Bone Research最新文献

{"title":"Inhibition of ERK5 activity ameliorates osteoarthritis by suppressing NLRP3 inflammasome-mediated chondrocyte pyroptosis.","authors":"Baolin Zhang, Peihang Fang, Jiahui Long, Deying Su, Hengyu Liu, Ricong Weng, Gengjia Chen, Yingtong Chen, GuanHong Chen, Zhiheng Liao, Taifeng Zhou, Shuqing Chen, Peiqiang Su, Caixia Xu","doi":"10.1038/s41413-026-00573-x","DOIUrl":"10.1038/s41413-026-00573-x","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a widespread degenerative joint disorder manifesting as chronic pain, functional impairment, and progressive disability, imposing a substantial burden on global public health. Despite extensive research, the precise molecular pathways underlying OA pathogenesis remain incompletely elucidated. Our data indicated that human OA cartilage and cartilaginous tissues from aged mice exhibited markedly elevated levels of extracellular signal-related kinase 5 (ERK5) enzyme activity. Using Col2a1-CreER^T2/Erk5^flox/flox mice, we found that Erk5 deletion in cartilage inhibited the progression of post-traumatic and aging OA mouse while constitutive activation of ERK5 significantly accelerated OA development via intra-articular injection of adeno-associated virus model. Mechanistically, ERK5 interacted with the PYD domain of NLRP3 and mediated NLRP3 phosphorylation at serine 198, which facilitated mature inflammasome assembly, triggered pyroptosis and subsequently exacerbated OA progression. Furthermore, we identified a small compound, Oroxylin A, which attenuated ERK5 activation and effectively ameliorated the development of post-traumatic and aging-induced OA in mice. Taken together, our studies demonstrate that ERK5 is a key regulator effecting chondrocytes inflammation and pyroptosis through activating NLRP3 inflammasome and ERK5 is a potential therapeutic target for OA treatment.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13538362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879137","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":"Macrophage-driven pathological ossification of the posterior longitudinal ligament: mechanistic insights and therapeutic opportunities.","authors":"Huohuo Xue, Tsutomu Endo, Ken Kadoya, Norimasa Iwasaki, M Alaa Terkawi","doi":"10.1038/s41413-026-00576-8","DOIUrl":"10.1038/s41413-026-00576-8","url":null,"abstract":"<p><p>Ossification of the posterior longitudinal ligament (OPLL) is a chronic degenerative spinal condition in which bone gradually forms within the ligament, compressing the spinal cord and causing progressive neurological decline. While genetic predisposition and metabolic disturbances are well-recognized contributors, growing evidence points to macrophages as central players in shaping the tissue environment that drives pathological bone formation. Macrophages are remarkably plastic cells whose phenotypes and functions are continuously molded by cues from their local tissue environment. While pro-inflammatory macrophages sustain chronic low-grade inflammation through cytokine release and matrix remodeling, anti-inflammatory macrophages paradoxically amplify disease progression by driving fibrotic remodeling, excessive matrix accumulation, and aberrant vascularization, collectively fostering a hypoxic, ossification-prone niche within the ligament. Supporting this notion, similar macrophage-mediated mechanisms have been described in heterotopic ossification, though OPLL represents a distinct pathological process. This review synthesizes current evidence on how macrophages shape the OPLL microenvironment, draws mechanistic connections between macrophage activity and disease progression, and explores whether targeting these cells could open new therapeutic avenues.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13538511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879161","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":"Mechano-metabolic axis involves mitochondrial responses via BMP/Smad regulatory effect on cyclophilin D.","authors":"Rubens Sautchuk, Josaranie Nieves Santana, Chen Yu, Hani Awad, Roman A Eliseev","doi":"10.1038/s41413-026-00580-y","DOIUrl":"10.1038/s41413-026-00580-y","url":null,"abstract":"<p><p>Mechanical stimulation is fundamental for anabolism in various tissues, including bone. Importantly, mechanical stimulation has been shown to induce reprogramming of cell metabolism, likely to adjust it to increased anabolism. The signal transduction within this mechano-metabolic axis is incompletely understood. Aiming to delineate such signal transduction, we exposed osteoprogenitors to fluid shear stress (FSS) and assessed cell signaling and bioenergetics. The BMP/Smad pathway is known to be activated by mechanical stress, and we indeed detected its activation by FSS. We previously reported that BMP downregulates cyclophilin D (CypD), an opener of the mitochondrial permeability transition pore (MPTP). Downregulation of CypD/MPTP improves mitochondrial inner membrane integrity and therefore oxidative function. We found that in FSS-stimulated cells, CypD was indeed downregulated and mitochondria were activated in a BMP-dependent manner. Meanwhile, the osteogenic effect of FSS was dependent on CypD downregulation and mitochondrial responses. To confirm our in vitro results in vivo, we optimized a novel model of tooth extraction-mediated unloading of craniofacial bones in mice. Such unloading led to bone loss and upregulation of CypD in the affected bone. Osteoblast-specific deletion of CypD protected against unloading-mediated bone loss, while CypD re-expression in these mice restored bone loss. In sum, we here present new evidence that the mechano-metabolic axis in osteogenic cells involves BMP/Smad-mediated downregulation of CypD and CypD-dependent mitochondrial responses. Such regulation is important for the osteoanabolic effect of mechanical stimulation. Our data also suggest that targeting CypD can be an effective strategy to prevent bone loss caused by unloading due to immobility, space flight, or tooth extraction.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13538553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879080","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":"Sensory nerves regulate bone homeostasis in response to mechanical unloading or reloading: evidence from a spaceflight experiment and ground-based mechanical unloading models.","authors":"Shohei Tsujino, Hiroki Ochi, Risa Okada, Daisuke Kamimura, Kurando Utagawa, Takaei Shin, Hironori Yamada, Aiko Unno, Satoko Sunamura, Chihiro Akazawa, Masafumi Muratani, Dai Shiba, Toshitaka Yoshii, Shingo Sato","doi":"10.1038/s41413-026-00563-z","DOIUrl":"10.1038/s41413-026-00563-z","url":null,"abstract":"<p><p>Mechanical loading is crucial for maintaining bone mass, and understanding how bone remodels in response to mechanical loading is essential for treating musculoskeletal disorders. Recently, sensory nerves inside bone were identified as mechanical regulators of bone homeostasis. However, how the structure and networks of sensory nerves are altered in response to changes in mechanical loading remains unclear. To address this question, we performed a spaceflight experiment on the International Space Station (ISS) and used two ground-based mechanical unloading models, tail suspension (TS) and hindlimb immobilization. In a spaceflight experiment, Sox10-Venus mice, in which green fluorescent protein is expressed in nerve fibers, were housed at the ISS for 3 weeks, and we demonstrated that microgravity exposure significantly decreased bone mass and impaired nerve abundance inside the bone. These changes were reproduced in both ground-based models. Mechanical reloading after TS induced the recovery of bone mass and nerve abundance. Retrograde tracing experiments revealed that mechanical changes specifically affected sensory innervation inside bone without altering the number of neurons in the dorsal root ganglia. Notably, continuous administration of calcitonin gene-related peptide (CGRP), a neuropeptide secreted from sensory nerves, prevented unloading-induced bone loss. Furthermore, both surgical and genetic ablation of sensory nerves inhibited loading-induced trabecular bone recovery. These findings demonstrate that sensory nerves inside bone play a critical role in regulating bone homeostasis in response to mechanical changes and may aid in the development of therapeutic strategies for bone loss induced by mechanical unloading, such as prolonged bed rest and long-term space travel.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839355","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":"Metabolic-pathway-based classification of tendinopathy reveals a precise therapeutic strategy targeting chondro-modulatory tenocytes.","authors":"Junchao Luo, Zetao Wang, Ruifu Lin, Jiayun Huang, Chenqi Tang, Honglu Cai, Yang Fei, Dengfeng Ruan, Xinji Wang, Peiru Li, Menyun Liu, Ruojin Yan, Chunmei Fan, Canlong Wang, Cunqi Ye, Hongwei Ouyang, Zi Yin, Xiao Chen, Weiliang Shen","doi":"10.1038/s41413-026-00574-w","DOIUrl":"10.1038/s41413-026-00574-w","url":null,"abstract":"<p><p>Tendinopathy is a prevalent degenerative condition driven by complex metabolic dysregulation, yet its inherent metabolic heterogeneity remains poorly characterized, hindering targeted therapeutic development. To address this, we performed systematic multi-omics profiling of human rotator cuff tendinopathy (n = 192). Unsupervised clustering based on the activity of 149 metabolic pathways, validated by pseudotargeted metabolomics, revealed three distinct metabolic-pathway-based classifications (MPCs): MPC-G (glycolytic), with upregulated carbohydrate and glycan metabolism; MPC-F (fatty acid oxidative), exhibiting elevated fatty acid oxidation and amino acid metabolism; and MPC-I (imbalanced), showing dysregulated metabolite homeostasis alongside moderate glycolysis increase and fatty acid oxidation decrease. Single-cell RNA sequencing identified classification-specific pathogenic cell populations. Mechanistically, hypoxia-induced glycolytic reprogramming via HIF-1α led to lactate accumulation, which in turn stabilized HIF-1α, forming a feed-forward loop that promoted the formation of chondro-modulatory tenocytes and drove MPC-G pathogenesis. Genetic inhibition of HIF-1α and direct targeting of lactate both attenuated disease progression, validating the critical role of this axis. Notably, we identified and validated the clinical drug temsirolimus as an effective agent specifically against MPC-G in experimental models. Collectively, our study delineates the metabolic heterogeneity of tendinopathy and establishes a classification framework that enables precision medicine strategies tailored to distinct metabolic profiles.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839316","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":"Multidisciplinary expert consensus on clinical diagnosis and therapies for low back pain.","authors":"Bo Gao, Rundong Chai, Guanyi Wang, Yanfang Song, Lei Shang, Jinghui Huang, Xu Cao, Yong Hai, Zhuojing Luo","doi":"10.1038/s41413-026-00572-y","DOIUrl":"10.1038/s41413-026-00572-y","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Low back pain (LBP) is one of the most frequently encountered conditions in orthopedics, physical therapy and rehabilitation, and pain medicine. Its etiology is multifactorial and its management options are diverse. However, a unified, standardized, and evidence-based clinical pathway for LBP remains lacking, leading to substantial variation in diagnostic reasoning, treatment selection, outcome assessment, and long-term care across healthcare settings and professional disciplines. To address this gap, Chinese Society for the Study of the Lumbar Spine, Chinese Association of Spine initiated this multidisciplinary expert consensus. The project was organized and implemented by Xijing Hospital of Fourth Military Medical University and Beijing Chaoyang Hospital of Capital Medical University, in collaboration with a national multicenter panel of clinical experts and methodologists. Using rigorous evidence-based methodology, the panel developed an expert consensus on recommendation levels for clinical diagnosis and treatment pathways in LBP. Comprehensive searches of multiple databases and guideline sources were performed from 1991 to December 2025 in this consensus. A total of 4 703 publications were initially retrieved, and 653 publications were ultimately selected to inform the development of the consensus statements, including 70 systematic reviews and 145 original studies that directly supported the formulation and grading of recommendations. Centered on key elements across the entire care continuum, including precise diagnostic assessment, stepwise treatment selection, multimodal comprehensive interventions, long-term outcome management, recurrence prevention, patient education, and self-management, this consensus provides a structured set of recommendations. It clarifies the core diagnostic criteria and intervention strategies for patients with low back pain caused by different etiologies, and classifies interventions as \"strong recommendation\", \"weak recommendation\", \"weak recommendation against\", or \"strong recommendation against\". The recommendations emphasize individualized and stepwise decision-making tailored to patient-specific circumstances, reaffirm the foundational role of conservative management, and define strict indications for surgery and other invasive interventions. In addition, the consensus evaluates the potential synergistic effects of combined treatment strategies and highlights the importance of recurrence prevention and functional rehabilitation in long-term care. It also provides guidance on multidisciplinary collaboration and referral criteria within the clinical pathway. Overall, this consensus aims to provide clinicians at all levels of healthcare with a clear and authoritative decision-making framework. By promoting a shift from experience-based and fragmented practice toward systematic, standardized, and evidence-based management, this consensus is expected to improve clinical outcomes, enhance patients' quality ","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839297","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":"Inhibition of cyclin-dependent kinase 8 modulates chondrocyte transition to hypertrophy and provides in vivo protection against spontaneous osteoarthritis.","authors":"Leah M Wells, Jacob A C Keen, Aikta Sharma, Neil Marr, Rebecca Hansen, Janice S Pereira, Toby Roe, Helen C Roberts, Udo Oppermann, Paul A Clarke, Andrew A Pitsillides, Scott J Roberts","doi":"10.1038/s41413-026-00551-3","DOIUrl":"10.1038/s41413-026-00551-3","url":null,"abstract":"<p><p>Chondrocyte hypertrophy is a key hallmark of osteoarthritis (OA) that drives a multitude of whole-joint disease processes. There are no approved disease-modifying pharmaceuticals in clinical use, emphasising the urgent need for innovative therapeutics. Screening of a focussed chemical library using a novel in vitro platform discovered that inhibition of CDK8/19 mediator kinases modulated chondrocyte behaviours with potential to limit OA hallmarks. Transcriptomic analysis of various chondrogenic cell populations revealed that CDK8/19-inhibitor treatment upregulated pro-anabolic/anti-catabolic markers, downregulated markers of hypertrophy and protected from IL1β-induced extracellular matrix degradation. CDK8 was also found to be upregulated in chondrocytes in vitro following IL1β stimulation. This translated to human OA cartilage, where CDK8, MED12 and pSTAT1 were found to co-localise to cartilage lesions. Exposure to CDK8/19-inhibitor modified cell metabolism in hypertrophic chondrocytes and reduced inflammatory processes in THP-1-derived macrophages. CDK8/19-inhibitor treatment of the STR/Ort mouse corrected gait asymmetry and improved treadmill completion rates, whilst suppressing weight gain and serum OA biomarkers. Histological analyses of STR/Ort mouse knee joints revealed that in vivo CDK8/19-inhibitor treatment upregulated chondromodulin-1, matrillin-3 and enhanced proteoglycan deposition in the pericellular matrix of growth plate/articular cartilage. Micro computed tomography (µCT) showed that CDK8/19-inhibitor treatment modified chondrocyte endochondral behaviours to limit the number and density of mineralised growth plate bridges, which otherwise accumulate with age in STR/Ort mice. Collectively, these data highlight CDK8/19 inhibition as a promising disease-modifying strategy for targeting whole-joint disease in OA and, for the first time, show that CDK8/19 inhibition exerts pivotal control of multiple cellular processes that are crucial to endochondral ossification/OA.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13503767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812001","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":"Neutrophil-derived apoptotic bodies function as decoy signals to preserve bone integrity during infectious osteomyelitis.","authors":"Qixiu Yu, Ying Qu, Jie Zhang, Ziyang Zhang, Shuquan Guo, Fei Luo, Ce Dou","doi":"10.1038/s41413-026-00571-z","DOIUrl":"10.1038/s41413-026-00571-z","url":null,"abstract":"<p><p>Bone infection represents a pathological intersection of immunity and skeletal remodeling, where inflammatory responses drive excessive bone loss. Neutrophils dominate the early immune infiltration during infection, yet how neutrophil fate within infected bone marrow influences disease progression remains poorly understood. Here, we identify neutrophil-derived apoptotic bodies (Neut-ABs) as key mediators of bone protection during infectious osteomyelitis. Bone infection triggers extensive neutrophil apoptosis, resulting in the accumulation of Neut-ABs. Integrated transcriptomic and proteomic profiling of these Neut-ABs revealed significant enrichment of TLR2 and the sialyltransferase ST3GAL1, and lectin blotting confirmed that TLR2 is modified with α2,3-linked sialic acids. Mechanistically, α2,3-sialylated TLR2 on Neut-ABs functions as a molecular decoy that competitively interferes with Siglec15-TLR2 interactions in osteoclast precursors, thereby preventing precursor fusion and suppressing bone-resorptive activity. This inhibitory effect requires both the formation and sialylation of Neut-ABs, as it was abolished in Fas-deficient (MRL/Lpr) mice, upon neuraminidase-mediated desialylation, or when using Neut-ABs derived from Tlr2^⁻/⁻ mice. Therapeutic delivery of Neut-ABs markedly attenuates osteolysis in infected mice without altering bacterial clearance. These findings uncover a neutrophil-to-bone signaling axis in which sialylated vesicular decoys selectively suppress osteoclast activation, illuminating a new paradigm linking innate immune turnover to skeletal homeostasis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13503865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812014","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":"Vascularized bone organoids: current advances and a biomimetic platform for osteonecrosis of the femoral head.","authors":"Yihao Tao, Yuxi Wang, Ping Wang, Bo Wang, Xiao Lv, Yong Feng","doi":"10.1038/s41413-026-00579-5","DOIUrl":"https://doi.org/10.1038/s41413-026-00579-5","url":null,"abstract":"<p><p>Osteonecrosis of the femoral head (ONFH) is a devastating ischemic bone disease. Its pathogenesis is multifactorial, including impaired bone remodeling, chronic inflammation, dysregulated lipid metabolism, and bone marrow edema, all intrinsically linked to vascular dysfunction. However, conventional experimental models fail to fully capture the complex pathophysiology of ONFH. Animal models suffer from interspecies differences and are inherently limited in investigating bone marrow edema and femoral head collapse. Therefore, the complex pathogenesis of ONFH remains poorly understood due to the limitations of existing models. Recently, organoids have emerged as a powerful tool for complex and biomimetic disease modeling, with vascularization strategies developed to enhance their structural and functional maturity. The central role of vascular dysfunction in ONFH underscores the value of vascularized bone organoids (VBOs) as a biomimetic model. In this review, we summarize vascularization strategies for bone organoids, including in vitro approaches, in vivo integration, and bioengineering technologies. For ONFH, VBOs provide an advanced experimental model for elucidating disrupted angiogenesis-osteogenesis coupling, inter-tissue crosstalk, and alterations in intraosseous pressure. VBOs also hold significant value for evaluating pro-angiogenic therapies, advancing regenerative medicine, and guiding personalized treatment. Overall, VBOs offer a promising platform for advancing mechanistic insights and therapeutic development in ONFH.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13490466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788091","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":"Biomolecular condensates as dynamic regulators of musculoskeletal homeostasis, disease, and therapeutic challenges.","authors":"Qichen Miao, Ruiqi Gao, Mingyang Huang, Guoqing Wang, Wengang Wang, Ming Luo","doi":"10.1038/s41413-026-00578-6","DOIUrl":"https://doi.org/10.1038/s41413-026-00578-6","url":null,"abstract":"<p><p>Biomolecular condensates are membraneless assemblies that concentrate proteins, nucleic acids, and other biomolecules into dynamic cellular compartments. Liquid-liquid phase separation (LLPS) is one important route by which such condensates form, particularly when multivalent interactions generate liquid-like, reversible assemblies. However, not every condensate or disease-associated assembly should be explained solely by LLPS. In the musculoskeletal system, condensates have been linked to transcription, signal transduction, RNA metabolism, stress responses, tissue development, homeostasis, and mechanoadaptation. Genetic mutations, altered post-translational modifications, and environmental stress can disturb these assemblies, but the evidence does not always establish whether condensates are causal drivers of disease or downstream responses to injury. This review examines how biomolecular condensates and LLPS-related mechanisms have been implicated in osteoporosis, osteoarthritis, skeletal muscle atrophy, bone and soft tissue sarcomas, and neuromusculoskeletal diseases. We focus on the strength of the available evidence, distinguish correlative observations from causal mechanisms where possible, and discuss how condensates may connect non-coding genetic variants, mechanical cues, metabolic signals, and disease phenotypes. We also assess the translational potential and limitations of condensate-based biomarkers, therapies that target pathological condensates, and phase-separation-inspired delivery systems. A central message is that biomolecular condensates offer a useful framework for musculoskeletal biology, but clinical translation will require disease-specific targets, human-relevant models, selective delivery, and rigorous tests of causality.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13484489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788077","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}