control group (n=10; age, 52.50±2.68 years). Estrogen and growth hormone showed no significant difference in the aerobic exercise group, resistance exercise group, and control group. Tumor marker alpha-fetoprotein was increased in the aerobic exercise, resistance exercise, and control groups (P<0.01). The metabolic syndrome risk factor was decreased in the aerobic and resistance exercise groups, which was shown by the reduction of weight (P<0.001), body fat percentage (P<0.001), waist circumference (P<0.05), and increase of high density lipoprotein-cholesterol (P<0.001). natural killer cell activity was increased in the aerobic exercise group, resistance exercise group, and control group (P<0.001). Oxidative stress was decreased in the aerobic exercise group, resistance exercise group, and control group (P<0.001). Maximum oxygen uptake was increased in the aerobic and resistance exercise groups, but aerobic exercise was more effective (P<0.05). Knee isokinetic extensor muscle was increased in both the aerobic and resistance exercise groups (P<0.001). Aerobic and resistance exercise of postmenopausal obese women can be considered an effective intervention program to prevent metabolic syndrome and improve physical fitness.
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Affiliation(s)
- Jae-Ryang Yoon
- Department of Physical Education, Korea National Sport University, Seoul, Korea
| | - Gi-Chul Ha
- Department of Physical Education, Korea National Sport University, Seoul, Korea
| | - Kwang-Jun Ko
- Department of Sports Medicine, National Fitness Center, Seoul, Korea
| | - Seol-Jung Kang
- Department of Physical Education, Changwon National University, Changwon, Korea
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23
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Rodrigues PM, Ribeiro AR, Serafini N, Meireles C, Di Santo JP, Alves NL. Intrathymic Deletion of IL-7 Reveals a Contribution of the Bone Marrow to Thymic Rebound Induced by Androgen Blockade. THE JOURNAL OF IMMUNOLOGY 2018; 200:1389-1398. [DOI: 10.4049/jimmunol.1701112] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Abstract
Despite the well-documented effect of castration in thymic regeneration, the singular contribution of the bone marrow (BM) versus the thymus to this process remains unclear. The chief role of IL-7 in pre- and intrathymic stages of T lymphopoiesis led us to investigate the impact of disrupting this cytokine during thymic rebound induced by androgen blockade. We found that castration promoted thymopoiesis in young and aged wild-type mice. In contrast, only young germline IL-7–deficient (Il7−/−) mice consistently augmented thymopoiesis after castration. The increase in T cell production was accompanied by the expansion of the sparse medullary thymic epithelial cell and the peripheral T cell compartment in young Il7−/− mice. In contrast to young Il7−/− and wild-type mice, the poor thymic response of aged Il7−/− mice after castration was associated with a defect in the expansion of BM hematopoietic progenitors. These findings suggest that BM-derived T cell precursors contribute to thymic rebound driven by androgen blockade. To assess the role of IL-7 within the thymus, we generated mice with conditional deletion of IL-7 (Il7 conditional knockout [cKO]) in thymic epithelial cells. As expected, Il7cKO mice presented a profound defect in T cell development while maintaining an intact BM hematopoietic compartment across life. Unlike Il7−/− mice, castration promoted the expansion of BM precursors and enhanced thymic activity in Il7cKO mice independently of age. Our findings suggest that the mobilization of BM precursors acts as a prime catalyst of castration-driven thymopoiesis.
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Affiliation(s)
- Pedro M. Rodrigues
- *Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- †Thymus Development and Function Laboratory, Institute for Molecular and Cellular Biology, 4200-135 Porto, Portugal
- ‡Doctoral Program in Biomedical Sciences, Abel Salazar Biomedical Sciences Institute, University of Porto, 4050-313 Porto, Portugal
| | - Ana R. Ribeiro
- *Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- †Thymus Development and Function Laboratory, Institute for Molecular and Cellular Biology, 4200-135 Porto, Portugal
| | - Nicolas Serafini
- §Innate Immunity Unit, Pasteur Institute, 75724 Paris, France; and
- ¶INSERM U1223, 75015 Paris, France
| | - Catarina Meireles
- *Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- †Thymus Development and Function Laboratory, Institute for Molecular and Cellular Biology, 4200-135 Porto, Portugal
| | - James P. Di Santo
- §Innate Immunity Unit, Pasteur Institute, 75724 Paris, France; and
- ¶INSERM U1223, 75015 Paris, France
| | - Nuno L. Alves
- *Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- †Thymus Development and Function Laboratory, Institute for Molecular and Cellular Biology, 4200-135 Porto, Portugal
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Xu X, Jia X, Mo L, Liu C, Zheng L, Yuan Q, Zhou X. Intestinal microbiota: a potential target for the treatment of postmenopausal osteoporosis. Bone Res 2017; 5:17046. [PMID: 28983411 PMCID: PMC5627629 DOI: 10.1038/boneres.2017.46] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Accepted: 07/24/2017] [Indexed: 02/08/2023] Open
Abstract
Postmenopausal osteoporosis (PMO) is a prevalent metabolic bone disease characterized by bone loss and structural destruction, which increases the risk of fracture in postmenopausal women. Owing to the high morbidity and serious complications of PMO, many efforts have been devoted to its prophylaxis and treatment. The intestinal microbiota is the complex community of microorganisms colonizing the gastrointestinal tract. Probiotics, which are dietary or medical supplements consisting of beneficial intestinal bacteria, work in concert with endogenous intestinal microorganisms to maintain host health. Recent studies have revealed that bone loss in PMO is closely related to host immunity, which is influenced by the intestinal microbiota. The curative effects of probiotics on metabolic bone diseases have also been demonstrated. The effects of the intestinal microbiota on bone metabolism suggest a promising target for PMO management. This review seeks to summarize the critical effects of the intestinal microbiota and probiotics on PMO, with a focus on the molecular mechanisms underlying the pathogenic relationship between bacteria and host, and to define the possible treatment options.
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Affiliation(s)
- Xin Xu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiaoyue Jia
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Longyi Mo
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chengcheng Liu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Liwei Zheng
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Quan Yuan
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Dental Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Abstract
Osteoporosis increases fracture risk, a cause of crippling morbidity and mortality. The immunoskeletal interface (ISI) is a centralization of cell and cytokine effectors shared between skeletal and immune systems. Consequently, the immune system mediates powerful effects on bone turnover. Physiologically, B cells secrete osteoprotegerin (OPG), a potent anti-osteoclastogenic factor that preserves bone mass. However, activated T cells and B cells secrete pro-osteoclastogenic factors including receptor activator of Nuclear factor-kappaB (NF-kB) ligand (RANKL), Interleukin (IL)-17A, and tumor necrosis factor (TNF)-α promoting bone loss in inflammatory states such as rheumatoid arthritis. Recently, ISI disruption has been linked to osteoporosis in human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS), where elevated B cell RANKL and diminished OPG drive bone resorption. HIV-antiretroviral therapy paradoxically intensifies bone loss during disease reversal, as immune reconstitution produces osteoclastogenic cytokines. Interestingly, in estrogen deficiency, activated T cells secrete RANKL, TNF, and IL-17A that amplify bone resorption and contribute to postmenopausal osteoporosis. T cell-produced TNF and IL-17A further contribute to bone loss in hyperparathyroidism, while T cell production of the anabolic Wingless integration site (Wnt) ligand, Wnt10b, promotes bone formation in response to anabolic parathyroid hormone and the immunomodulatory costimulation inhibitor cytotoxic T lymphocyte-associated protein-4-IgG (abatacept). These findings provide a window into the workings of the ISI and suggest novel targets for future therapeutic interventions to reduce fracture risk.
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Affiliation(s)
- M Neale Weitzmann
- 1 Department of Veterans Affairs, Atlanta VA Medical Center, Decatur, Georgia, USA
- 2 Department of Medicine, Division of Endocrinology and Metabolism and Lipids, Emory University School of Medicine, Atlanta, Georgia, USA
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26
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Xu X, Li R, Zhou Y, Zou Q, Ding Q, Wang J, Jin W, Hua G, Gao J. Dysregulated systemic lymphocytes affect the balance of osteogenic/adipogenic differentiation of bone mesenchymal stem cells after local irradiation. Stem Cell Res Ther 2017; 8:71. [PMID: 28320453 PMCID: PMC5360074 DOI: 10.1186/s13287-017-0527-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 02/19/2017] [Accepted: 03/02/2017] [Indexed: 11/10/2022] Open
Abstract
Background While it is known that irradiation can induce local and systemic bone loss over time, how focal irradiation induces systemic bone complications remains unclear. Immune cells are thought to be crucial to bone homeostasis, and abnormal immune cells lead to serious disruption of bone homeostasis, such as in acute lymphoblastic leukaemia. This disruption primarily occurs due to inhibition of the osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Methods In this study, we detected local and systemic bone loss in trabecular bone by micro-computed tomography (micro-CT) and measurement of peroxisome proliferator-activated receptor gamma (PPARγ) and runt-related transcription factor 2 (RUNX2) expression in BMSCs using real-time polymerase chain reaction and western blotting. Additionally, changes in lymphocytes (B cells and CD4+ and CD8+ T cells) in the peripheral blood and bone marrow were analysed by flow cytometry. BMSC-derived osteoblasts and adipocytes, cultured in osteogenic or adipogenic media or co-cultured with lymphocytes, were detected by BCIP/NBT, Alizarin Red S and Oil Red O staining. Results Focal irradiation induced local and systemic bone loss in trabecular bone. Increased PPARγ expression and decreased RUNX2 expression were observed, accompanied by upregulated adipogenesis and downregulated osteogenesis of BMSCs. B cells and CD8+ T lymphocytes were increased in the blood and bone marrow after irradiation, while CD4+ T lymphocytes were decreased in the blood. Inhibition of RUNX2 expression and reduction of alkaline phosphatase activity and mineralization deposits were observed in lymphocyte-co-cultured BMSCs, accompanied by an increase in PPARγ expression and in the number of lipid droplets. Conclusions Focal irradiation induced local and systemic bone loss in trabecular bone. Increased B cells and CD8+ T lymphocytes led to systemic bone loss by decreasing BMSC osteogenesis.
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Affiliation(s)
- Xiaoya Xu
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai, 200032, China
| | - Ruixia Li
- Obstetrics and Gynecology Hospital of Fudan University, No. 419 Fangxie Road, Shanghai, 200011, China
| | - Yi Zhou
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai, 200032, China
| | - Qiong Zou
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai, 200032, China
| | - Qiaoling Ding
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai, 200032, China
| | - Jinfeng Wang
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai, 200032, China
| | - Weifang Jin
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai, 200032, China
| | - Guoqiang Hua
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai, 200032, China
| | - Jianjun Gao
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai, 200032, China. .,Department of Bone Metabolism, Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai, 200032, China.
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27
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Sex and age as determinants of rat T-cell phenotypic characteristics: influence of peripubertal gonadectomy. Mol Cell Biochem 2017; 431:169-185. [PMID: 28281185 DOI: 10.1007/s11010-017-2989-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 02/24/2017] [Indexed: 12/19/2022]
Abstract
The study examined the influence of age, sex and peripubertal gonadectomy on a set of T-cell phenotypic parameters. Rats of both sexes were gonadectomised at the age of 1 month and peripheral blood and spleen T lymphocytes from non-gonadectomised and gonadectomised 3- and 11-month-old rats were examined for the expression of differentiation/activation (CD90/CD45RC) and immunoregulatory markers. Peripheral blood T lymphocytes from non-gonadectomised rats showed age-dependent sexual dimorphisms in (1) total count (lower in female than male 11-month-old rats); (2) CD4+:CD8 + cell ratio (higher in female than male rats of both ages); (3) the proportion of recent thymic emigrants in CD8 + T cells (lower in female than male 3-month-old rats) and (4) the proportions of mature naïve and memory/activated cells (irrespective of age, the proportion of naïve cells was higher, whereas that of memory/activated cells was lower in females). Gonadectomy influenced magnitudes or direction of these sex differences. Additionally, sex differences in peripheral blood T-lymphocyte parameters did not fully correspond to those observed in T-splenocyte parameters, suggesting the compartment-specific regulation of the major T-cell subpopulations' and their subsets' composition. Furthermore, there was no sexual dimorphism in the proportion of either CD25 + Foxp3 + cells among CD4 + or CD161+ (NKT) cells within CD8 + T lymphocytes. However, there was gonadal hormone-independent age-associated sexual dimorphism in the proportion of CD161 + cells (NKT cells) in CD8 + T splenocytes. Overall, the study revealed age-dependent variations in sexual dimorphisms in T-cell parameters relevant for immune response efficacy and showed that they are T-cell compartment-specific and partly gonadal hormone-related.
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29
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Abstract
PURPOSE OF REVIEW There is increasing evidence pointing toward an important role of heightened immune activation and inflammation in people living with HIV contributing to the development of non-AIDS comorbidities. This review aims to explore low bone mineral density (BMD) in HIV with a focus on the underlying mechanisms and relationships between the immune and skeletal systems. RECENT FINDINGS Baseline immune activation and inflammation negatively impact BMD at antiretroviral therapy (ART) initiation. B- and T-cell alterations in HIV lead to an imbalance in the osteoblastic osteoprotegerin (OPG) and osteoclastic receptor activator of NF-κB ligand (RANKL) cytokines which favours osteoclastogenesis and bone resorption. These findings suggest an important role for immune-mediated mechanisms in the pathogenesis of low BMD in HIV. SUMMARY Bone homeostasis is in part regulated by cells of the immune system through complex interactions with the RANK/RANKL/OPG axis. Disturbances in the normal functioning of T, B cells, and monocytes in HIV and the resulting proinflammatory state may contribute to dysregulation of this finely controlled balance leading to increased bone loss. Pre-ART levels of immune activation and inflammation have a consistently negative effect on BMD and further suggest the immunocentric basis of bone loss in HIV alongside supporting the benefits of earlier ART initiation. Further longitudinal studies will help determine the effect this will have on fracture risk in people living with HIV.
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30
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Li JY, Chassaing B, Tyagi AM, Vaccaro C, Luo T, Adams J, Darby TM, Weitzmann MN, Mulle JG, Gewirtz AT, Jones RM, Pacifici R. Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J Clin Invest 2016; 126:2049-63. [PMID: 27111232 DOI: 10.1172/jci86062] [Citation(s) in RCA: 439] [Impact Index Per Article: 48.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 03/01/2016] [Indexed: 12/22/2022] Open
Abstract
A eubiotic microbiota influences many physiological processes in the metazoan host, including development and intestinal homeostasis. Here, we have shown that the intestinal microbiota modulates inflammatory responses caused by sex steroid deficiency, leading to trabecular bone loss. In murine models, sex steroid deficiency increased gut permeability, expanded Th17 cells, and upregulated the osteoclastogenic cytokines TNFα (TNF), RANKL, and IL-17 in the small intestine and the BM. In germ-free (GF) mice, sex steroid deficiency failed to increase osteoclastogenic cytokine production, stimulate bone resorption, and cause trabecular bone loss, demonstrating that the gut microbiota is central in sex steroid deficiency-induced trabecular bone loss. Furthermore, we demonstrated that twice-weekly treatment of sex steroid-deficient mice with the probiotics Lactobacillus rhamnosus GG (LGG) or the commercially available probiotic supplement VSL#3 reduces gut permeability, dampens intestinal and BM inflammation, and completely protects against bone loss. In contrast, supplementation with a nonprobiotic strain of E. coli or a mutant LGG was not protective. Together, these data highlight the role that the gut luminal microbiota and increased gut permeability play in triggering inflammatory pathways that are critical for inducing bone loss in sex steroid-deficient mice. Our data further suggest that probiotics that decrease gut permeability have potential as a therapeutic strategy for postmenopausal osteoporosis.
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31
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Xu Y, Chu N, Qiu X, Gober HJ, Li D, Wang L. The interconnected role of chemokines and estrogen in bone metabolism. Biosci Trends 2016; 10:433-444. [DOI: 10.5582/bst.2016.01072] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Yingping Xu
- Obstetrics and Gynecology Hospital of Fudan University
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases
- Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, IBS, Shanghai Medical College, Fudan University
- The Academy of Integrative Medicine of Fudan University
| | - Nan Chu
- Obstetrics and Gynecology Hospital of Fudan University
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases
- Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, IBS, Shanghai Medical College, Fudan University
| | - Xuemin Qiu
- Obstetrics and Gynecology Hospital of Fudan University
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases
- Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, IBS, Shanghai Medical College, Fudan University
- The Academy of Integrative Medicine of Fudan University
| | | | - Dajin Li
- Obstetrics and Gynecology Hospital of Fudan University
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases
- Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, IBS, Shanghai Medical College, Fudan University
- The Academy of Integrative Medicine of Fudan University
| | - Ling Wang
- Obstetrics and Gynecology Hospital of Fudan University
- Shanghai Key Laboratory of Female Reproductive Endocrine-related Diseases
- Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, IBS, Shanghai Medical College, Fudan University
- The Academy of Integrative Medicine of Fudan University
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Abstract
Breast cancer is one of the most common malignancies of women. The majority of breast cancers express estrogen and/or progesterone receptors, permitting anticancer targeting strategies to reduce estrogen signaling in the cancer cells and thereby lowering the risk of breast cancer recurrence. The development of the selective estrogen receptor modulator (SERM) tamoxifen marked a significant milestone in breast cancer care that transcended older estrogen ablative strategies such as oophorectomy and ovarian irradiation. An unintended benefit of tamoxifen in postmenopausal women was bone density preservation. The third generation of aromatase inhibitors (AIs) have demonstrated superior efficacy to tamoxifen in improving disease-free survival in postmenopausal women. However, the AIs significantly increase bone resorption, reduce bone mineral density, and increase the risk of fracture above that of tamoxifen. As a consequence of this, clinical oncologists have assumed a larger role in the screening and treatment of the skeletal complications of breast cancer therapies. The key features of managing bone health in women with early stage breast cancer receiving adjuvant endocrine therapy are reviewed here.
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Affiliation(s)
- Gregory A Clines
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA,
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El Azreq MA, Arseneault C, Boisvert M, Pagé N, Allaeys I, Poubelle PE, Tessier PA, Aoudjit F. Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss. THE JOURNAL OF IMMUNOLOGY 2015; 195:4198-209. [DOI: 10.4049/jimmunol.1500437] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 08/20/2015] [Indexed: 01/15/2023]
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Mori G, D'Amelio P, Faccio R, Brunetti G. Bone-immune cell crosstalk: bone diseases. J Immunol Res 2015; 2015:108451. [PMID: 26000310 PMCID: PMC4427089 DOI: 10.1155/2015/108451] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 01/22/2015] [Accepted: 01/25/2015] [Indexed: 01/14/2023] Open
Abstract
Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma.
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Affiliation(s)
- Giorgio Mori
- Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy
| | - Patrizia D'Amelio
- Department of Medical Science, Section of Gerontology and Bone Metabolism Diseases, University of Torino, 10126 Torino, Italy
| | - Roberta Faccio
- Department of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Giacomina Brunetti
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, 70124 Bari, Italy
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Arsenović-Ranin N, Kosec D, Nacka-Aleksić M, Pilipović I, Stojić-Vukanić Z, Djikić J, Bufan B, Leposavić G. Ovarian hormone level alterations during rat post-reproductive life-span influence CD8 + T-cell homeostasis. Exp Biol Med (Maywood) 2015; 240:1319-32. [PMID: 25716018 DOI: 10.1177/1535370215570817] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 12/21/2014] [Indexed: 01/01/2023] Open
Abstract
The study examined the putative role of ovarian hormones in shaping of rat peripheral T-cell compartment during post-reproductive period. In 20-month-old rats ovariectomized (Ox) at the very end of reproductive period, thymic output, cellularity and composition of major TCRαβ + peripheral blood lymphocyte and splenocyte subsets were analyzed. Ovariectomy led to the enlargement of CD8 + peripheral blood lymphocyte and splenocyte subpopulations. This reflected: (i) a more efficient thymic generation of CD8 + cells as indicated by increased number of CD4+CD8 + double positive and the most mature CD4-CD8+TCRαβ(high) thymocytes and CD8 + recent thymic emigrants (RTEs) in peripheral blood, but not in the spleen of Ox rats, and (ii) the expansion of CD8 + memory/activated peripheral blood lymphocytes and splenocytes. The latter was consistent with a greater frequency of proliferating cells among freshly isolated memory/activated CD8 + peripheral blood lymphocytes and splenocytes and increased proliferative response of CD8 + splenocytes to stimulation with plate-bound anti-CD3 antibody. The former could be related to the rise in splenic IL-7 and IL-15 mRNA expression. Although ovariectomy affected the overall number of CD4 + T cells in none of the examined compartments, it increased CD4+FoxP3 + peripheral blood lymphocyte and splenocyte counts by enhancing their generation in periphery. Collectively, the results suggest that ovariectomy-induced long-lasting disturbances in ovarian hormone levels (mirrored in diminished progesterone serum level in 20-month-old rats) affects both thymic CD8 + cell generation and peripheral homeostasis and leads to the expansion of CD4+FoxP3 + cells in the periphery, thereby enhancing autoreactive cell control on account of immune system efficacy to combat infections and tumors.
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Affiliation(s)
- Nevena Arsenović-Ranin
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia
| | - Duško Kosec
- Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", 11221 Belgrade, Serbia
| | - Mirjana Nacka-Aleksić
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia
| | - Ivan Pilipović
- Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", 11221 Belgrade, Serbia
| | - Zorica Stojić-Vukanić
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia
| | - Jasmina Djikić
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia
| | - Biljana Bufan
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia
| | - Gordana Leposavić
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia
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Abstract
PURPOSE OF REVIEW Bone disease is a leading cause of fractures and continues to be a source of significant morbidity and mortality worldwide. As the underlying mechanisms of osteoporosis are elucidated, immune dysfunction continues to emerge as a key precipitating factor in multiple bone disease contexts. This review examines recent findings in the osteoimmunology field and their implications for bone disease and for novel future therapeutic approaches to rejuvenate the skeleton. RECENT FINDINGS T-cells and B-cells have long been recognized to play important roles in the etiology of inflammatory bone disease; however, new findings continue to challenge our understanding of the depth of the immuno-skeletal interface. In this review, we examine recent evidence for new roles of B-cells in oestrogen deficiency bone loss; central actions of interleukin-7 in the cause of T-cell mediated tissue destruction in rheumatoid arthritis; novel RANKL-independent alveolar bone loss in periodontal infection; and a putative role for γδ T-cells in bisphosphonate-associated osteonecrosis of the jaw. Finally, evidence for novel bone anabolic activities mediated through T-cells by the CD28 antagonist CTLA-4Ig and by intermittently administered parathyroid hormone are examined. SUMMARY As the field of osteoimmunology continues to mature, new interrelationships between immune cells and bone turnover continue to emerge.
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Affiliation(s)
- M. Neale Weitzmann
- Atlanta Department of Veterans Affairs Medical Center, Decatur, Emory University School of Medicine, Atlanta, Georgia, USA
- Department of Medicine, Division of Endocrinology and Metabolism and Lipids, Emory University School of Medicine, Atlanta, Georgia, USA
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Ortona E, Pierdominici M, Berstein L. Autoantibodies to estrogen receptors and their involvement in autoimmune diseases and cancer. J Steroid Biochem Mol Biol 2014; 144 Pt B:260-7. [PMID: 25038321 DOI: 10.1016/j.jsbmb.2014.07.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 07/09/2014] [Accepted: 07/14/2014] [Indexed: 02/07/2023]
Abstract
The involvement of estrogens, which influence many physiologic processes, has been shown in the development or progression of several diseases including some cancers, most notably breast cancer, and autoimmune disorders. Estrogenic signal is transferred via estrogen receptors (ER) which have dual localization, predominantly intracellular but also in plasma membrane. The discovery of membrane-associated ER (mER) has greatly expanded our understanding of estrogen action; upon ligand binding, mER rapidly activate different signaling pathways inducing downstream transcription factors. Some target genes of the mER pathway may be activated independently of the intracellular ER. Additionally, intracellular ER action can be modulated by mER-initiated signaling. Most notably, the identification of autoantibodies reacting with ER (ERAB) and their possible pathogenic role in autoimmunity and cancer have opened a new path for the research in the estrogen-related receptor activity. In this review, we briefly recapitulate the localization and function of ER and mostly discuss the possible role of ERAB as novel potential prognostic and/or predictive tools in autoimmunity and cancer.
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Affiliation(s)
- Elena Ortona
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy; Istituto San Raffaele Sulmona, L'Aquila, Italy
| | - Marina Pierdominici
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
| | - Lev Berstein
- Laboratory of Oncoendocrinology, N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia
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Phospholipase cε, an effector of ras and rap small GTPases, is required for airway inflammatory response in a mouse model of bronchial asthma. PLoS One 2014; 9:e108373. [PMID: 25269075 PMCID: PMC4182471 DOI: 10.1371/journal.pone.0108373] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 08/20/2014] [Indexed: 11/29/2022] Open
Abstract
Background Phospholipase Cε (PLCε) is an effector of Ras and Rap small GTPases and expressed in non-immune cells. It is well established that PLCε plays an important role in skin inflammation, such as that elicited by phorbol ester painting or ultraviolet irradiation and contact dermatitis that is mediated by T helper (Th) 1 cells, through upregulating inflammatory cytokine production by keratinocytes and dermal fibroblasts. However, little is known about whether PLCε is involved in regulation of inflammation in the respiratory system, such as Th2-cells-mediated allergic asthma. Methods We prepared a mouse model of allergic asthma using PLCε+/+ mice and PLCεΔX/ΔX mutant mice in which PLCε was catalytically-inactive. Mice with different PLCε genotypes were immunized with ovalbumin (OVA) followed by the challenge with an OVA-containing aerosol to induce asthmatic response, which was assessed by analyzing airway hyper-responsiveness, bronchoalveolar lavage fluids, inflammatory cytokine levels, and OVA-specific immunoglobulin (Ig) levels. Effects of PLCε genotype on cytokine production were also examined with primary-cultured bronchial epithelial cells. Results After OVA challenge, the OVA-immunized PLCεΔX/ΔX mice exhibited substantially attenuated airway hyper-responsiveness and broncial inflammation, which were accompanied by reduced Th2 cytokine content in the bronchoalveolar lavage fluids. In contrast, the serum levels of OVA-specific IgGs and IgE were not affected by the PLCε genotype, suggesting that sensitization was PLCε-independent. In the challenged mice, PLCε deficiency reduced proinflammatory cytokine production in the bronchial epithelial cells. Primary-cultured bronchial epithelial cells prepared from PLCεΔX/ΔX mice showed attenuated pro-inflammatory cytokine production when stimulated with tumor necrosis factor-α, suggesting that reduced cytokine production in PLCεΔX/ΔX mice was due to cell-autonomous effect of PLCε deficiency. Conclusions PLCε plays an important role in the pathogenesis of bronchial asthma through upregulating inflammatory cytokine production by the bronchial epithelial cells.
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Adeel S, Singh K, Vydareny KH, Kumari M, Shah E, Weitzmann MN, Tangpricha V. Bone loss in surgically ovariectomized premenopausal women is associated with T lymphocyte activation and thymic hypertrophy. J Investig Med 2014; 61:1178-83. [PMID: 24141238 DOI: 10.2310/jim.0000000000000016] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Postmenopausal osteoporosis is associated with estrogen deficiency and rapid bone loss. The mechanism by which estrogen deficiency results in bone loss has not been fully explained. Studies in mice rendered acutely estrogen deficient by ovariectomy have suggested that estrogen deficiency results in an activated T-lymphocyte phenotype and increased production of pro-osteoclastic cytokines. The aim of this study was to translate these findings from mouse models that suggest that the T lymphocyte plays an important role in the etiology of postmenopausal osteoporosis. We recruited premenopausal women who underwent ovariectomy for benign gynecologic conditions or for prophylaxis against ovarian cancer and a group of matched control women without ovariectomy (OVX). Subjects provided blood samples to characterize T-lymphocyte phenotype by flow cytometry and for T-lymphocyte culture and collection of conditioned media. Bone mineral density at the lumbar spine and left femoral neck was performed annually for 2 years, and volumetric measurements by computed tomography (CT) of the thymus were obtained during the first 6 months. We enrolled 6 patients who underwent OVX and 13 control women. The OVX subjects had a significant loss of bone mineral density at the lumbar spine and left femoral neck. The volumetric thymus measurements suggested an increase in thymus size in the OVX subjects but did not reach statistical significance owing to the small sample size. The T-lymphocyte phenotype in the OVX subjects demonstrated increased T-lymphocyte activation by flow cytometry compared to the control subjects. Our findings support the hypothesis that estrogen deficiency leads to an activated T-lymphocyte phenotype, which may contribute to the bone loss seen in estrogen deficiency. Larger clinical studies are necessary to confirm these findings.
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Affiliation(s)
- Saira Adeel
- From the *Division of Endocrinology, Metabolism and Lipids, Department of Medicine, †Department of Surgery, and ‡Department of Radiology, Emory University School of Medicine, Atlanta; and §Atlanta VA Medical Center, Decatur, GA
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Abstract
PURPOSE OF REVIEW Low bone mineral density (BMD) is common in those with HIV, associated with higher bone turnover and a higher prevalence of fractures. This review explores low BMD in HIV, focusing on underlying mechanisms and relationships between low BMD and HIV infection, immune dysfunction, and antiretroviral therapy (ART). RECENT FINDINGS Greater reductions in BMD accompanying reductions in HIV viremia at initiation of first-line or second-line ART suggest an important role for immune- or viral-mediated mechanisms in its pathogenesis. SUMMARY As bone metabolism is part-regulated by T cells and B cells, we propose that earlier initiation of ART at higher CD4 T-cell counts may attenuate BMD loss by abrogating immune- and viral-mediated disturbances in bone metabolism that accompany ART initiation. Further pathogenesis-based research is required in this field, focusing on the complex interaction between virus, immune system, ART, and bone metabolism.
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Roato I. Bone metastases: When and how lung cancer interacts with bone. World J Clin Oncol 2014; 5:149-155. [PMID: 24829862 PMCID: PMC4014787 DOI: 10.5306/wjco.v5.i2.149] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/21/2014] [Accepted: 03/18/2014] [Indexed: 02/06/2023] Open
Abstract
Bone metastasis is a common and debilitating consequence of lung cancer: 30%-40% of patients with non-small cell lung cancer develop bone metastases during the course of their disease. Lung cancer cells find a favorable soil in the bone microenvironment due to factors released by the bone matrix, the immune system cells, and the same cancer cells. Many aspects of the cross-talk among lung tumor cells, the immune system, and bone cells are not clear, but this review aims to summarize the recent findings in this field, with particular attention to studies conducted to identify biomarkers for early detection of lung cancer bone metastases.
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Adeel S, Singh K, Vydareny KH, Kumari M, Shah E, Weitzmann MN, Tangpricha V. Bone loss in surgically ovariectomized premenopausal women is associated with T lymphocyte activation and thymic hypertrophy. J Investig Med 2013; 61. [PMID: 24141238 PMCID: PMC3918442 DOI: 10.231/jim.0000000000000016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Postmenopausal osteoporosis is associated with estrogen deficiency and rapid bone loss. The mechanism by which estrogen deficiency results in bone loss has not been fully explained. Studies in mice rendered acutely estrogen deficient by ovariectomy have suggested that estrogen deficiency results in an activated T-lymphocyte phenotype and increased production of pro-osteoclastic cytokines. The aim of this study was to translate these findings from mouse models that suggest that the T lymphocyte plays an important role in the etiology of postmenopausal osteoporosis. We recruited premenopausal women who underwent ovariectomy for benign gynecologic conditions or for prophylaxis against ovarian cancer and a group of matched control women without ovariectomy (OVX). Subjects provided blood samples to characterize T-lymphocyte phenotype by flow cytometry and for T-lymphocyte culture and collection of conditioned media. Bone mineral density at the lumbar spine and left femoral neck was performed annually for 2 years, and volumetric measurements by computed tomography (CT) of the thymus were obtained during the first 6 months. We enrolled 6 patients who underwent OVX and 13 control women. The OVX subjects had a significant loss of bone mineral density at the lumbar spine and left femoral neck. The volumetric thymus measurements suggested an increase in thymus size in the OVX subjects but did not reach statistical significance owing to the small sample size. The T-lymphocyte phenotype in the OVX subjects demonstrated increased T-lymphocyte activation by flow cytometry compared to the control subjects. Our findings support the hypothesis that estrogen deficiency leads to an activated T-lymphocyte phenotype, which may contribute to the bone loss seen in estrogen deficiency. Larger clinical studies are necessary to confirm these findings.
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Affiliation(s)
- Saira Adeel
- Division of Endocrinology, Metabolism & Lipids,
Department of Medicine, Emory University School of Medicine, Atlanta, GA USA
| | - Karnail Singh
- Department of Surgery, Emory University School of
Medicine, Atlanta, GA USA
| | - Kay H. Vydareny
- Department of Radiology, Emory University School of
Medicine, Atlanta, GA USA
| | - Meena Kumari
- Division of Endocrinology, Metabolism & Lipids,
Department of Medicine, Emory University School of Medicine, Atlanta, GA USA
| | - Era Shah
- Division of Endocrinology, Metabolism & Lipids,
Department of Medicine, Emory University School of Medicine, Atlanta, GA USA
| | - Mervyn Neale Weitzmann
- Division of Endocrinology, Metabolism & Lipids,
Department of Medicine, Emory University School of Medicine, Atlanta, GA USA., Atlanta VA Medical Center, Decatur, GA USA
| | - Vin Tangpricha
- Division of Endocrinology, Metabolism & Lipids,
Department of Medicine, Emory University School of Medicine, Atlanta, GA USA., Atlanta VA Medical Center, Decatur, GA USA
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Karieb S, Fox SW. Suppression of T cell-induced osteoclast formation. Biochem Biophys Res Commun 2013; 436:619-24. [DOI: 10.1016/j.bbrc.2013.05.140] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Accepted: 05/31/2013] [Indexed: 10/26/2022]
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Interaction among cells of bone, immune system, and solid tumors leads to bone metastases. Clin Dev Immunol 2013; 2013:315024. [PMID: 23710201 PMCID: PMC3655477 DOI: 10.1155/2013/315024] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Accepted: 04/08/2013] [Indexed: 01/05/2023]
Abstract
Bone metastases are a dismal consequence for different types of solid tumors, such as breast, prostate, lung, and kidney cancer. The mechanisms regulating the interactions among bone, immune system, and tumor cells have been deeply investigated, and many studies are ongoing to define the specific role of the different cells in the bone metastatic process. The affinity of some tumors to growth in bone results from the special microenvironment provided by bone. Moreover, immune system and bone have a bidirectional relationship: bone cells express surface molecules ruling the expansion of hemopoietic stem cells from which all cells of the mammalian immune system derive, and various immunoregulatory cytokines influence the fate of bone cells. The last findings allow to extend the concept of vicious cycle and add T cells as mediators of the tumor growth in bone.
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Imai Y, Youn MY, Inoue K, Takada I, Kouzmenko A, Kato S. Nuclear receptors in bone physiology and diseases. Physiol Rev 2013; 93:481-523. [PMID: 23589826 PMCID: PMC3768103 DOI: 10.1152/physrev.00008.2012] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
During the last decade, our view on the skeleton as a mere solid physical support structure has been transformed, as bone emerged as a dynamic, constantly remodeling tissue with systemic regulatory functions including those of an endocrine organ. Reflecting this remarkable functional complexity, distinct classes of humoral and intracellular regulatory factors have been shown to control vital processes in the bone. Among these regulators, nuclear receptors (NRs) play fundamental roles in bone development, growth, and maintenance. NRs are DNA-binding transcription factors that act as intracellular transducers of the respective ligand signaling pathways through modulation of expression of specific sets of cognate target genes. Aberrant NR signaling caused by receptor or ligand deficiency may profoundly affect bone health and compromise skeletal functions. Ligand dependency of NR action underlies a major strategy of therapeutic intervention to correct aberrant NR signaling, and significant efforts have been made to design novel synthetic NR ligands with enhanced beneficial properties and reduced potential negative side effects. As an example, estrogen deficiency causes bone loss and leads to development of osteoporosis, the most prevalent skeletal disorder in postmenopausal women. Since administration of natural estrogens for the treatment of osteoporosis often associates with undesirable side effects, several synthetic estrogen receptor ligands have been developed with higher therapeutic efficacy and specificity. This review presents current progress in our understanding of the roles of various nuclear receptor-mediated signaling pathways in bone physiology and disease, and in development of advanced NR ligands for treatment of common skeletal disorders.
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Affiliation(s)
- Yuuki Imai
- Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
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Gazzola L, Bellistri GM, Tincati C, Ierardi V, Savoldi A, Del Sole A, Tagliabue L, d'Arminio Monforte A, Marchetti G. Association between peripheral T-Lymphocyte activation and impaired bone mineral density in HIV-infected patients. J Transl Med 2013; 11:51. [PMID: 23448662 PMCID: PMC3598927 DOI: 10.1186/1479-5876-11-51] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Accepted: 02/21/2013] [Indexed: 11/12/2022] Open
Abstract
Background HIV-infected patients display an increased and early incidence of osteopenia/osteoporosis. We investigated whether bone metabolism disorders in HIV-infected patients are related to immune hyperactivation and premature immune senescence. Methods Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA): low BMD (LBMD) was defined as T-score or z-score < -1. CD4+/CD8+ phenotype (CD38/HLA-DR, CD127, CD28/CD57), and circulating IL-7, TNF-α, RANKL, OPG were measured. The variables with p < .05 were evaluated by multivariate logistic regression. Results 78 patients were enrolled: 55 were LBMD. LBMD patients showed increased activated HDLADR + CD4+ and CD8+ (p = .03 and p = .002, respectively). Interestingly, no differences in senescent CD28-CD57 + CD4+/CD8+ T-cells were observed between groups. However, LBMD patients displayed a decreased CD4 + CD28- phenotype (p = .04) at the advantage of the CD28+ pool (p = .03), possibly reflecting heightened apoptosis of highly differentiated CD28-negative cells. Activated HLADR + CD4+/CD8+ and CD28 + CD4+ cells were independently associated with impaired BMD (AOR = 1.08 for each additional HLADR + CD4+ percentage higher; CI 95%,1.01-1.15; p = .02; AOR = 1.07 for each additional HLADR + CD8+ percentage higher; CI 95%,1.01-1.11; p = .01; AOR = 1.06 for each additional CD28 + CD4+ percentage higher; CI 95%,1.0-1.13; p = .05). Conclusions Heightened T-cell activation in HIV-infected patients independently predicts BMD disorders, suggesting a critical role of immune activation in the pathogenesis of osteopenia/osteoporosis, even in patients achieving full viral suppression with HAART. Electronic supplementary material The online version of this article (doi:10.1186/1479-5876-11-51) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lidia Gazzola
- Department of Health Sciences, Clinic of Infectious Diseases, San Paolo Hospital, University of Milan, Via A, Di Rudinì, 8, Milan 20142, Italy
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Weitzmann MN. The Role of Inflammatory Cytokines, the RANKL/OPG Axis, and the Immunoskeletal Interface in Physiological Bone Turnover and Osteoporosis. SCIENTIFICA 2013; 2013:125705. [PMID: 24278766 PMCID: PMC3820310 DOI: 10.1155/2013/125705] [Citation(s) in RCA: 137] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Accepted: 12/24/2012] [Indexed: 05/30/2023]
Abstract
Although it has long been recognized that inflammation, a consequence of immune-driven processes, significantly impacts bone turnover, the degree of centralization of skeletal and immune functions has begun to be dissected only recently. It is now recognized that formation of osteoclasts, the bone resorbing cells of the body, is centered on the key osteoclastogenic cytokine, receptor activator of NF- κ B ligand (RANKL). Although numerous inflammatory cytokines are now recognized to promote osteoclast formation and skeletal degradation, with just a few exceptions, RANKL is now considered to be the final downstream effector cytokine that drives osteoclastogenesis and regulates osteoclastic bone resorption. The biological activity of RANKL is moderated by its physiological decoy receptor, osteoprotegerin (OPG). New discoveries concerning the sources and regulation of RANKL and OPG in physiological bone turnover as well as under pathological (osteoporotic) conditions continue to be made, opening a window to the complex regulatory processes that control skeletal integrity and the depth of integration of the skeleton within the immune response. This paper will examine the interconnection between bone turnover and the immune system and the implications thereof for physiological and pathological bone turnover.
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Affiliation(s)
- M. Neale Weitzmann
- Atlanta Department of Veterans Affairs Medical Center, Decatur, GA 30033, USA
- Division of Endocrinology and Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, 101 Woodruff Circle, 1305 WMRB, Atlanta, GA 30322, USA
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