Pub Date : 2026-01-03DOI: 10.1038/s41413-025-00478-1
Rafael Scaf de Molon,Rolando Vernal,Gabriela Ezequiel Oliveira,Joao Paulo Steffens,Edilson Ervolino,Leticia Helena Theodoro,Jeroen J J P van den Beucken,Sotirios Tetradis
Bone resorption is a vital physiological process that enables skeletal remodeling, maintenance, and adaptation to mechanical forces throughout life. While tightly regulated under the physiological state, its dysregulation contributes to pathological conditions such as osteoporosis, rheumatoid arthritis, and periodontitis. Periodontitis is a highly prevalent chronic inflammatory disease driven by dysbiotic biofilms that disrupt the oral microbiome, leading to the progressive breakdown of the periodontal ligament, cementum, and alveolar bone and ultimately resulting in tooth loss. This review outlines the molecular and cellular mechanisms underlying periodontitis, focusing on osteoclastogenesis, the differentiation and activation of osteoclasts, the primary mediators of bone resorption. Key transcriptional regulators, including NFATc1, c-Fos, and c-Src are discussed alongside major signaling pathways such as Mitogen Activated Protein Kinase (MAPK), Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), Nuclear Factor Kappa B (NF-κB), and Phosphoinositide 3-kinase (PI3K)/Akt, to elucidate their roles in the initiation and progression of periodontal bone loss. These pathways orchestrate the inflammatory response and osteoclast activity, underscoring their relevance in periodontitis and other osteolytic conditions. Hallmark features of periodontitis, including chronic inflammation, immune dysregulation, and tissue destruction are highlighted, with emphasis on current and emerging therapeutic strategies targeting these molecular pathways. Special attention is given to small molecules, biologics, and natural compounds that have the potential to modulate key signaling pathways. Although advances in understanding these mechanisms have identified promising therapeutic targets, translation into effective clinical interventions remains challenging. Continued research into regulating bone-resorptive signaling pathways is essential for developing more effective treatments for periodontitis and related inflammatory bone diseases.
{"title":"Inflammatory bone loss and signaling pathways in periodontitis: mechanistic insights and emerging therapeutic strategies.","authors":"Rafael Scaf de Molon,Rolando Vernal,Gabriela Ezequiel Oliveira,Joao Paulo Steffens,Edilson Ervolino,Leticia Helena Theodoro,Jeroen J J P van den Beucken,Sotirios Tetradis","doi":"10.1038/s41413-025-00478-1","DOIUrl":"https://doi.org/10.1038/s41413-025-00478-1","url":null,"abstract":"Bone resorption is a vital physiological process that enables skeletal remodeling, maintenance, and adaptation to mechanical forces throughout life. While tightly regulated under the physiological state, its dysregulation contributes to pathological conditions such as osteoporosis, rheumatoid arthritis, and periodontitis. Periodontitis is a highly prevalent chronic inflammatory disease driven by dysbiotic biofilms that disrupt the oral microbiome, leading to the progressive breakdown of the periodontal ligament, cementum, and alveolar bone and ultimately resulting in tooth loss. This review outlines the molecular and cellular mechanisms underlying periodontitis, focusing on osteoclastogenesis, the differentiation and activation of osteoclasts, the primary mediators of bone resorption. Key transcriptional regulators, including NFATc1, c-Fos, and c-Src are discussed alongside major signaling pathways such as Mitogen Activated Protein Kinase (MAPK), Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), Nuclear Factor Kappa B (NF-κB), and Phosphoinositide 3-kinase (PI3K)/Akt, to elucidate their roles in the initiation and progression of periodontal bone loss. These pathways orchestrate the inflammatory response and osteoclast activity, underscoring their relevance in periodontitis and other osteolytic conditions. Hallmark features of periodontitis, including chronic inflammation, immune dysregulation, and tissue destruction are highlighted, with emphasis on current and emerging therapeutic strategies targeting these molecular pathways. Special attention is given to small molecules, biologics, and natural compounds that have the potential to modulate key signaling pathways. Although advances in understanding these mechanisms have identified promising therapeutic targets, translation into effective clinical interventions remains challenging. Continued research into regulating bone-resorptive signaling pathways is essential for developing more effective treatments for periodontitis and related inflammatory bone diseases.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"24 1","pages":"1"},"PeriodicalIF":12.7,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osteoarthritis (OA) is a common degenerative joint disease with complex risk factors, and its underlying mechanism remains unclear. The disease has a subtle onset and mild early symptoms, and its progression is irreversible. Current treatments do not offer a complete cure. Therefore, developing new therapies, early prevention strategies, and reliable biomarkers is essential to reduce the disease burden and improve the quality of life for OA patients. Extracellular vesicles, with their natural biocompatibility and low immunogenicity, have shown great potential in drug delivery and acellular therapies. To provide a complete understanding of the current research and future prospects of extracellular vesicles in OA, this study used bibliometric analysis and Latent Dirichlet Allocation (LDA) methods to systematically evaluate international collaborations, research hotspots, and emerging trends in the field. Our aim is to offer a scientific basis and reference for innovative OA treatment strategies and the clinical application of extracellular vesicles.
{"title":"Bibliometric and LDA analysis of extracellular vesicles in osteoarthritis.","authors":"Hongyu Xie,Lin Zhao,Lunwei Kang,Weikun Meng,Jianshu Tan,Ga Liao","doi":"10.1038/s41413-025-00484-3","DOIUrl":"https://doi.org/10.1038/s41413-025-00484-3","url":null,"abstract":"Osteoarthritis (OA) is a common degenerative joint disease with complex risk factors, and its underlying mechanism remains unclear. The disease has a subtle onset and mild early symptoms, and its progression is irreversible. Current treatments do not offer a complete cure. Therefore, developing new therapies, early prevention strategies, and reliable biomarkers is essential to reduce the disease burden and improve the quality of life for OA patients. Extracellular vesicles, with their natural biocompatibility and low immunogenicity, have shown great potential in drug delivery and acellular therapies. To provide a complete understanding of the current research and future prospects of extracellular vesicles in OA, this study used bibliometric analysis and Latent Dirichlet Allocation (LDA) methods to systematically evaluate international collaborations, research hotspots, and emerging trends in the field. Our aim is to offer a scientific basis and reference for innovative OA treatment strategies and the clinical application of extracellular vesicles.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"99 1","pages":"105"},"PeriodicalIF":12.7,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Evidence on the association between osteoporosis and dementia is not fully clear. This study aimed to investigate the potential association between osteoporosis and the subsequent risk of dementia among older adults. We performed a cohort study of 176 150 community-dwelling older adults aged ≥65 years and free of cognitive impairment between 2018 and 2022 using integrated healthcare data from Shenzhen, China. Diagnoses of osteoporosis, osteoporotic fractures, and dementia were identified through linked outpatient and inpatient medical records and death registration records. Multivariate Cox proportional hazards models were used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of incident dementia associated with osteoporosis and osteoporotic fractures. The mean (SD) age of the total study population was 70.7 (5.4) years, and 9 605 had a previous diagnosis of osteoporosis. Over a median follow-up of 2.2 (IQR: 1.8-4.3, maximum: 5.5) years, corresponding to 505 423 person-years at risk, 1 367 incident all-cause dementia cases, including 617 Alzheimer's disease and 298 vascular dementia cases, occurred. Physician-diagnosed osteoporosis was associated with a higher risk of all-cause dementia (HR: 1.80, 95% CI: 1.53-2.12). The increased dementia risk tended to be more prominent among patients with osteoporotic fractures (HR: 2.43, 95% CI: 1.83-3.23) than those without (HR: 1.63, 95% CI: 1.35-1.97). Results were similar for Alzheimer's disease and vascular dementia. This study provides evidence that older adults with osteoporosis, especially those with osteoporotic fractures, have an elevated risk of incident dementia. Effective prevention and management of osteoporosis among the older population may be promising to mitigate the dual burden of osteoporosis and dementia.
{"title":"Osteoporosis and risk of dementia among older adults: a population‑based cohort study.","authors":"Jiangshui Wang,Shuang Wang,Cheng Jin,Xia Li,Chunbao Mo,Jing Zheng,Xiangfeng Lu,Fengchao Liang,Dongfeng Gu","doi":"10.1038/s41413-025-00480-7","DOIUrl":"https://doi.org/10.1038/s41413-025-00480-7","url":null,"abstract":"Evidence on the association between osteoporosis and dementia is not fully clear. This study aimed to investigate the potential association between osteoporosis and the subsequent risk of dementia among older adults. We performed a cohort study of 176 150 community-dwelling older adults aged ≥65 years and free of cognitive impairment between 2018 and 2022 using integrated healthcare data from Shenzhen, China. Diagnoses of osteoporosis, osteoporotic fractures, and dementia were identified through linked outpatient and inpatient medical records and death registration records. Multivariate Cox proportional hazards models were used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of incident dementia associated with osteoporosis and osteoporotic fractures. The mean (SD) age of the total study population was 70.7 (5.4) years, and 9 605 had a previous diagnosis of osteoporosis. Over a median follow-up of 2.2 (IQR: 1.8-4.3, maximum: 5.5) years, corresponding to 505 423 person-years at risk, 1 367 incident all-cause dementia cases, including 617 Alzheimer's disease and 298 vascular dementia cases, occurred. Physician-diagnosed osteoporosis was associated with a higher risk of all-cause dementia (HR: 1.80, 95% CI: 1.53-2.12). The increased dementia risk tended to be more prominent among patients with osteoporotic fractures (HR: 2.43, 95% CI: 1.83-3.23) than those without (HR: 1.63, 95% CI: 1.35-1.97). Results were similar for Alzheimer's disease and vascular dementia. This study provides evidence that older adults with osteoporosis, especially those with osteoporotic fractures, have an elevated risk of incident dementia. Effective prevention and management of osteoporosis among the older population may be promising to mitigate the dual burden of osteoporosis and dementia.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"30 1","pages":"104"},"PeriodicalIF":12.7,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neurofibromatosis type 1 (NF1) is a genetic disorder affecting 1 in 3 000 people due to heterozygous mutations in the NF1 gene. Patients with NF1 can develop multiple symptoms, such as neurofibromas, skin hyperpigmentation, and bone abnormalities, including tibial pseudarthrosis and spine deformity. Here, we aimed to elucidate the cellular origin and pathogenic mechanism of NF1 spine deformity. We explored the Prss56-Nf1 knockout (KO) mouse model that recapitulates neurofibromas and pseudarthrosis by carrying Nf1 gene inactivation in Prss56-expressing boundary cap cells, a neural crest subset, and their derivatives. Micro-CT analyses showed that Prss56-Nf1 KO mice exhibit spine deformity from 12 months of age, associated with vertebral anomalies reminiscent of patients with NF1. Fate mapping revealed a significant increase in OSX+ osteoblasts of the Prss56 lineage in vertebrae of Prss56-Nf1 KO mice. Increased traced Nf1-deficient cells correlated with increased vertebral bone volume and kyphosis spine curvature. Finally, we showed that treating Prss56-Nf1 KO mice with RAS-MAPK pathway inhibitors prevented spine deformity. Overall, the Prss56-Nf1 KO mouse model unravels the role of osteoblasts from the Prss56 lineage as the cellular origin of NF1 spine deformity and highlights RAS-MAPK pathway inhibition as a promising therapeutic strategy for preventing NF1 spine deformity.
{"title":"Pharmacological inhibition of RAS pathway alleviates spine deformity in a mouse model of neurofibromatosis type 1.","authors":"Franceska Kovaci,Cassandre Goachet,Simon Perrin,Lotfi Slimani,Fanny Coulpier,Françoise Tilotta,Piotr Topilko,Céline Colnot","doi":"10.1038/s41413-025-00492-3","DOIUrl":"https://doi.org/10.1038/s41413-025-00492-3","url":null,"abstract":"Neurofibromatosis type 1 (NF1) is a genetic disorder affecting 1 in 3 000 people due to heterozygous mutations in the NF1 gene. Patients with NF1 can develop multiple symptoms, such as neurofibromas, skin hyperpigmentation, and bone abnormalities, including tibial pseudarthrosis and spine deformity. Here, we aimed to elucidate the cellular origin and pathogenic mechanism of NF1 spine deformity. We explored the Prss56-Nf1 knockout (KO) mouse model that recapitulates neurofibromas and pseudarthrosis by carrying Nf1 gene inactivation in Prss56-expressing boundary cap cells, a neural crest subset, and their derivatives. Micro-CT analyses showed that Prss56-Nf1 KO mice exhibit spine deformity from 12 months of age, associated with vertebral anomalies reminiscent of patients with NF1. Fate mapping revealed a significant increase in OSX+ osteoblasts of the Prss56 lineage in vertebrae of Prss56-Nf1 KO mice. Increased traced Nf1-deficient cells correlated with increased vertebral bone volume and kyphosis spine curvature. Finally, we showed that treating Prss56-Nf1 KO mice with RAS-MAPK pathway inhibitors prevented spine deformity. Overall, the Prss56-Nf1 KO mouse model unravels the role of osteoblasts from the Prss56 lineage as the cellular origin of NF1 spine deformity and highlights RAS-MAPK pathway inhibition as a promising therapeutic strategy for preventing NF1 spine deformity.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"1 1","pages":"103"},"PeriodicalIF":12.7,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The bone marrow microenvironment is critical for the maintenance and functionality of stem/progenitor cells, which are essential for bone development and regeneration. However, the composition and potential use of bone marrow interstitial fluid have not been well explored. In this study, we report the role of neonatal bovine bone marrow interstitial fluid (NBIF) in enhancing the bone regeneration capacity of human bone marrow mesenchymal stem cells (hBMSCs). Unlike adult bovine bone marrow interstitial fluid (ABIF), NBIF-fed hBMSCs exhibit enhanced self-renewal and osteogenic potential and bone marrow homing ability, along with transcriptome changes as compared to hBMSCs cultured in standard fetal bovine serum (FBS) supplemented medium. Mass spectrometry analysis reveals that multiple secreted factors associated with tissue repair and bone development are enriched in NBIF compared to FBS and ABIF. The combined use of NBIF-enriched Nerve Growth Factor (NGF), Lactoferrin (LTF), and High Mobility Group Protein B1 (HMGB1), together with Insulin-Like Growth Factor 1(IGF1) for culturing hBMSCs in the presence of FBS can enhance osteogenic potential and bone marrow homing ability, mimicking NBIF's effects. These findings highlight the role of interstitial fluid in the bone marrow microenvironment and its potential to optimize stem cell-based therapies.
{"title":"Neonatal bone marrow interstitial fluid supports expansion and osteogenic ability of human bone marrow mesenchymal stromal cells.","authors":"Junfeng Zhang,Tengjiao Ma,Lan Ke,Huan Zhang,Jiaxin Hu,Shunping Li,Hailong Wang,Anming Meng","doi":"10.1038/s41413-025-00496-z","DOIUrl":"https://doi.org/10.1038/s41413-025-00496-z","url":null,"abstract":"The bone marrow microenvironment is critical for the maintenance and functionality of stem/progenitor cells, which are essential for bone development and regeneration. However, the composition and potential use of bone marrow interstitial fluid have not been well explored. In this study, we report the role of neonatal bovine bone marrow interstitial fluid (NBIF) in enhancing the bone regeneration capacity of human bone marrow mesenchymal stem cells (hBMSCs). Unlike adult bovine bone marrow interstitial fluid (ABIF), NBIF-fed hBMSCs exhibit enhanced self-renewal and osteogenic potential and bone marrow homing ability, along with transcriptome changes as compared to hBMSCs cultured in standard fetal bovine serum (FBS) supplemented medium. Mass spectrometry analysis reveals that multiple secreted factors associated with tissue repair and bone development are enriched in NBIF compared to FBS and ABIF. The combined use of NBIF-enriched Nerve Growth Factor (NGF), Lactoferrin (LTF), and High Mobility Group Protein B1 (HMGB1), together with Insulin-Like Growth Factor 1(IGF1) for culturing hBMSCs in the presence of FBS can enhance osteogenic potential and bone marrow homing ability, mimicking NBIF's effects. These findings highlight the role of interstitial fluid in the bone marrow microenvironment and its potential to optimize stem cell-based therapies.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"16 1","pages":"102"},"PeriodicalIF":12.7,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1038/s41413-025-00443-y
Manli Tu, Mi Yang, Nanxi Yu, Gehua Zhen, Mei Wan, Wenlong Liu, Baochao Ji, Hairong Ma, Qiaoyue Guo, Peijian Tong, Li Cao, Xianghang Luo, Xu Cao
{"title":"Author Correction: Inhibition of cyclooxygenase-2 activity in subchondral bone modifies a subtype of osteoarthritis.","authors":"Manli Tu, Mi Yang, Nanxi Yu, Gehua Zhen, Mei Wan, Wenlong Liu, Baochao Ji, Hairong Ma, Qiaoyue Guo, Peijian Tong, Li Cao, Xianghang Luo, Xu Cao","doi":"10.1038/s41413-025-00443-y","DOIUrl":"10.1038/s41413-025-00443-y","url":null,"abstract":"","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"13 1","pages":"101"},"PeriodicalIF":15.0,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osteoclast-development patterns and their alterations across Ankylosing Spondylitis (AS) conditions are mysterious, making AS treatment difficult. Our study aims to clarify osteoclast-precursor (OCP) development patterns from monocytes and their variations under AS conditions. We performed single-cell transcriptomics in peripheral blood mononuclear cells (PBMCs) from healthy donors and AS patients in the early, aggravated and remission stages. After monocytic reclustering, OCP-development patterns and the alterations upon AS onset and different outcomes were revealed based on single-cell trajectory. The trajectories revealed two monocyte states with strong OCP features, and AS pathogenesis was characterized by their reduction. Ribosome synthesis was considered the essential function for the development towards OCP-featured states, and this function and its representative molecule, RPS17, showed a decreasing trend with AS onset and outcomes. Histology assessment showed that RPS17 underexpression participated in AS inflammatory osteogenesis and ankylosing destruction. Conditional knockout of RPS17 ameliorated ovariectomy-induced bone loss and enhanced osteoclastogenesis, and RPS17 overexpression improved the phenotype of AS-like mice. Importantly, local injection of RPS17-overexpressed monocytic OCPs markedly ameliorated the joint alterations of AS-like mice without promoting bone loss; this was associated with enhanced osteoclastogenesis adjacent to the articular surface and T-cell-suppressive property in monocytic OCPs. Overall, the evolution of monocytes towards OCP-lineage fate mainly depends on ribosome synthesis, and OCP-development disorder participates in AS lesions due to a reduction in RPS17-dependent ribosome synthesis. Notably, RPS17-overexpressed monocytic OCPs have translational potential in preventing and treating AS peripheral lesions.
{"title":"Human peripheral osteoclast-precursor-development patterns reveal the significance of RPS17-dependent ribosome synthesis to Ankylosing Spondylitis lesions.","authors":"Dianshan Ke,Hanhao Dai,Junyong Han,Yibin Su,Hongyi Zhu,Rongsheng Zhang,Tingwei Gao,Linhai Yang,Yunlong Yu,Xiaochun Bai,Changqing Zhang,Jie Xu","doi":"10.1038/s41413-025-00474-5","DOIUrl":"https://doi.org/10.1038/s41413-025-00474-5","url":null,"abstract":"Osteoclast-development patterns and their alterations across Ankylosing Spondylitis (AS) conditions are mysterious, making AS treatment difficult. Our study aims to clarify osteoclast-precursor (OCP) development patterns from monocytes and their variations under AS conditions. We performed single-cell transcriptomics in peripheral blood mononuclear cells (PBMCs) from healthy donors and AS patients in the early, aggravated and remission stages. After monocytic reclustering, OCP-development patterns and the alterations upon AS onset and different outcomes were revealed based on single-cell trajectory. The trajectories revealed two monocyte states with strong OCP features, and AS pathogenesis was characterized by their reduction. Ribosome synthesis was considered the essential function for the development towards OCP-featured states, and this function and its representative molecule, RPS17, showed a decreasing trend with AS onset and outcomes. Histology assessment showed that RPS17 underexpression participated in AS inflammatory osteogenesis and ankylosing destruction. Conditional knockout of RPS17 ameliorated ovariectomy-induced bone loss and enhanced osteoclastogenesis, and RPS17 overexpression improved the phenotype of AS-like mice. Importantly, local injection of RPS17-overexpressed monocytic OCPs markedly ameliorated the joint alterations of AS-like mice without promoting bone loss; this was associated with enhanced osteoclastogenesis adjacent to the articular surface and T-cell-suppressive property in monocytic OCPs. Overall, the evolution of monocytes towards OCP-lineage fate mainly depends on ribosome synthesis, and OCP-development disorder participates in AS lesions due to a reduction in RPS17-dependent ribosome synthesis. Notably, RPS17-overexpressed monocytic OCPs have translational potential in preventing and treating AS peripheral lesions.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"19 1","pages":"100"},"PeriodicalIF":12.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Weight loss, whether resulting from disease-related conditions or intentional interventions, has been increasingly recognized as a significant risk factor for compromised skeletal integrity. While moderate weight reduction may yield metabolic benefits, rapid or sustained weight loss is frequently associated with decreased bone mineral density, deterioration of bone microarchitecture, and heightened fracture risk. The mechanisms underlying weight loss-induced bone loss are complex and multifactorial. Emerging evidence highlights a range of contributing factors, including reduced mechanical loading, increased bone marrow adiposity, hormonal and endocrine alterations, nutritional deficiencies, and disruptions in energy metabolism. These mechanisms are intricately interconnected, ultimately impairing bone remodeling and homeostatic balance. In this review, we provide a comprehensive analysis of the current literature on the mechanistic pathways, clinical consequences, and therapeutic strategies related to weight loss-induced bone loss. We further differentiate the skeletal effects of disease-associated versus intervention-induced weight loss, with a focus on their distinct molecular underpinnings. Our goal is to offer novel insights into the optimization of bone health management in the context of weight loss, guided by a translational medicine perspective.
{"title":"Weight loss induced bone loss: mechanism of action and clinical implications.","authors":"Hanghang Liu, Bolun Li, Linyi Liu, Wangyang Ying, Clifford J Rosen","doi":"10.1038/s41413-025-00483-4","DOIUrl":"10.1038/s41413-025-00483-4","url":null,"abstract":"<p><p>Weight loss, whether resulting from disease-related conditions or intentional interventions, has been increasingly recognized as a significant risk factor for compromised skeletal integrity. While moderate weight reduction may yield metabolic benefits, rapid or sustained weight loss is frequently associated with decreased bone mineral density, deterioration of bone microarchitecture, and heightened fracture risk. The mechanisms underlying weight loss-induced bone loss are complex and multifactorial. Emerging evidence highlights a range of contributing factors, including reduced mechanical loading, increased bone marrow adiposity, hormonal and endocrine alterations, nutritional deficiencies, and disruptions in energy metabolism. These mechanisms are intricately interconnected, ultimately impairing bone remodeling and homeostatic balance. In this review, we provide a comprehensive analysis of the current literature on the mechanistic pathways, clinical consequences, and therapeutic strategies related to weight loss-induced bone loss. We further differentiate the skeletal effects of disease-associated versus intervention-induced weight loss, with a focus on their distinct molecular underpinnings. Our goal is to offer novel insights into the optimization of bone health management in the context of weight loss, guided by a translational medicine perspective.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"13 1","pages":"99"},"PeriodicalIF":15.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12669760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The global aging crisis has increased the prevalence of skeletal disorders, necessitating innovative therapeutic strategies. This review employs the brain-bone axis (BBA) framework to examine the role of the sympathetic nervous system (SNS) in bone metabolism. The research systematically elucidates the molecular mechanisms by which the SNS mediates signaling pathways through neurofibers and neurotransmitters, such as norepinephrine, dopamine, neuropeptide Y, and leptin, regulating interactions between bone-related cells to maintain skeletal homeostasis. It also identifies the pathological associations between the dysregulation of these pathways and the progression of bone-related conditions, such as osteoporosis, osteoarthritis, and intervertebral disc degeneration. By integrating current evidence, we identify novel therapeutic targets within the BBA and propose neuro-centric intervention strategies to mitigate skeletal diseases. This review deepens the understanding of neuro-skeletal interactions and lays a foundation for innovative treatments for bone-related pathologies.
{"title":"Molecular mechanisms and therapeutic implications of the sympathetic nervous system in bone-related disorders: a brain-bone axis perspective.","authors":"Mingdong Liu, Yaqi Liu, Jiayao Yu, Jiaqi Gong, Chunguang Zhao, Zheng Liu","doi":"10.1038/s41413-025-00494-1","DOIUrl":"10.1038/s41413-025-00494-1","url":null,"abstract":"<p><p>The global aging crisis has increased the prevalence of skeletal disorders, necessitating innovative therapeutic strategies. This review employs the brain-bone axis (BBA) framework to examine the role of the sympathetic nervous system (SNS) in bone metabolism. The research systematically elucidates the molecular mechanisms by which the SNS mediates signaling pathways through neurofibers and neurotransmitters, such as norepinephrine, dopamine, neuropeptide Y, and leptin, regulating interactions between bone-related cells to maintain skeletal homeostasis. It also identifies the pathological associations between the dysregulation of these pathways and the progression of bone-related conditions, such as osteoporosis, osteoarthritis, and intervertebral disc degeneration. By integrating current evidence, we identify novel therapeutic targets within the BBA and propose neuro-centric intervention strategies to mitigate skeletal diseases. This review deepens the understanding of neuro-skeletal interactions and lays a foundation for innovative treatments for bone-related pathologies.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"13 1","pages":"98"},"PeriodicalIF":15.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12669603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Survival of motor neuron (SMN) protein encoded by SMN1 gene, is the essential and ubiquitously expressed protein in all tissues. Prior studies demonstrated that SMN deficiency impaired bone development, but the underlying mechanism of abnormal endochondral ossification remains obscure. Here, we showed SMN is involved in hypertrophic chondrocytes differentiation through regulating RNA splicing and protein degradation via analyzing single cell RNA-sequencing data of hypertrophic chondrocytes. Of note, SMN loss induced dwarfism and delayed endochondral ossification in Smn1 depletion-severe spinal muscular atrophy (SMA) mouse model and Smn1 chondrocyte conditional knockdown mouse. Histological analysis revealed that SMN deficiency expanded the zone of hypertrophic chondrocytes in the growth plates, but delayed turnover from hypertrophic to ossification zone. Widespread changes in endochondral ossification related gene expression and alternative splicing profiles were identified via RNA sequencing of growth plate cartilages from SMA mice on postnatal day 4. Importantly, Mass spectrometry-based proteomics analysis elucidated Y-box-binding protein 1 (YBX1) as a vital SMN-binding factor, was decreased in SMA mice. YBX1 knockdown reproduced the aberrant gene expression and splicing changes observed in SMA growth plate cartilages. Comparing the binding proteins of SMN and YBX1 revealed TNF receptor-associated factor 6 (TRAF6), which promoted ubiquitination degradation of YBX1. By conditionally deleting Smn1 in chondrocytes of WT mice and overexpressing Smn1 in chondrocytes of SMA mice, we proved that SMN expression in chondrocytes is critical for hypertrophic chondrocyte-mediated endochondral ossification. Collectively, these results demonstrate that SMN deficiency contributes to rapid systemic bone dysplasia syndrome by promoting TRAF6-induced ubiquitination degradation of YBX1 in growth plate cartilages of SMA mice.
由SMN1基因编码的运动神经元存活蛋白（Survival of motor neuron， SMN）是所有组织中必不可少且普遍表达的蛋白。先前的研究表明，SMN缺乏会损害骨发育，但异常软骨内成骨的潜在机制尚不清楚。在这里，我们通过分析增生性软骨细胞的单细胞RNA测序数据，发现SMN通过调节RNA剪接和蛋白质降解参与了增生性软骨细胞的分化。值得注意的是，Smn1缺失在Smn1缺失-严重脊髓性肌萎缩症（SMA）小鼠模型和Smn1软骨细胞条件敲低小鼠中诱导侏儒症和软骨内成骨延迟。组织学分析显示，SMN缺乏扩大了生长板中肥大软骨细胞区，但延迟了从肥大软骨细胞到骨化区的转变。通过对出生后第4天的SMA小鼠生长板软骨的RNA测序，发现软骨内成骨相关基因表达和剪接谱的广泛变化。重要的是，基于质谱的蛋白质组学分析阐明了y- box结合蛋白1 （YBX1）作为重要的smn结合因子，在SMA小鼠中减少。YBX1基因敲低可复制SMA生长板软骨中观察到的异常基因表达和剪接变化。比较SMN和YBX1的结合蛋白发现TNF受体相关因子6 （TRAF6）促进YBX1的泛素化降解。通过有条件地删除WT小鼠软骨细胞中的Smn1，并在SMA小鼠软骨细胞中过表达Smn1，我们证明了SMN在软骨细胞中的表达对于肥大软骨细胞介导的软骨内成骨至关重要。综上所述，这些结果表明SMN缺乏通过促进traf6诱导的SMA小鼠生长板软骨中YBX1的泛素化降解而导致快速的全身性骨发育不良综合征。
{"title":"SMN deficiency inhibits endochondral ossification via promoting TRAF6-induced ubiquitination degradation of YBX1 in spinal muscular atrophy.","authors":"Zijie Zhou,Xinbin Fan,Taiyang Xiang,Yinxuan Suo,Xiaoyan Shi,Yaoyao Li,Yimin Hua,Lei Sheng,Xiaozhong Zhou","doi":"10.1038/s41413-025-00473-6","DOIUrl":"https://doi.org/10.1038/s41413-025-00473-6","url":null,"abstract":"Survival of motor neuron (SMN) protein encoded by SMN1 gene, is the essential and ubiquitously expressed protein in all tissues. Prior studies demonstrated that SMN deficiency impaired bone development, but the underlying mechanism of abnormal endochondral ossification remains obscure. Here, we showed SMN is involved in hypertrophic chondrocytes differentiation through regulating RNA splicing and protein degradation via analyzing single cell RNA-sequencing data of hypertrophic chondrocytes. Of note, SMN loss induced dwarfism and delayed endochondral ossification in Smn1 depletion-severe spinal muscular atrophy (SMA) mouse model and Smn1 chondrocyte conditional knockdown mouse. Histological analysis revealed that SMN deficiency expanded the zone of hypertrophic chondrocytes in the growth plates, but delayed turnover from hypertrophic to ossification zone. Widespread changes in endochondral ossification related gene expression and alternative splicing profiles were identified via RNA sequencing of growth plate cartilages from SMA mice on postnatal day 4. Importantly, Mass spectrometry-based proteomics analysis elucidated Y-box-binding protein 1 (YBX1) as a vital SMN-binding factor, was decreased in SMA mice. YBX1 knockdown reproduced the aberrant gene expression and splicing changes observed in SMA growth plate cartilages. Comparing the binding proteins of SMN and YBX1 revealed TNF receptor-associated factor 6 (TRAF6), which promoted ubiquitination degradation of YBX1. By conditionally deleting Smn1 in chondrocytes of WT mice and overexpressing Smn1 in chondrocytes of SMA mice, we proved that SMN expression in chondrocytes is critical for hypertrophic chondrocyte-mediated endochondral ossification. Collectively, these results demonstrate that SMN deficiency contributes to rapid systemic bone dysplasia syndrome by promoting TRAF6-induced ubiquitination degradation of YBX1 in growth plate cartilages of SMA mice.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"1 1","pages":"97"},"PeriodicalIF":12.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145645051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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