Bone Research最新文献

{"title":"Novel therapeutic strategies for osteoarthritis: from mechanistic insights to precision medicine.","authors":"Muhammad Umar, Ziling Wang, Jingwen Li, Zhen Li, Gang Li, Liping Tong, Di Chen","doi":"10.1038/s41413-026-00540-6","DOIUrl":"10.1038/s41413-026-00540-6","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a prevalent chronic degenerative joint disease that significantly impacts the quality of life for over 500 million individuals affected. OA is increasingly recognized as a whole-joint disorder characterized by complex biochemical and cellular changes across various joint tissues. However, traditional approaches such as nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids often fall short in halting disease progression or restoring joint function. Thereby, recent innovations in OA management are focused on underlying pathophysiology, driving the development of regenerative therapies, targeted anti-inflammatory agents and senolytic or senomorphic approaches. Accordingly, this paper reviews current progress in these areas by integrating evidence from clinical and pre-clinical studies to clarify therapeutic limitations, unresolved mechanistic and phenotypic gaps and the emerging strategies required to advance disease-modifying therapy in OA. It further outlines pathways toward precision, phenotype-aligned interventions, an integration that current literature has not yet consolidated.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13260458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223351","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}

{"title":"JMJD3-driven epigenetic reprogramming of p16^INK4a-positive cells promotes tendon regeneration.","authors":"Xiaonan Liu, Wenhao Lu, Yicheng Wang, Peilin Zhang, Zhongyi Su, Ting Cao, Yifei Zhang, Junjie Zhao, Jiayi Wang, Hulin Xiang, Weijun Huang, Kai Wang, Sa Pang, Minkai Chen, Yusheng Li, Shen Liu","doi":"10.1038/s41413-026-00537-1","DOIUrl":"10.1038/s41413-026-00537-1","url":null,"abstract":"<p><p>Tendon healing is a complex biological process that involves inflammation, cellular reprogramming, and extracellular matrix (ECM) remodeling. The cyclin-dependent kinase inhibitor p16^INK4a is a well-characterized tumor suppressor associated with cell-cycle regulation under conditions of cellular stress and senescence. Although genetic ablation of p16^INK4a+ cells has shown beneficial effects in age-associated tendinopathies, the cellular identity and functional contribution of p16^INK4a+ cells during tendon regeneration remain poorly understood. In this study, we demonstrate that an injury-induced accumulation of p16^INK4a+ cells in a murine Achilles tendon injury model promotes tendon structural and functional recovery. Using a murine tendon puncture model combined with single-cell RNA sequencing and in situ immunostaining, we identify these p16^INK4a+ cells as predominantly mesenchymal cells characterized by elevated ECM gene expression. Mechanistically, p16^INK4a+ cells exhibit increased activity of the histone demethylase JMJD3 (KDM6B), accompanied by reduced H3K27me3 levels and enhanced expression of ECM-related genes, including Col1a1 and Col3a1, thus supporting organized collagen deposition and tissue remodeling. Genetic deletion or pharmacological inhibition of JMJD3 resulted in increased H3K27me3 levels, disrupted collagen organization, and reduced biomechanical strength. Conversely, pharmacological reduction of H3K27me3 was associated with enhanced ECM gene expression and accelerated tendon repair. Together, these findings identify a JMJD3-associated epigenetic program in p16^INK4a+ cells that contributes to ECM remodeling during tendon healing, highlighting the beneficial and context-dependent role of p16^INK4a+ cells in musculoskeletal tissue repair.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13261133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223285","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}

{"title":"Hijacking the bone niche: mechanistic insights into bone metastasis in breast cancer.","authors":"Jiadi Wu, Min Deng, Feng Ye, Wei Deng, Zichao Wu, Xinhao Zheng, Cailu Song, Yutian Zou, Hailin Tang","doi":"10.1038/s41413-026-00547-z","DOIUrl":"10.1038/s41413-026-00547-z","url":null,"abstract":"<p><p>Breast cancer is one of the most common malignant tumors worldwide, with metastasis being the leading cause of mortality among patients. Bone is the most frequent site of metastasis in breast cancer, accounting for approximately 70% of metastatic cases. Before bone metastasis, primary breast cancer cells secrete circulating factors (e.g., exosomal RNAs, metabolites, and cytokines) to precondition the bone microenvironment and establish a supportive pre-metastatic niche (PMN). After dissemination, tumor cells further hijack the bone niche by releasing receptor activator of nuclear factor-κB ligand (RANKL), parathyroid hormone-related protein (PTHrP), and transforming growth factor-β (TGF-β), thereby disrupting bone homeostasis through osteoclast activation and osteoblast dysregulation. Bone matrix degradation subsequently releases latent growth factors that in turn fuel tumor cell proliferation, thereby establishing a self-reinforcing vicious cycle. Meanwhile, breast cancer cells actively induce local immunosuppression and promote angiogenesis, remodeling a pro-tumor bone niche conducive to metastatic outgrowth. This review highlights the immunosuppressive roles of immune cells and key molecular mediators in the vicious cycle, systematically analyzes intercellular crosstalk within both the bone PMN and the hijacked niche, and summarizes emerging therapeutic strategies (including novel targeted inhibitors, immune-based combinations, epigenetic modulation, and nanomedicines) beyond conventional treatments. These insights provide a theoretical framework and identify promising therapeutic targets for future treatment strategies against breast cancer bone metastasis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13254371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216579","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}

{"title":"Sex specific effects of irisin on the skeleton.","authors":"Anika Shimonty, Lynda F Bonewald","doi":"10.1038/s41413-026-00542-4","DOIUrl":"10.1038/s41413-026-00542-4","url":null,"abstract":"<p><p>Irisin, the circulating protein derived from cleavage of fibronectin type III domain containing protein 5 (FNDC5) has attracted considerable attention regarding its positive effects on a number of organs/tissues such as fat, brain, and heart. However, effects on bone can appear to be either positive or negative depending on context and sex. Sex differences have also been described in Alzheimer's disease also emphasizing sex differences in response to irisin. Here in this review, we outline and focus on the effects of irisin on osteoblasts, osteoclasts, and osteocytes, murine models, and human studies. The consideration of sex effects is necessary especially in the context of irisin serving as a therapeutic.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13254336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216556","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}

{"title":"Coral-inspired immunoreprogramming scaffold reverses the “immune-freeze” microenvironment to promote bone regeneration in steroid-induced osteonecrosis of the femoral head","authors":"Yue Luo, Qianhao Li, Changjun Chen, Xin Zhao, Zhouyuan Yang, Donghai Li, Ke Jiang, Yan Xiong, Meng Tian, Pengde Kang","doi":"10.1038/s41413-026-00557-x","DOIUrl":"https://doi.org/10.1038/s41413-026-00557-x","url":null,"abstract":"The core pathological mechanism of steroid-induced osteonecrosis of the femoral head (SONFH) is an “immune freeze” microenvironment—where corticosteroids continuously drive macrophages toward a pro-inflammatory M1 phenotype, inhibiting the conversion to reparative M2 macrophages, thereby impairing bone regeneration. To address this bottleneck, this study was inspired by the hierarchical pore structure of coral. Using low-temperature deposition 3D printing technology, we constructed an immunoreprogramming biomimetic scaffold that integrates multi-walled carbon nanotubes (MWCNT) and nano-hydroxyapatite (nHA) (MWCNT bionic scaffold). The scaffold leverages the active immune regulatory function of MWCNT to activate the PI3K-AKT signaling pathway, driving macrophages to transition from the M1 to M2 phenotype, effectively breaking the “immunological freeze” state and reshaping the pro-regenerative bone immune microenvironment. Meanwhile, the nHA component provides a biomimetic mineralization matrix and sustained release of calcium and phosphate ions, synergizing with the nanofiber structure of MWCNT to promote the migration and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and angiogenesis. In vivo experiments confirm that scaffold implantation reverses the local “immune freeze” state, drives macrophage polarization toward the M2 phenotype, reduces inflammatory responses, and enhances the maturation and functional vascular network formation of new bone matrix in bone defect areas, ultimately achieving bone structural reconstruction. The coral-inspired immunoreprogramming strategy proposed in this study provides a new strategy for targeting the regulation of the pathological microenvironment in SONFH.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"25 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148355666","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}

{"title":"The gut-bone axis: impact of diet on gut microbiome and osteoporosis.","authors":"Yue Wang, Miao Xu, Qinzuo Dong, Xuan Lin, Qiang Zhang, Hua Shi, Xiaoning Lin, Huan Liu, Min Yu, Jianlin Shen","doi":"10.1038/s41413-026-00550-4","DOIUrl":"10.1038/s41413-026-00550-4","url":null,"abstract":"<p><p>Osteoporosis, a global health challenge characterized by reduced bone mineral density (BMD) and increased fracture risk, is closely linked to interactions between dietary patterns and gut microbiota (GM). Recent advances in GM research highlight the gut-bone axis as a pivotal focus in osteoporosis studies, revealing that variations in dietary habits and nutrient intake differentially modulate GM composition and metabolic activity, thereby influencing skeletal health. This review synthesizes current evidence on the interplay between dietary practices, GM, and bone health, aiming to identify preventive and therapeutic strategies for osteoporosis management. Collectively, these findings underscore the potential of dietary interventions targeting GM modulation as a novel therapeutic approach, advocating for personalized nutritional strategies to improve skeletal health in high-risk populations.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13237057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161756","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}

{"title":"Exploring mitochondrial functions and dysfunctions in chondrocytes: toward the identification of novel therapies for osteoarthritis.","authors":"Lucie Danet, Jérôme Guicheux, Marie-Astrid Boutet, Claire Vinatier","doi":"10.1038/s41413-026-00548-y","DOIUrl":"10.1038/s41413-026-00548-y","url":null,"abstract":"<p><p>Mitochondria are essential organelles primarily described for their vital role in producing energy through oxidative phosphorylation (OxPhos). Due to the hypoxic environment of chondrocytes and their heavy reliance on glycolysis, mitochondrial functions have long been considered of minimal relevance in these cells. However, as major suppliers of energy through the ATP they produce by OxPhos, mitochondria help to regulate the balance between anabolism and catabolism. In osteoarthritis (OA), the most prevalent joint disease, this balance is dysregulated. In addition, correlations between metabolic disorders and the risk of developing OA are also increasingly studied. In this context, mitochondrial dysfunctions in OA chondrocytes are emerging as a relevant area to propose efficient, yet unavailable, disease-modifying OA drugs (DMOADs). This narrative review examines the underlying mechanisms by which the mitochondrial functions become dysregulated in chondrocytes during OA. Drawing on up-to-date literature, it highlights how both structural and functional alterations of mitochondria contribute to OA pathology in chondrocytes. Finally, this review discusses the potential of mitochondria-targeted therapeutic strategies for OA, framed within a conceptual \"repair or replace\" approach.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13226731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142716","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}

{"title":"A tissue engineering approach to regenerate the cranial suture skeletal stem cell niche with a multicompartment biomaterial scaffold.","authors":"W Benton Swanson, Lindsey Douglas, Seth M Woodbury, Jackson Albright, Haichun Pan, Maiko Omi-Sugihara, Miranda Eberle, Jake Herremans, Hwa Kyung Nam, Rafael Correia Cavalcante, Coral Chen, Peter X Ma, Nan E Hatch, Yuji Mishina","doi":"10.1038/s41413-026-00539-z","DOIUrl":"10.1038/s41413-026-00539-z","url":null,"abstract":"<p><p>Craniosynostosis is a debilitating congenital anomaly characterized by the premature fusion of cranial sutures in the skull, resulting from the abnormal fate specification of critical skeletal stem cells. This leads to disrupted craniofacial development and dysmorphology. As an alternative to invasive cranial vault remodeling surgery, we propose a tissue engineering approach to effectively restore the damaged or absent suture stem cell niche using a biomaterial capable of regioselective stem cell maintenance, marking a significant paradigm shift. By harnessing the role of biomaterial scaffold pore design to direct cell fate, we developed a \"bone-suture-bone\" design within a triphasic scaffold. We demonstrate that this unique scaffold design maintains stemness in a central region while promoting osteogenic differentiation in the surrounding areas, replicating the interfaces and function of the native suture. The scaffold's ability to reconstitute an engineered skeletal stem cell niche and facilitate the functional recovery of the craniosynostosis phenotype is validated in a caBmpr1a; Wnt1-Cre murine model of midline craniosynostosis, the most common nonsyndromic clinical presentation in humans. This work shows significant promise for improving patient outcomes through a rational tissue engineering strategy for reconstituting a native stem cell niche.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13219457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052690","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}

{"title":"KDM6B safeguards mineralized tissue homeostasis from mechanical stress through epigenetic control of PIEZO1-mediated mechanotransduction in the mouse incisor.","authors":"Lin Meng, Mingyi Zhang, Jifan Feng, Tingwei Guo, Hana Hekmat, Heliya Ziaei, Peng Chen, Aaron Harouni, Thach-Vu Ho, Yang Chai","doi":"10.1038/s41413-026-00544-2","DOIUrl":"10.1038/s41413-026-00544-2","url":null,"abstract":"<p><p>Mechanical forces shape the growth and regeneration of mineralized tissues such as bones and teeth, yet how these tissues adapt to sustained mechanical stress remains poorly understood. Here, using mouse incisor models with varying degrees of loading, we identified that the histone demethylase KDM6B is a critical epigenetic regulator that preserves mineralized tissue homeostasis by protecting progenitor transit-amplifying cells from mechanical stress-induced apoptosis. Loss of Kdm6b impairs this balance by enhancing PIEZO1-dependent mechanotransduction, leading to excessive Ca²⁺ influx and apoptosis in transit-amplifying cells. Mechanistically, Kdm6b deficiency increases H3K27me3 at the Bmi1 promoter, silencing its expression and derepressing Piezo1 expression. Importantly, Piezo1 haploinsufficiency in Kdm6b-deficient mice restores Ca²⁺ influx restriction, rescuing transit-amplifying cell defects and tissue homeostasis. These findings reveal that KDM6B-H3K27me3-BMI1-PIEZO1 is a critical epigenetic \"mechanostat\" that protects dental progenitor cells from mechanical stress, ensuring sustained tissue homeostasis. This chromatin-based mechanism of tissue mechano-adaptation could be targeted to prevent mechanically induced degeneration in mineralized tissues.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13219498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052659","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}

{"title":"Bacterial specificity of the gut microbiome predicts bone density in primary hyperparathyroidism.","authors":"Hamid Y Dar, Jiali Fang, Sanchiti Patil, Nand K Roy, Sanchita Agarwal, M Neale Weitzmann, Rheinallt M Jones, John P Bilezikian, Roberto Pacifici","doi":"10.1038/s41413-026-00529-1","DOIUrl":"10.1038/s41413-026-00529-1","url":null,"abstract":"<p><p>Primary hyperparathyroidism causes mild-to-severe bone loss, but the reason for this heterogeneity is unclear. We investigated the role of the microbiome in 50 primary hyperparathyroidism patients. Microbiome transfers from primary hyperparathyroidism patients with and without osteoporosis to germ-free mice replicated the human bone phenotype and regulated TNF⁺ T cells and Th17 cells in mice. Accordingly, circulating TNF⁺ T cells and Th17 cells and TNF/IL17 production predicted bone density in primary hyperparathyroidism patients. Bifidobacterium longum, TNF⁺ T cells, and Th17 cells were mediators of bone loss in primary hyperparathyroidism patients, while Bifidobacterium longum supplementation caused PTH to expand TNF⁺ T cells and Th17 cells and induce bone loss in mice. Our findings link Bifidobacterium longum-induced TNF⁺ T cells and Th17 cells to bone loss in patients with primary hyperparathyroidism. Bifidobacterium longum abundance may determine the skeletal phenotypes of patients with primary hyperparathyroidism and allow prediction of their risk of bone loss. Microbiome modifications by antibiotics or precision probiotics might offer novel preventive approaches for the skeletal complications of primary hyperparathyroidism.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13201753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013476","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}