Pub Date : 2025-10-21DOI: 10.1038/s41413-025-00472-7
Giselle Kaneda,Lea Zila,Jacob T Wechsler,Karim Shafi,Karandeep Cheema,Hyun Bae,Sang D Kim,Alexander Tuchman,Debiao Li,Dmitriy Sheyn
Chronic lower back pain (LBP) is the leading cause of disability worldwide. Due to its close relationship with intervertebral disc (IVD) degeneration (IVDD), research has historically focused more on understanding the mechanism behind IVDD while clinical efforts prioritize pain management. More recently, there has been a shift toward understanding LBP as a distinct pathological entity. This review synthesizes current knowledge on discogenic LBP, combining known pathophysiology, molecular mechanisms, risk factors, diagnostic challenges, and available experimental models. IVDD is a complex, multifactorial process involving biochemical, mechanical, and inflammatory changes within the disc, leading to structural breakdown and potential discogenic pain. Key mechanisms include extracellular matrix degradation, upregulation of inflammatory mediators, immune cell infiltration, and aberrant nerve and vascular ingrowth. However, not all cases of IVDD result in LBP, highlighting the need for further investigation into the cellular, molecular, and biomechanical factors contributing to symptom development. Current diagnostic tools and experimental models for studying discogenic LBP remain limited, impeding the development of targeted treatments. Existing therapies primarily focus on symptom management rather than addressing underlying disease mechanisms.
{"title":"What a pain in the back: etiology, diagnosis and future treatment directions for discogenic low back pain.","authors":"Giselle Kaneda,Lea Zila,Jacob T Wechsler,Karim Shafi,Karandeep Cheema,Hyun Bae,Sang D Kim,Alexander Tuchman,Debiao Li,Dmitriy Sheyn","doi":"10.1038/s41413-025-00472-7","DOIUrl":"https://doi.org/10.1038/s41413-025-00472-7","url":null,"abstract":"Chronic lower back pain (LBP) is the leading cause of disability worldwide. Due to its close relationship with intervertebral disc (IVD) degeneration (IVDD), research has historically focused more on understanding the mechanism behind IVDD while clinical efforts prioritize pain management. More recently, there has been a shift toward understanding LBP as a distinct pathological entity. This review synthesizes current knowledge on discogenic LBP, combining known pathophysiology, molecular mechanisms, risk factors, diagnostic challenges, and available experimental models. IVDD is a complex, multifactorial process involving biochemical, mechanical, and inflammatory changes within the disc, leading to structural breakdown and potential discogenic pain. Key mechanisms include extracellular matrix degradation, upregulation of inflammatory mediators, immune cell infiltration, and aberrant nerve and vascular ingrowth. However, not all cases of IVDD result in LBP, highlighting the need for further investigation into the cellular, molecular, and biomechanical factors contributing to symptom development. Current diagnostic tools and experimental models for studying discogenic LBP remain limited, impeding the development of targeted treatments. Existing therapies primarily focus on symptom management rather than addressing underlying disease mechanisms.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"12 1","pages":"89"},"PeriodicalIF":12.7,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338687","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 formation of traumatic heterotopic ossification (HO) is an abnormal repair process after soft tissue injury. Recent studies establish the involvement of immune cells and cellular metabolism in the tissue healing process; however, their role in HO remains unknown. Here, by using murine burn/tenotomy model in vivo and tendon stem/progenitor cells (TSPCs) osteogenic differentiation model in vitro, together with techniques including transgenic knockout, gene knockdown, transcriptome and proteome sequencings, mass spectrometry, co-immunoprecipitation, seahorse, etc., we reveal a novel p21-activated kinase 4 (Pak4) mediated crosstalk where the necroptotic macrophages arouse TSPCs with reduced fatty acid β-oxidation (FAO), to promote aberrant osteogenic differentiation during HO formation. Necroptosis blockade with Mlkl knockout (C57BL/6JGpt-Mlklem1Cd1679/Gpt) significantly reduces HO than WT mice. Extracellular vesicle (EVs) secreted from necroptotic bone marrow-derived macrophages (BMDMs, NecroMφ-EVs) are determined to motivate FAO reduction in TSPCs and result in higher osteogenic activity. Pak4 conditional knockout (C57BL/6JGpt-Pak4em1Cflox/Gpt) in macrophage significantly increases FAO and reduces HO than Flox mice, as well as local injection of PAK4-/--EVs (NecroMφ-EVs with Pak4 knockout) than NecroMφ-EVs, and the protective effects are reversed after transfection of Fabp3S122D, a phosphomimetic mutant of S122 on fatty acid binding protein 3 (Fabp3) phosphorylation site. Mechanically, after soft tissue injury, macrophages infiltrate, and necroptosis occurs, accompanied by paracrine EVs-derived Pak4, which binds directly to Fabp3 and phosphorylates it at the S122 site in TSPCs, results in reduced FAO, finally osteogenic behavior, and HO formation. This study adds perceptiveness into abnormal regeneration-based theory for traumatic HO and raises treatment strategy development.
{"title":"Pak4-mediated crosstalk between necroptotic macrophages and tendon stem/progenitor cells contributes to traumatic heterotopic ossification formation.","authors":"Ziyang Sun,Hang Liu,Yi Xu,Qian Chen,Gang Luo,Zhengqiang Yuan,Zhenyu Chen,Kuangyu He,Cunyi Fan,Juehong Li,Hongjiang Ruan","doi":"10.1038/s41413-025-00463-8","DOIUrl":"https://doi.org/10.1038/s41413-025-00463-8","url":null,"abstract":"The formation of traumatic heterotopic ossification (HO) is an abnormal repair process after soft tissue injury. Recent studies establish the involvement of immune cells and cellular metabolism in the tissue healing process; however, their role in HO remains unknown. Here, by using murine burn/tenotomy model in vivo and tendon stem/progenitor cells (TSPCs) osteogenic differentiation model in vitro, together with techniques including transgenic knockout, gene knockdown, transcriptome and proteome sequencings, mass spectrometry, co-immunoprecipitation, seahorse, etc., we reveal a novel p21-activated kinase 4 (Pak4) mediated crosstalk where the necroptotic macrophages arouse TSPCs with reduced fatty acid β-oxidation (FAO), to promote aberrant osteogenic differentiation during HO formation. Necroptosis blockade with Mlkl knockout (C57BL/6JGpt-Mlklem1Cd1679/Gpt) significantly reduces HO than WT mice. Extracellular vesicle (EVs) secreted from necroptotic bone marrow-derived macrophages (BMDMs, NecroMφ-EVs) are determined to motivate FAO reduction in TSPCs and result in higher osteogenic activity. Pak4 conditional knockout (C57BL/6JGpt-Pak4em1Cflox/Gpt) in macrophage significantly increases FAO and reduces HO than Flox mice, as well as local injection of PAK4-/--EVs (NecroMφ-EVs with Pak4 knockout) than NecroMφ-EVs, and the protective effects are reversed after transfection of Fabp3S122D, a phosphomimetic mutant of S122 on fatty acid binding protein 3 (Fabp3) phosphorylation site. Mechanically, after soft tissue injury, macrophages infiltrate, and necroptosis occurs, accompanied by paracrine EVs-derived Pak4, which binds directly to Fabp3 and phosphorylates it at the S122 site in TSPCs, results in reduced FAO, finally osteogenic behavior, and HO formation. This study adds perceptiveness into abnormal regeneration-based theory for traumatic HO and raises treatment strategy development.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"42 1","pages":"88"},"PeriodicalIF":12.7,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145319248","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 : 2025-10-17DOI: 10.1038/s41413-025-00462-9
Chuangxin Lin, Liangliang Liu, Chun Zeng, Zhong-Kai Cui, Yuhui Chen, Pinling Lai, Hong Wang, Yan Shao, Haiyan Zhang, Rongkai Zhang, Chang Zhao, Hang Fang, Daozhang Cai, Xiaochun Bai
{"title":"Author Correction: Activation of mTORC1 in subchondral bone preosteoblasts promotes osteoarthritis by stimulating bone sclerosis and secretion of CXCL12.","authors":"Chuangxin Lin, Liangliang Liu, Chun Zeng, Zhong-Kai Cui, Yuhui Chen, Pinling Lai, Hong Wang, Yan Shao, Haiyan Zhang, Rongkai Zhang, Chang Zhao, Hang Fang, Daozhang Cai, Xiaochun Bai","doi":"10.1038/s41413-025-00462-9","DOIUrl":"10.1038/s41413-025-00462-9","url":null,"abstract":"","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"13 1","pages":"87"},"PeriodicalIF":15.0,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12532457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306978","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}
Osteoarthritis (OA) is a widespread joint disorder that has emerged as a significant global healthcare challenge. Over the past decade, advancements in material science and medicine have transformed the development of functional materials aimed at addressing the complex issues associated with the diagnosis and treatment of OA. This review synthesizes the latest advancements in various types of intelligent micro-structured materials and their design principles. By examining the exceptional structural characteristics of materials with unique properties such as tailored attributes, controllability, biocompatibility, and bioactivity, we emphasize the design of composite materials for precise and early intervention in OA. This is achieved through advanced imaging techniques and machine learning-based analysis, alongside the customization of micro-structured material properties to align with the biological and mechanical requirements of specific joint tissues. This review offers an in-depth analysis of the transformative potential of advanced technologies and artificial intelligence (AI) in the development of innovative solutions for OA diagnosis and therapy. It aims to inform future research and inspire the creation of next-generation smart materials with unprecedented performance, thereby enhancing our capabilities in the prevention and treatment of OA.
{"title":"Intelligent microstructure materials for diagnosis and treatment of osteoarthritis: progress and AI-enpowered future.","authors":"Weijin Gao,Jiahui Zhong,Xinyi Liu,Dan Bai,Mengjie Wu","doi":"10.1038/s41413-025-00458-5","DOIUrl":"https://doi.org/10.1038/s41413-025-00458-5","url":null,"abstract":"Osteoarthritis (OA) is a widespread joint disorder that has emerged as a significant global healthcare challenge. Over the past decade, advancements in material science and medicine have transformed the development of functional materials aimed at addressing the complex issues associated with the diagnosis and treatment of OA. This review synthesizes the latest advancements in various types of intelligent micro-structured materials and their design principles. By examining the exceptional structural characteristics of materials with unique properties such as tailored attributes, controllability, biocompatibility, and bioactivity, we emphasize the design of composite materials for precise and early intervention in OA. This is achieved through advanced imaging techniques and machine learning-based analysis, alongside the customization of micro-structured material properties to align with the biological and mechanical requirements of specific joint tissues. This review offers an in-depth analysis of the transformative potential of advanced technologies and artificial intelligence (AI) in the development of innovative solutions for OA diagnosis and therapy. It aims to inform future research and inspire the creation of next-generation smart materials with unprecedented performance, thereby enhancing our capabilities in the prevention and treatment of OA.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"11 1","pages":"85"},"PeriodicalIF":12.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296243","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 : 2025-10-15DOI: 10.1038/s41413-025-00470-9
Guiwu Huang,Chaopeng He,Wenyu Fu,Jingwei Bi,Jianji Wang,Daniel H Wiznia,Chuan-Ju Liu
Osteoarthritis (OA) and intervertebral disc degeneration (IVDD) are degenerative musculoskeletal disorders characterized by degeneration of cartilaginous tissues and inflammation. While inflammation is implicated in the pathogenesis of OA and IVDD, and cytosolic phospholipase A2 (cPLA2) is a key mediator of inflammation, direct evidence linking cPLA2 to chondrocyte homeostasis and cartilage degeneration is lacking. This study aims to investigate the role of cPLA2 in chondrocytes and its contribution to the development of cartilage degenerative conditions such as OA and IVDD. Here, single-cell RNA sequencing was used to examine cPLA2 expression in chondrocytes. To explore its importance in chondrocytes and OA/IVDD, various cell-based assays and genetically modified mouse models with age-related and surgically induced OA/IVDD were employed. Furthermore, the therapeutic potential of fexofenadine, an over-the-counter drug recently identified as a cPLA2 inhibitor, was explored in these models. cPLA2 is predominantly expressed in prehypertrophic chondrocytes, characterized by elevated levels of cartilage degeneration markers and senescence-related genes. Genetic deletion and pharmacological inhibition of cPLA2 reduced inflammation induced catabolic activity and senescence in chondrocytes, as well as cartilage degeneration in various OA and IVDD models. This study identifies cPLA2 as a pivotal driver of cartilage degeneration and senescence in OA and IVDD, highlighting its potential as a dual-action therapeutic target that suppresses both inflammation and senescence to preserve cartilage integrity. These findings position cPLA2 as a promising candidate for developing disease-modifying therapies for cartilage degenerative conditions such as OA and IVDD.
{"title":"Cytosolic phospholipase A2 as a therapeutic target for degenerative joint diseases.","authors":"Guiwu Huang,Chaopeng He,Wenyu Fu,Jingwei Bi,Jianji Wang,Daniel H Wiznia,Chuan-Ju Liu","doi":"10.1038/s41413-025-00470-9","DOIUrl":"https://doi.org/10.1038/s41413-025-00470-9","url":null,"abstract":"Osteoarthritis (OA) and intervertebral disc degeneration (IVDD) are degenerative musculoskeletal disorders characterized by degeneration of cartilaginous tissues and inflammation. While inflammation is implicated in the pathogenesis of OA and IVDD, and cytosolic phospholipase A2 (cPLA2) is a key mediator of inflammation, direct evidence linking cPLA2 to chondrocyte homeostasis and cartilage degeneration is lacking. This study aims to investigate the role of cPLA2 in chondrocytes and its contribution to the development of cartilage degenerative conditions such as OA and IVDD. Here, single-cell RNA sequencing was used to examine cPLA2 expression in chondrocytes. To explore its importance in chondrocytes and OA/IVDD, various cell-based assays and genetically modified mouse models with age-related and surgically induced OA/IVDD were employed. Furthermore, the therapeutic potential of fexofenadine, an over-the-counter drug recently identified as a cPLA2 inhibitor, was explored in these models. cPLA2 is predominantly expressed in prehypertrophic chondrocytes, characterized by elevated levels of cartilage degeneration markers and senescence-related genes. Genetic deletion and pharmacological inhibition of cPLA2 reduced inflammation induced catabolic activity and senescence in chondrocytes, as well as cartilage degeneration in various OA and IVDD models. This study identifies cPLA2 as a pivotal driver of cartilage degeneration and senescence in OA and IVDD, highlighting its potential as a dual-action therapeutic target that suppresses both inflammation and senescence to preserve cartilage integrity. These findings position cPLA2 as a promising candidate for developing disease-modifying therapies for cartilage degenerative conditions such as OA and IVDD.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"119 1","pages":"86"},"PeriodicalIF":12.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296242","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 one of the most common degenerative and age-related diseases in joints, which affects 654 million people worldwide. Current therapies could not fundamentally reverse the pathologic process of OA due to the complex pathogenesis. Although OA mechanisms have been investigated on a large scale over the past decade, the OA pathology correlated with aging-associated changes is still largely unrevealed. Therefore, in-depth analysis of the aging microenvironment and aging-related molecular mechanisms in OA may offer additional strategies for clinical prevention and treatment. In this review, we discuss the potential pathogenesis of OA in light of aging-associated changes and summarize three main components of the aging microenvironment of the OA joint: immune homeostatic imbalance, cellular senescence, and stem cell exhaustion, which could be induced by aging and further exacerbate OA progression. Additionally, it is emphasized that immune homeostatic imbalance appears before established OA, which occurs in the early stage and is the therapeutic window of opportunity for better clinical outcomes. Importantly, we evaluate recent therapeutic targets and promising interventions against these components, as well as the challenges and prospects for precise and individualized therapies of OA patients, which we believe would guide the construction of novel combined strategies targeting aging-related factors against OA for better treatments in the future.
{"title":"Aging microenvironment in osteoarthritis focusing on early-stage alterations and targeted therapies.","authors":"Yifan Dang,Yuhang Liu,Bingjun Zhang,Xiaoling Zhang","doi":"10.1038/s41413-025-00465-6","DOIUrl":"https://doi.org/10.1038/s41413-025-00465-6","url":null,"abstract":"Osteoarthritis (OA) is one of the most common degenerative and age-related diseases in joints, which affects 654 million people worldwide. Current therapies could not fundamentally reverse the pathologic process of OA due to the complex pathogenesis. Although OA mechanisms have been investigated on a large scale over the past decade, the OA pathology correlated with aging-associated changes is still largely unrevealed. Therefore, in-depth analysis of the aging microenvironment and aging-related molecular mechanisms in OA may offer additional strategies for clinical prevention and treatment. In this review, we discuss the potential pathogenesis of OA in light of aging-associated changes and summarize three main components of the aging microenvironment of the OA joint: immune homeostatic imbalance, cellular senescence, and stem cell exhaustion, which could be induced by aging and further exacerbate OA progression. Additionally, it is emphasized that immune homeostatic imbalance appears before established OA, which occurs in the early stage and is the therapeutic window of opportunity for better clinical outcomes. Importantly, we evaluate recent therapeutic targets and promising interventions against these components, as well as the challenges and prospects for precise and individualized therapies of OA patients, which we believe would guide the construction of novel combined strategies targeting aging-related factors against OA for better treatments in the future.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"121 1","pages":"84"},"PeriodicalIF":12.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261521","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 : 2025-10-02DOI: 10.1038/s41413-025-00454-9
Tong Shen,Kai Dai,Shuang Zhang,Jing Wang,Changsheng Liu
The treatment of severe diabetic foot remains a clinical challenge. While it is established that bone can exert systemic effects through the secretion of osteokines on other organs, whether this endocrine function can be harnessed to promote diabetic wound healing remains unexplored. Here, we investigate the impact of a bone injury strategy on diabetic wound healing, leveraging the body's innate regenerative capacity to stimulate osteokine release and influence remote skin wound repair. This study demonstrates that the tibial defect significantly accelerates ipsilateral diabetic foot skin wound healing. Mechanistically, we identify osteokines, platelet-derived growth factor-BB (PDGF-BB), as the key to initiating this process. Bone defect triggers a substantial release of PDGF-BB, which reaches the skin wound site via peripheral circulation. At the skin wound site, PDGF-BB mediates the secretion of keratinocyte growth factor (KGF) from fibroblasts via the PDGFRβ signaling pathway, thereby promoting the rapid re-epithelialization of epidermal cells through a paracrine pathway. Additionally, elevated PDGF-BB levels enhance the regeneration of CD31hi Emcnhi blood vessels within the wound. Importantly, we demonstrate the therapeutic potential of osteokines by showing that a collagen hydrogel loaded with osteokines promotes wound healing in diabetic mice. Our findings reveal a clear link between bone and skin wound healing, providing a therapeutic inspiration for chronic wounds that are difficult to treat locally.
{"title":"Injured bone-triggered osteokines secretion promotes diabetic wound healing.","authors":"Tong Shen,Kai Dai,Shuang Zhang,Jing Wang,Changsheng Liu","doi":"10.1038/s41413-025-00454-9","DOIUrl":"https://doi.org/10.1038/s41413-025-00454-9","url":null,"abstract":"The treatment of severe diabetic foot remains a clinical challenge. While it is established that bone can exert systemic effects through the secretion of osteokines on other organs, whether this endocrine function can be harnessed to promote diabetic wound healing remains unexplored. Here, we investigate the impact of a bone injury strategy on diabetic wound healing, leveraging the body's innate regenerative capacity to stimulate osteokine release and influence remote skin wound repair. This study demonstrates that the tibial defect significantly accelerates ipsilateral diabetic foot skin wound healing. Mechanistically, we identify osteokines, platelet-derived growth factor-BB (PDGF-BB), as the key to initiating this process. Bone defect triggers a substantial release of PDGF-BB, which reaches the skin wound site via peripheral circulation. At the skin wound site, PDGF-BB mediates the secretion of keratinocyte growth factor (KGF) from fibroblasts via the PDGFRβ signaling pathway, thereby promoting the rapid re-epithelialization of epidermal cells through a paracrine pathway. Additionally, elevated PDGF-BB levels enhance the regeneration of CD31hi Emcnhi blood vessels within the wound. Importantly, we demonstrate the therapeutic potential of osteokines by showing that a collagen hydrogel loaded with osteokines promotes wound healing in diabetic mice. Our findings reveal a clear link between bone and skin wound healing, providing a therapeutic inspiration for chronic wounds that are difficult to treat locally.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"114 1","pages":"83"},"PeriodicalIF":12.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209187","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}
Bone repair and regeneration is a complex spatiotemporal process recruiting a variety of cell types, which need to precisely mediated for effective healing post-damage. The concept of osteoimmunology emphasizes the extensive and intricate crosstalk between the bone and the immune system. Despite the significant advancements in understanding osteoimmunology, the precise role of dendritic cells (DCs) in this field remains under investigation. As key antigen-presenting cells, DCs are critical in orchestrating adaptive immune responses and maintaining tissue homeostasis. Recent researches have further revealed the potential of DCs to influence the development or acceleration of inflammatory and autoimmune bone disease, as well as their interaction with skeletal cells in the context of bone repair and regeneration. Therefore, an in-depth understanding of DCs in the osteoimmunology would be valuable. Herein, we discuss the effects of DCs on bone homeostasis and bone-related diseases (i.e., rheumatoid arthritis (RA), periodontitis, bone regeneration, and other bone abnormalities diseases), and introduce the innovative DCs-targeting biomaterials, aimed at promoting bone repair and regeneration. Furthermore, we summarize the underlying crosstalk between DCs and other cells (i.e., osteoclasts, mesenchymal stromal stem cells (MSCs), hematopoietic stem and progenitor cells (HSPCs), T and B cells) in the bone homeostasis and bone-related diseases. In conclusion, we propose that osteoimmunology offers a promising perspective for unraveling the mechanisms of bone-related diseases; meanwhile, targeting DCs from the perspective of osteoimmunology may provide innovative ideas and resolutions to achieve the internal homeostasis balance.
{"title":"Unraveling the mechanisms of bone diseases: targeting dendritic cells in osteoimmunology for internal homeostasis balance.","authors":"Yanqi Chen,Siyuan Wang,Xiaoyu Chen,Zhifang Wu,Fuming He,Qianming Chen","doi":"10.1038/s41413-025-00456-7","DOIUrl":"https://doi.org/10.1038/s41413-025-00456-7","url":null,"abstract":"Bone repair and regeneration is a complex spatiotemporal process recruiting a variety of cell types, which need to precisely mediated for effective healing post-damage. The concept of osteoimmunology emphasizes the extensive and intricate crosstalk between the bone and the immune system. Despite the significant advancements in understanding osteoimmunology, the precise role of dendritic cells (DCs) in this field remains under investigation. As key antigen-presenting cells, DCs are critical in orchestrating adaptive immune responses and maintaining tissue homeostasis. Recent researches have further revealed the potential of DCs to influence the development or acceleration of inflammatory and autoimmune bone disease, as well as their interaction with skeletal cells in the context of bone repair and regeneration. Therefore, an in-depth understanding of DCs in the osteoimmunology would be valuable. Herein, we discuss the effects of DCs on bone homeostasis and bone-related diseases (i.e., rheumatoid arthritis (RA), periodontitis, bone regeneration, and other bone abnormalities diseases), and introduce the innovative DCs-targeting biomaterials, aimed at promoting bone repair and regeneration. Furthermore, we summarize the underlying crosstalk between DCs and other cells (i.e., osteoclasts, mesenchymal stromal stem cells (MSCs), hematopoietic stem and progenitor cells (HSPCs), T and B cells) in the bone homeostasis and bone-related diseases. In conclusion, we propose that osteoimmunology offers a promising perspective for unraveling the mechanisms of bone-related diseases; meanwhile, targeting DCs from the perspective of osteoimmunology may provide innovative ideas and resolutions to achieve the internal homeostasis balance.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"103 1","pages":"81"},"PeriodicalIF":12.7,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181168","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}
Piezo1, a key mechanosensor in bone homeostasis, plays a crucial role in fracture healing. However, the mechanisms through which Piezo1 regulates chondrocytes and affects endochondral ossification remain poorly understood. This study aimed to investigate the regulatory mechanisms of Piezo1 in chondrocytes during endochondral ossification. Using lineage tracing, we identified chondrocyte-to-osteoblast transdifferentiation during endochondral ossification, which was impaired by chondrocyte-specific Piezo1 knockout. Piezo1 deficiency disrupted mitochondrial bioenergetics, characterized by diminished membrane potential, reduced adenosine triphosphate (ATP) synthesis, suppressed oxygen consumption rates (basal and maximal respiration), and elevated mitochondrial superoxide generation, thereby impairing endochondral ossification during fracture healing. Single-cell RNA sequencing revealed upregulated Lars2 expression in hypertrophic chondrocytes following Piezo1 knockout. Inhibition of Lars2 in chondrocytes normalized mitochondrial dynamics-related markers (MFN1, MFN2, OPA1, DRP1) and restored mitochondrial functional homeostasis. This intervention concurrently reversed Piezo1 knockout-induced suppression of osteogenic markers (Col1, ALP, OCN, OPN, RUNX2), thereby enhancing fracture repair. Protein interaction analyses confirmed direct binding between β-catenin and Lars2. Mechanistically, Piezo1 governs Lars2 expression via β-catenin signaling. Our findings demonstrate that Piezo1 activation via Yoda1 enhances mitochondrial bioenergetics and accelerates fracture repair through the β-catenin/Lars2 axis, offering novel insights and therapeutic avenues for fracture treatment.
{"title":"Mechanism of Piezo1 regulating chondrocyte mitochondrial function and promoting fracture healing through β-catenin/LARS2 signaling pathway.","authors":"Tao Zhang,Hongzhi Lv,Siming Jia,Lijun Wang,Weijian Liu,Kai Ding,Xiaofeng Du,Guangzhao Hou,Zhiyong Hou,Yingze Zhang,Weiguo Zou,Wei Chen,Yanbin Zhu","doi":"10.1038/s41413-025-00459-4","DOIUrl":"https://doi.org/10.1038/s41413-025-00459-4","url":null,"abstract":"Piezo1, a key mechanosensor in bone homeostasis, plays a crucial role in fracture healing. However, the mechanisms through which Piezo1 regulates chondrocytes and affects endochondral ossification remain poorly understood. This study aimed to investigate the regulatory mechanisms of Piezo1 in chondrocytes during endochondral ossification. Using lineage tracing, we identified chondrocyte-to-osteoblast transdifferentiation during endochondral ossification, which was impaired by chondrocyte-specific Piezo1 knockout. Piezo1 deficiency disrupted mitochondrial bioenergetics, characterized by diminished membrane potential, reduced adenosine triphosphate (ATP) synthesis, suppressed oxygen consumption rates (basal and maximal respiration), and elevated mitochondrial superoxide generation, thereby impairing endochondral ossification during fracture healing. Single-cell RNA sequencing revealed upregulated Lars2 expression in hypertrophic chondrocytes following Piezo1 knockout. Inhibition of Lars2 in chondrocytes normalized mitochondrial dynamics-related markers (MFN1, MFN2, OPA1, DRP1) and restored mitochondrial functional homeostasis. This intervention concurrently reversed Piezo1 knockout-induced suppression of osteogenic markers (Col1, ALP, OCN, OPN, RUNX2), thereby enhancing fracture repair. Protein interaction analyses confirmed direct binding between β-catenin and Lars2. Mechanistically, Piezo1 governs Lars2 expression via β-catenin signaling. Our findings demonstrate that Piezo1 activation via Yoda1 enhances mitochondrial bioenergetics and accelerates fracture repair through the β-catenin/Lars2 axis, offering novel insights and therapeutic avenues for fracture treatment.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"94 1","pages":"79"},"PeriodicalIF":12.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133986","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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