{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T11:58:54Z","timestamp":1793793534254,"version":"4.6.1"},"reference-count":167,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82374427"],"award-info":[{"award-number":["82374427"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82374427"],"award-info":[{"award-number":["82374427"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Yunnan Province Major Science and Technology Special Plan Biomedical Special Project","award":["202402AA310028"],"award-info":[{"award-number":["202402AA310028"]}]},{"name":"Innovative Scientific Research Project of \u201ckey support and characteristic discipline of Yunnan first-class discipline\u2014traditional Chinese Medicine\u201d","award":["ZYXYB202407"],"award-info":[{"award-number":["ZYXYB202407"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoporosis (OP) and osteoarthritis (OA) are two common degenerative musculoskeletal disorders associated with aging and are traditionally classified and managed as distinct disease entities. Emerging evidence suggests that OP and OA may share bidirectional associations and common biological mechanisms, and that under specific pathological conditions they may develop into a mutually reinforcing comorbid state. The comorbidity of osteoporosis and osteoarthritis (OP\u2013OA) is not a simple superimposition of bone loss and cartilage degeneration; rather, it represents a disorder of the osteochondral unit centered on disruption of the subchondral bone microenvironment. Alterations in the structural strength, remodeling dynamics, vascular and neural status, and bone marrow lesions of subchondral bone collectively reshape the local microenvironment, thereby directly affecting mechanical signal transmission and cellular behavior within the joint. Focusing on the subchondral bone microenvironment as the central pathological nexus, this review systematically summarizes how mechanical imbalance, aberrant bone remodeling, inflammatory activation, metabolic dysregulation, and cellular senescence jointly remodel the local niche in OP\u2013OA comorbidity. These microenvironmental changes further induce phenotypic remodeling and fate deviation of bone marrow mesenchymal stem cells, bone remodeling-related cells, osteoimmune cells, and chondrocytes. On this basis, we integrate the regulatory roles of developmental signaling, mechanotransduction pathways, and inflammatory\u2013immune signaling networks, and propose that microenvironment-driven cell fate plasticity may serve as a key mechanistic hub promoting the initiation and progression of OP\u2013OA comorbidity as well as the persistent destabilization of the osteochondral unit. This perspective may help overcome the limitations of current studies that address OP and OA separately, and may provide a theoretical framework for early identification and stratification, biomarker discovery, and combined precision-targeted interventions for this comorbid condition.<\/jats:p>","DOI":"10.3390\/ijms27135757","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:49:23Z","timestamp":1782434963000},"page":"5757","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mechanistic Links Underlying the Comorbidity of Osteoporosis and Osteoarthritis: Cell Fate Plasticity Driven by the Subchondral Bone Microenvironment"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9305-701X","authenticated-orcid":false,"given":"Jian","family":"Zhang","sequence":"first","affiliation":[{"name":"The First Clinical Medical College, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingbing","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Basic Medical Sciences, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Yang","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3165-7763","authenticated-orcid":false,"given":"Heguo","family":"Yan","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6254-5658","authenticated-orcid":false,"given":"Niqin","family":"Xiao","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1006-0532","authenticated-orcid":false,"given":"Yundong","family":"Xu","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjin","family":"Zeng","sequence":"additional","affiliation":[{"name":"College of Basic Medical Sciences, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyi","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Basic Medical Sciences, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Basic Medical Sciences, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Qian","sequence":"additional","affiliation":[{"name":"College of Basic Medical Sciences, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohu","family":"Xie","sequence":"additional","affiliation":[{"name":"College of Basic Medical Sciences, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xie","sequence":"additional","affiliation":[{"name":"College of Basic Medical Sciences, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaofu","family":"Li","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Yunnan University of Chinese Medicine, No. 1076 Yuhua Street, Chenggong District, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wang, Y., Tang, X., Peng, J.-R., Deng, Y., Lan, S., Yen, Y., and Tang, Y. (2025). Global, regional, and national burden of osteoarthritis among middle-aged and older adults: Estimates from the global burden of disease study 2021 and projections to 2050. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1696929"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1186\/s13018-021-02772-0","article-title":"The global prevalence of osteoporosis in the world: A comprehensive systematic review and meta-analysis","volume":"16","author":"Salari","year":"2021","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"112788","DOI":"10.1016\/j.exger.2025.112788","article-title":"Genetic analysis of comorbidities between osteoarthritis, sarcopenia, and osteoporosis","volume":"206","author":"Liu","year":"2025","journal-title":"Exp. Gerontol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Franco-Trepat, E., Guillan-Fresco, M., Alonso-Perez, A., Jorge-Mora, A., Francisco, V., Gualillo, O., and Gomez, R. (2019). Visfatin Connection: Present and Future in Osteoarthritis and Osteoporosis. J. Clin. Med., 8.","DOI":"10.3390\/jcm8081178"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lin, L., Luo, P., Yang, M., Wang, J., Hou, W., and Xu, P. (2022). Causal relationship between osteoporosis and osteoarthritis: A two-sample Mendelian randomized study. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1011246"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Yang, C., Deng, Z., Huang, G., and Chen, Y. (2024). Editorial: Novel insights about subchondral bone remodeling in arthropathies. Front. Physiol., 15.","DOI":"10.3389\/fphys.2024.1369928"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1136\/annrheumdis-2020-218089","article-title":"Microenvironment in subchondral bone: Predominant regulator for the treatment of osteoarthritis","volume":"80","author":"Hu","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41413-021-00147-z","article-title":"Subchondral bone microenvironment in osteoarthritis and pain","volume":"9","author":"Hu","year":"2021","journal-title":"Bone Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/jbmr.3909","article-title":"Articular Cartilage Degradation and Aberrant Subchondral Bone Remodeling in Patients with Osteoarthritis and Osteoporosis","volume":"35","author":"Chu","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/s13075-023-03213-5","article-title":"Osteoporosis and osteoarthritis: A bi-directional Mendelian randomization study","volume":"25","author":"Qu","year":"2023","journal-title":"Arthritis Res. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5087","DOI":"10.2147\/IJWH.S550710","article-title":"Study on Bone Mineral Density Around the Knee in Postmenopausal Women with Osteoarthritis and Osteoporosis","volume":"17","author":"Guo","year":"2025","journal-title":"Int. J. Womens Health"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1007\/s00198-022-06376-0","article-title":"Prevalence of osteoporosis in osteoarthritis: A systematic review and meta-analysis","volume":"33","author":"Kim","year":"2022","journal-title":"Osteoporos. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.nut.2018.09.001","article-title":"Influence of dietary vitamin D deficiency on bone strength, body composition, and muscle in ovariectomized rats fed a high-fat diet","volume":"60","author":"Nakaoka","year":"2019","journal-title":"Nutrition"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1186\/s13018-025-05578-6","article-title":"RANKL-mediated osteoclastic subchondral bone loss at a very early stage precedes subsequent cartilage degeneration and uncoupled bone remodeling in a mouse knee osteoarthritis model","volume":"20","author":"Hashimoto","year":"2025","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00223-024-01315-z","article-title":"Individuals with Knee Osteoarthritis and Osteoporosis Represent a Distinctive Subgroup Whose Symptoms Originate from Differences in Subchondral Bone Rather than Cartilage","volume":"116","author":"Wong","year":"2024","journal-title":"Calcif. Tissue Int."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Aho, O.-M., Finnil\u00e4, M., Thevenot, J., Saarakkala, S., and Lehenkari, P. (2017). Subchondral bone histology and grading in osteoarthritis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173726"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1016\/j.joca.2011.07.003","article-title":"Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis preceded by osteoporosis","volume":"19","author":"Bellido","year":"2011","journal-title":"Osteoarthr. Cartil."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.1002\/jor.25018","article-title":"Subchondral bone microarchitecture and mineral density in human osteoarthritis and osteoporosis: A regional and compartmental analysis","volume":"39","author":"Li","year":"2021","journal-title":"J. Orthop. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"152140","DOI":"10.1016\/j.semarthrit.2022.152140","article-title":"Unsupervised machine-learning algorithms for the identification of clinical phenotypes in the osteoarthritis initiative database","volume":"58","author":"Demanse","year":"2023","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41584-024-01126-4","article-title":"Clinical phenotypes, molecular endotypes and theratypes in OA therapeutic development","volume":"20","author":"Mobasheri","year":"2024","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yokota, S., Ishizu, H., Miyazaki, T., Takahashi, D., Iwasaki, N., and Shimizu, T. (2024). Osteoporosis, Osteoarthritis, and Subchondral Insufficiency Fracture: Recent Insights. Biomedicines, 12.","DOI":"10.3390\/biomedicines12040843"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1021\/acsbiomaterials.2c01321","article-title":"Osteochondral Interface: Regenerative Engineering and Challenges","volume":"9","author":"Yildirim","year":"2023","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1186\/ar4405","article-title":"Subchondral bone in osteoarthritis: Insight into risk factors and microstructural changes","volume":"15","author":"Li","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1177\/1941738109350438","article-title":"The basic science of articular cartilage: Structure, composition, and function","volume":"1","author":"Bedi","year":"2009","journal-title":"Sports Health"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Berni, M., Marchiori, G., Baleani, M., Giavaresi, G., and Lopomo, N.F. (2024). Biomechanics of the Human Osteochondral Unit: A Systematic Review. Materials, 17.","DOI":"10.3390\/ma17071698"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1186\/s13075-014-0494-0","article-title":"Targeting subchondral bone in osteoporotic osteoarthritis","volume":"16","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1136\/ard.56.4.247","article-title":"Mechanical and material properties of the subchondral bone plate from the femoral head of patients with osteoarthritis or osteoporosis","volume":"56","author":"Li","year":"1997","journal-title":"Ann. Rheum. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.joca.2014.05.023","article-title":"Bone-cartilage interface crosstalk in osteoarthritis: Potential pathways and future therapeutic strategies","volume":"22","author":"Yuan","year":"2014","journal-title":"Osteoarthr. Cartil."},{"key":"ref_29","first-page":"1700","article-title":"Mineral Crystal Thickness in Calcified Cartilage and Subchondral Bone in Healthy and Osteoarthritic Human Knees","volume":"37","author":"Turunen","year":"2022","journal-title":"J. Bone Miner. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Fan, X., Wu, X., Crawford, R., Xiao, Y., and Prasadam, I. (2021). Macro, Micro, and Molecular. Changes of the Osteochondral Interface in Osteoarthritis Development. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.659654"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"R152","DOI":"10.1186\/ar3103","article-title":"Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis","volume":"12","author":"Bellido","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhou, F., Chu, L., Liu, X., He, Z., Han, X., Yan, M., Qu, X., Li, X., and Yu, Z. (2021). Subchondral Trabecular Microstructure and Articular Cartilage Damage Variations Between Osteoarthritis and Osteoporotic Osteoarthritis: A Cross-sectional Cohort Study. Front. Med., 8.","DOI":"10.3389\/fmed.2021.617200"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1016\/j.joca.2024.06.002","article-title":"Temporal progression of subchondral bone alterations in OA models involving induction of compromised meniscus integrity in mice and rats: A scoping review","volume":"32","author":"Cucchiarini","year":"2024","journal-title":"Osteoarthr. Cartil."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s11684-024-1061-y","article-title":"Pathological progression of osteoarthritis: A perspective on subchondral bone","volume":"18","author":"Li","year":"2024","journal-title":"Front. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1038\/s41598-023-29802-7","article-title":"The effect of postmenopausal osteoporosis on subchondral bone pathology in a rat model of knee osteoarthritis","volume":"13","author":"Wada","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100043","DOI":"10.1016\/j.mbm.2024.100043","article-title":"Mechanotransduction in subchondral bone microenvironment and targeted interventions for osteoarthritis","volume":"2","author":"Feng","year":"2024","journal-title":"Mechanobiol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5346","DOI":"10.1007\/s00167-023-07579-6","article-title":"Subchondral bone remodeling patterns in larger animal models of meniscal injuries inducing knee osteoarthritis\u2014A systematic review","volume":"31","author":"Cucchiarini","year":"2023","journal-title":"Knee Surg. Sports Traumatol. Arthrosc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"R11","DOI":"10.1186\/ar2601","article-title":"Bone marrow lesions from osteoarthritis knees are characterized by sclerotic bone that is less well mineralized","volume":"11","author":"Hunter","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101667","DOI":"10.1016\/j.bonr.2023.101667","article-title":"Bone marrow lesions in osteoarthritis: From basic science to clinical implications","volume":"18","author":"Shi","year":"2023","journal-title":"Bone Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s00256-024-04725-0","article-title":"Bone marrow lesions in osteoarthritis: Biomarker or treatment target? A narrative review","volume":"54","author":"Ge","year":"2025","journal-title":"Skelet. Radiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/s41584-023-00971-z","article-title":"Bone marrow lesions: Plugging the holes in our knowledge using animal models","volume":"19","author":"Hansen","year":"2023","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1136\/ard.2008.096834","article-title":"Change in MRI-detected subchondral bone marrow lesions is associated with cartilage loss: The MOST Study. A longitudinal multicentre study of knee osteoarthritis","volume":"68","author":"Roemer","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1002\/jbmr.4171","article-title":"Bone Vasculature and Bone Marrow Vascular Niches in Health and Disease","volume":"35","author":"Chen","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Liu, X., Zhang, P., Gu, Y., Guo, Q., and Liu, Y. (2023). Type H vessels: Functions in bone development and diseases. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1236545"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1093\/rheumatology\/keac539","article-title":"Type H vessels-a bridge connecting subchondral bone remodelling and articular cartilage degeneration in osteoarthritis development","volume":"62","author":"Liu","year":"2023","journal-title":"Rheumatology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/s41413-022-00229-6","article-title":"Endothelial PDGF-BB\/PDGFR-\u03b2 signaling promotes osteoarthritis by enhancing angiogenesis-dependent abnormal subchondral bone formation","volume":"10","author":"Cui","year":"2022","journal-title":"Bone Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1080\/08923973.2024.2424297","article-title":"Inhibition of Slit3\/Robo1 signaling alleviates osteoarthritis in mice by reducing abnormal H-type vessel formation in subchondral bone","volume":"46","author":"Li","year":"2024","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1136\/annrheumdis-2015-207923","article-title":"Halofuginone attenuates osteoarthritis by inhibition of TGF-\u03b2 activity and H-type vessel formation in subchondral bone","volume":"75","author":"Cui","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Huang, L., Du, W., Jin, X., Chen, B., and Meng, Z. (2025). Swimming exercise reduces H-type vessels by down-regulating the Hif-1\u03b1\/VEGFa pathway in mice with osteoarthritis of the knee. BMC Musculoskelet. Disord., 26.","DOI":"10.1186\/s12891-025-08903-6"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1002\/jbmr.3388","article-title":"Positive-Feedback Regulation of Subchondral H-Type Vessel Formation by Chondrocyte Promotes Osteoarthritis Development in Mice","volume":"33","author":"Lu","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s00418-025-02365-6","article-title":"Increased vascularization of the subchondral region in human osteoarthritic femoral head in the elderly","volume":"163","author":"He","year":"2025","journal-title":"Histochem. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"100531","DOI":"10.1016\/j.ocarto.2024.100531","article-title":"Bone marrow lesions in osteoarthritis: Characterising genetic and histological changes to understand disease pathophysiology","volume":"6","author":"Sofat","year":"2024","journal-title":"Osteoarthr. Cartil. Open"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Volkov, A., Lyalina, V., Eshmotova, G., Serejnikova, N., Petrova, S., Airapetov, G., Parshina, E., Zalygin, A., Belitskaya, E., and Oleinikov, V. (2026). A Novel Concept of Tissue Micro-Instability as the Underlying Mechanism of Osteophytosis in Human Knee Osteoarthritis. Biomedicines, 14.","DOI":"10.3390\/biomedicines14020283"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1016\/j.joca.2022.07.003","article-title":"Time course and localization of nerve growth factor expression and sensory nerve growth during progression of knee osteoarthritis in rats","volume":"30","author":"Aso","year":"2022","journal-title":"Osteoarthr. Cartil."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/s41584-025-01257-2","article-title":"Targeting osteoarthritis where it hurts: The osteochondral junction","volume":"21","author":"Malfait","year":"2025","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1172\/JCI121561","article-title":"Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain","volume":"129","author":"Zhu","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"102372","DOI":"10.1016\/j.arr.2024.102372","article-title":"Sensory nerve regulation of bone homeostasis: Emerging therapeutic opportunities for bone-related diseases","volume":"99","author":"Chen","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nrrheum.2012.80","article-title":"Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis","volume":"8","author":"Mapp","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Zeng, M., Wang, X., Chen, T., Ruan, G., Li, J., Xue, S., Zhao, Y., Hu, Z., Xie, Y., and Fan, T. (2023). Comprehensive analysis on subchondral bone marrow lesions of human osteoarthritis by integrating bulk and single-cell transcriptomes. BMC Musculoskelet. Disord., 24.","DOI":"10.1186\/s12891-023-06676-4"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41413-025-00467-4","article-title":"Single-cell sequencing reveals a senescent immune landscape in bone marrow lesions inducing articular cartilage damage in osteoarthritis","volume":"13","author":"Lou","year":"2025","journal-title":"Bone Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nrrheum.2012.130","article-title":"Bone remodelling in osteoarthritis","volume":"8","author":"Burr","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/nrrheum.2016.148","article-title":"Changes in the osteochondral unit during osteoarthritis: Structure, function and cartilage-bone crosstalk","volume":"12","author":"Goldring","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/s41584-024-01130-8","article-title":"Integrin signalling in joint development, homeostasis and osteoarthritis","volume":"20","author":"Miao","year":"2024","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5408","DOI":"10.1111\/jcmm.15204","article-title":"Mechanotransduction pathways in the regulation of cartilage chondrocyte homoeostasis","volume":"24","author":"Zhao","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.joca.2023.04.006","article-title":"Yes-associated protein nuclear translocation promotes anabolic activity in human articular chondrocytes","volume":"31","author":"Cui","year":"2023","journal-title":"Osteoarthr. Cartil."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Steinecker-Frohnwieser, B., Lohberger, B., Toegel, S., Windhager, R., Glanz, V., Kratschmann, C., Leithner, A., and Weigl, L. (2023). Activation of the Mechanosensitive Ion Channels Piezo1 and TRPV4 in Primary Human Healthy and Osteoarthritic Chondrocytes Exhibits Ion Channel Crosstalk and Modulates Gene Expression. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24097868"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.cell.2006.06.044","article-title":"Matrix elasticity directs stem cell lineage specification","volume":"126","author":"Engler","year":"2006","journal-title":"Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1007\/s11033-021-07075-5","article-title":"Relationship of matrix stiffness and cell morphology in regulation of osteogenesis and adipogenesis of BMSCs","volume":"49","author":"Guo","year":"2022","journal-title":"Mol. Biol. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Huang, K., and Cai, H. (2025). Matrix stiffness in osteoarthritis: From mechanism introduction to biomaterial-based therapies. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1571502"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/art.27290","article-title":"The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis","volume":"62","author":"Bondeson","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.bone.2012.02.012","article-title":"The role of synovitis in osteoarthritis pathogenesis","volume":"51","author":"Scanzello","year":"2012","journal-title":"Bone"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrrheum.2010.196","article-title":"Role of proinflammatory cytokines in the pathophysiology of osteoarthritis","volume":"7","author":"Kapoor","year":"2011","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/nm.3143","article-title":"Inhibition of TGF-\u03b2 signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis","volume":"19","author":"Zhen","year":"2013","journal-title":"Nat. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1016\/j.biocel.2013.08.018","article-title":"The NF-\u03baB signalling pathway in osteoarthritis","volume":"45","author":"Rigoglou","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1097\/BOR.0000000000000449","article-title":"Inflammation in bone physiology and pathology","volume":"30","author":"Adamopoulos","year":"2018","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nrrheum.2012.153","article-title":"Bone erosion in rheumatoid arthritis: Mechanisms, diagnosis and treatment","volume":"8","author":"Schett","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"119735","DOI":"10.1016\/j.cca.2024.119735","article-title":"Metabolomic analysis reveals macrophage metabolic reprogramming and polarization under different nutritional cues","volume":"560","author":"Zhang","year":"2024","journal-title":"Clin. Chim. Acta"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"101249","DOI":"10.1016\/j.arr.2020.101249","article-title":"The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis","volume":"66","author":"Zheng","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/nm.2153","article-title":"Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction","volume":"16","author":"Yang","year":"2010","journal-title":"Nat. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/nm.2146","article-title":"Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development","volume":"16","author":"Saito","year":"2010","journal-title":"Nat. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/nrrheum.2017.50","article-title":"The role of metabolism in the pathogenesis of osteoarthritis","volume":"13","author":"Mobasheri","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.1038\/s41467-020-17242-0","article-title":"LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis","volume":"11","author":"Arra","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s11658-023-00489-y","article-title":"Oxidative stress as a key modulator of cell fate decision in osteoarthritis and osteoporosis: A narrative review","volume":"28","author":"Riegger","year":"2023","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"107649","DOI":"10.1016\/j.phrs.2025.107649","article-title":"The role of HIF-1\u03b1 in hypoxic metabolic reprogramming in osteoarthritis","volume":"213","author":"Zhang","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41413-025-00460-x","article-title":"The impact of mitochondrial dysfunction on osteoarthritis cartilage: Current insights and emerging mitochondria-targeted therapies","volume":"13","author":"Tan","year":"2025","journal-title":"Bone Res."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Liu, J., Gao, Z., and Liu, X. (2024). Mitochondrial dysfunction and therapeutic perspectives in osteoporosis. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1325317"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1186\/s13287-025-04833-1","article-title":"Senescent bone marrow mesenchymal stem cells exacerbate subchondral bone sclerosis and osteoarthritis via the senescence-associated secretory phenotype","volume":"16","author":"Yang","year":"2025","journal-title":"Stem Cell Res. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/nm.4385","article-title":"Targeting cellular senescence prevents age-related bone loss in mice","volume":"23","author":"Farr","year":"2017","journal-title":"Nat. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s00223-023-01100-4","article-title":"\u201cBone-SASP\u201d in Skeletal Aging","volume":"113","author":"Fang","year":"2023","journal-title":"Calcif. Tissue Int."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.cellsig.2011.12.006","article-title":"Emerging role of NF-\u03baB signaling in the induction of senescence-associated secretory phenotype (SASP)","volume":"24","author":"Salminen","year":"2012","journal-title":"Cell. Signal."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"R58","DOI":"10.1186\/ar4494","article-title":"p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis","volume":"16","author":"Philipot","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"eadu2294","DOI":"10.1126\/sciadv.adu2294","article-title":"Multiomic identification of senescent stem cell populations critical for osteoarthritis progression and therapy in subchondral bones","volume":"11","author":"Li","year":"2025","journal-title":"Sci. Adv."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e70513","DOI":"10.1002\/ctm2.70513","article-title":"Altered nicotinamide adenine dinucleotide metabolism drives cartilage degeneration and osteoarthritis","volume":"15","author":"Wu","year":"2025","journal-title":"Clin. Transl. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"259","DOI":"10.2147\/DDDT.S287280","article-title":"Effects of Caffeic Acid and Its Derivatives on Bone: A Systematic Review","volume":"15","author":"Ekeuku","year":"2021","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Liang, G., Zhao, J., Zhao, D., Dou, Y., Huang, H., Yang, W., Zhou, G., Gu, Z., Pan, J., and Liu, J. (2023). Longbie capsules reduce bone loss in the subchondral bone of rats with comorbid osteoporosis and osteoarthritis by regulating metabolite alterations. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1256238"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"5521","DOI":"10.1002\/j.2040-4603.2024.tb00300.x","article-title":"Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations","volume":"14","author":"Zhang","year":"2024","journal-title":"Compr. Physiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e54695","DOI":"10.7554\/eLife.54695","article-title":"Single cell transcriptomics identifies a unique adipose lineage cell population that regulates bone marrow environment","volume":"9","author":"Zhong","year":"2020","journal-title":"eLife"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s13679-024-00594-9","article-title":"Bone Marrow Adipocytes as Novel Regulators of Metabolic Homeostasis: Clinical Consequences of Bone Marrow Adiposity","volume":"14","author":"Liu","year":"2025","journal-title":"Curr. Obes. Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1016\/j.celrep.2019.04.066","article-title":"Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone Fragility","volume":"27","author":"Tencerova","year":"2019","journal-title":"Cell Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e140214","DOI":"10.1172\/JCI140214","article-title":"Bone marrow adipogenic lineage precursors promote osteoclastogenesis in bone remodeling and pathologic bone loss","volume":"131","author":"Yu","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1634\/stemcells.2007-0509","article-title":"Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells","volume":"26","author":"Chen","year":"2008","journal-title":"Stem Cells"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1186\/s13287-022-03088-4","article-title":"Downregulation of DNA methyltransferase-3a ameliorates the osteogenic differentiation ability of adipose-derived stem cells in diabetic osteoporosis via Wnt\/\u03b2-catenin signaling pathway","volume":"13","author":"Zhang","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.stem.2012.04.009","article-title":"Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs","volume":"11","author":"Ye","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"5251","DOI":"10.1172\/JCI99044","article-title":"Long noncoding RNA Bmncr regulates mesenchymal stem cell fate during skeletal aging","volume":"128","author":"Li","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1172\/JCI77716","article-title":"MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation","volume":"125","author":"Li","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1097\/BOR.0000000000000162","article-title":"Biologic basis of osteoarthritis: State of the evidence","volume":"27","author":"Malemud","year":"2015","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1038\/nm.3668","article-title":"PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis","volume":"20","author":"Xie","year":"2014","journal-title":"Nat. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/s41413-019-0070-y","article-title":"Osteocyte dysfunction promotes osteoarthritis through MMP13-dependent suppression of subchondral bone homeostasis","volume":"7","author":"Mazur","year":"2019","journal-title":"Bone Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1007\/s00223-024-01226-z","article-title":"Subchondral Bone Osteocyte Lacunae Morphology in End-Stage Osteoarthritis of the Human Tibial Plateau","volume":"115","author":"Azari","year":"2024","journal-title":"Calcif. Tissue Int."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.1002\/jcp.25969","article-title":"Osteoblast role in osteoarthritis pathogenesis","volume":"232","author":"Maruotti","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3399","DOI":"10.1096\/fj.201902117R","article-title":"Knee loading repairs osteoporotic osteoarthritis by relieving abnormal remodeling of subchondral bone via Wnt\/\u03b2-catenin signaling","volume":"34","author":"Zheng","year":"2020","journal-title":"FASEB J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e70107","DOI":"10.1111\/cpr.70107","article-title":"Mechanism of ITGB2 in Osteoclast Differentiation in Osteoarthritis","volume":"59","author":"Yang","year":"2026","journal-title":"Cell Prolif."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"115472","DOI":"10.1016\/j.intimp.2025.115472","article-title":"Dimethyl fumarate mitigates osteoarthritis progression through Nrf2 activation-mediated suppression of oxidative stress and subchondral osteoclastogenesis","volume":"165","author":"Shen","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_115","first-page":"108","article-title":"Osteoclast-derived apoptotic bodies accelerate the pathological progression of osteoarthritis via disturbing subchondral bone remodeling","volume":"51","author":"Ai","year":"2025","journal-title":"J. Orthop. Transl."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.joca.2025.06.013","article-title":"Osteoclast-secreted galectin-3 promotes articular cartilage degeneration in OVX rats via LRP1\/beta-catenin axis","volume":"34","author":"Chen","year":"2026","journal-title":"Osteoarthr. Cartil."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e17545","DOI":"10.1002\/advs.202517545","article-title":"Osteoclast-Derived SLIT3 Mediates Osteoarthritis Pain and Degenerative Changes","volume":"13","author":"Zhu","year":"2026","journal-title":"Adv. Sci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1016\/j.joca.2015.07.021","article-title":"Multicolor flow cytometry-based cellular phenotyping identifies osteoprogenitors and inflammatory cells in the osteoarthritic subchondral bone marrow compartment","volume":"23","author":"Pippenger","year":"2015","journal-title":"Osteoarthr. Cartil."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1002\/jbmr.4773","article-title":"Macrophages and Bone Remodeling","volume":"38","author":"Weivoda","year":"2023","journal-title":"J. Bone Miner. Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.joca.2020.01.007","article-title":"Macrophages regulate the progression of osteoarthritis","volume":"28","author":"Zhang","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Sebastian, A., Hum, N.R., McCool, J.L., Wilson, S.P., Murugesh, D.K., Martin, K.A., Rios-Arce, N.D., Amiri, B., Christiansen, B.A., and Loots, G.G. (2022). Single-cell RNA-Seq reveals changes in immune landscape in post-traumatic osteoarthritis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.938075"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"4121","DOI":"10.2147\/JIR.S514002","article-title":"Osteoimmunology in Osteoarthritis: Unraveling the Interplay of Immunity, Inflammation, and Joint Degeneration","volume":"18","author":"Hu","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Qi, Z., Luo, J., Xiao, Z., and Yang, D. (2025). Functional roles of immune cells in osteoporosis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1698283"},{"key":"ref_124","first-page":"499","article-title":"Subchondral osteoclasts and osteoarthritis: New insights and potential therapeutic avenues","volume":"56","author":"Chen","year":"2024","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1038\/cr.2014.111","article-title":"Osteogenic fate of hypertrophic chondrocytes","volume":"24","author":"Yang","year":"2014","journal-title":"Cell Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1016\/j.gendis.2022.12.016","article-title":"DLX5 promotes Col10a1 expression and chondrocyte hypertrophy and is involved in osteoarthritis progression","volume":"10","author":"Chen","year":"2023","journal-title":"Genes Dis."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Pan, B., Yao, P., Ma, J., Lin, X., Zhou, L., Lin, C., Zhang, Y., Lin, B., and Lin, C. (2024). Identification of key biomarkers related to fibrocartilage chondrocytes for osteoarthritis based on bulk, single-cell transcriptomic data. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1482361"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"4564","DOI":"10.1038\/s41467-018-07022-2","article-title":"Reciprocal inhibition of YAP\/TAZ and NF-\u03baB regulates osteoarthritic cartilage degradation","volume":"9","author":"Deng","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"103613","DOI":"10.1016\/j.etap.2021.103613","article-title":"The role of TGF-\u03b21\/Smad3 signaling pathway and oxidative stress in the inhibition of osteoblast mineralization by copper chloride","volume":"84","author":"Qi","year":"2021","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"16009","DOI":"10.1038\/boneres.2016.9","article-title":"TGF-\u03b2 and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease","volume":"4","author":"Wu","year":"2016","journal-title":"Bone Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41422-023-00918-9","article-title":"The roles and regulatory mechanisms of TGF-\u03b2 and BMP signaling in bone and cartilage development, homeostasis and disease","volume":"34","author":"Wu","year":"2024","journal-title":"Cell Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/s41413-024-00342-8","article-title":"Wnt\/\u03b2-catenin signaling components and mechanisms in bone formation, homeostasis, and disease","volume":"12","author":"Hu","year":"2024","journal-title":"Bone Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/j.gendis.2022.07.011","article-title":"Wnt signaling: Essential roles in osteoblast differentiation, bone metabolism and therapeutic implications for bone and skeletal disorders","volume":"10","author":"Vlashi","year":"2022","journal-title":"Genes Dis."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13075-015-0540-6","article-title":"Loss of sclerostin promotes osteoarthritis in mice via \u03b2-catenin-dependent and -independent Wnt pathways","volume":"17","author":"Bouaziz","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/labinvest.2015.142","article-title":"Wnt signaling in cartilage development and diseases: Lessons from animal studies","volume":"96","author":"Usami","year":"2016","journal-title":"Lab. Investig."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.joca.2012.03.010","article-title":"Activation of Indian hedgehog promotes chondrocyte hypertrophy and upregulation of MMP-13 in human osteoarthritic cartilage","volume":"20","author":"Wei","year":"2012","journal-title":"Osteoarthr. Cartil."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"R11","DOI":"10.1186\/ar4437","article-title":"Disrupting the Indian hedgehog signaling pathway in vivo attenuates surgically induced osteoarthritis progression in Col2a1-CreERT2; Ihhfl\/fl mice","volume":"16","author":"Zhou","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.devcel.2008.02.003","article-title":"Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression","volume":"14","author":"Mak","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"10859","DOI":"10.1038\/s41467-025-65636-9","article-title":"Piezo1-mediated mechanotransduction controls osteocyte maturation and dendrite development via a YAP-CCN-Src signaling axis","volume":"16","author":"Hu","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"e52779","DOI":"10.7554\/eLife.52779","article-title":"Piezo1\/2 mediate mechanotransduction essential for bone formation through concerted activation of NFAT-YAP1-\u00df-catenin","volume":"9","author":"Zhou","year":"2020","journal-title":"eLife"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"e2001611118","DOI":"10.1073\/pnas.2001611118","article-title":"Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis","volume":"118","author":"Lee","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.1017\/erm.2021.16","article-title":"Integrins, cadherins and channels in cartilage mechanotransduction: Perspectives for future regeneration strategies","volume":"23","author":"Dieterle","year":"2021","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Jin, H., Jiang, S., Wang, R., Zhang, Y., Dong, J., and Li, Y. (2021). Mechanistic Insight Into the Roles of Integrins in Osteoarthritis. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.693484"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Hwang, J.-H., Byun, M.R., Kim, A.R., Kim, K.M., Cho, H.J., Lee, Y.H., Kim, J., Jeong, M.G., Hwang, E.S., and Hong, J.-H. (2015). Extracellular Matrix Stiffness Regulates Osteogenic Differentiation through MAPK Activation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135519"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Dong, D.-L., and Jin, G.-Z. (2025). Substrate Stiffness Modulates Hypertrophic Chondrocyte Reversion and Chondrogenic Phenotype Restoration. Cells, 14.","DOI":"10.20944\/preprints202506.1180.v1"},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Zarka, M., Ha\u00ff, E., and Cohen-Solal, M. (2022). YAP\/TAZ in Bone and Cartilage Biology. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.788773"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/jbmr.3876","article-title":"YAP and TAZ Mediate Osteocyte Perilacunar\/Canalicular Remodeling","volume":"35","author":"Kegelman","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"119724","DOI":"10.1016\/j.biomaterials.2019.119724","article-title":"Targeting downstream subcellular YAP activity as a function of matrix stiffness with Verteporfin-encapsulated chitosan microsphere attenuates osteoarthritis","volume":"232","author":"Zhang","year":"2020","journal-title":"Biomaterials"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"734","DOI":"10.3390\/cells8070734","article-title":"NF-\u03baB Signaling Pathways in Osteoarthritic Cartilage Destruction","volume":"8","author":"Choi","year":"2019","journal-title":"Cells"},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Zhang, X.-A., and Kong, H. (2023). Mechanism of HIFs in osteoarthritis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1168799"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1038\/s42003-024-06581-z","article-title":"Differential but complementary roles of HIF-1\u03b1 and HIF-2\u03b1 in the regulation of bone homeostasis","volume":"7","author":"Lee","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1186\/s13018-023-04092-x","article-title":"PPAR\u03b3 activation suppresses chondrocyte ferroptosis through mitophagy in osteoarthritis","volume":"18","author":"Xue","year":"2023","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.abb.2008.03.018","article-title":"Functions of RANKL\/RANK\/OPG in bone modeling and remodeling","volume":"473","author":"Boyce","year":"2008","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Tateiwa, D., Yoshikawa, H., and Kaito, T. (2019). Cartilage and Bone Destruction in Arthritis: Pathogenesis and Treatment Strategy: A Literature Review. Cells, 8.","DOI":"10.3390\/cells8080818"},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Zhu, X., Chan, Y.T., Yung, P.S.H., Tuan, R.S., and Jiang, Y. (2021). Subchondral Bone Remodeling: A Therapeutic Target for Osteoarthritis. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.607764"},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Zhou, Q., Ren, Q., Jiao, L., Huang, J., Yi, J., Chen, J., Lai, J., Ji, G., and Zheng, T. (2022). The potential roles of JAK\/STAT signaling in the progression of osteoarthritis. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1069057"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"112614","DOI":"10.1016\/j.exger.2024.112614","article-title":"The interplay between osteoarthritis and osteoporosis: Mechanisms, implications, and treatment considerations\u2014A narrative review","volume":"197","author":"Huang","year":"2024","journal-title":"Exp. Gerontol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1002\/art.1780361205","article-title":"Bone mineral density and knee osteoarthritis in elderly men and women. The Framingham Study","volume":"36","author":"Hannan","year":"1993","journal-title":"Arthritis Rheum."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/978-1-4615-4857-7_63","article-title":"The inverse relationship between osteoporosis and osteoarthritis","volume":"455","author":"Dequeker","year":"1999","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/nm.3228","article-title":"TGF-\u03b2 and osteoarthritis\u2014The good and the bad","volume":"19","author":"Bush","year":"2013","journal-title":"Nat. Med."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.joca.2018.09.016","article-title":"Models of osteoarthritis: The good, the bad and the promising","volume":"27","author":"Cope","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1302\/2046-3758.118.BJR-2022-0217.R1","article-title":"Animal models of osteoarthritis: The benefits and costs of reducing variability","volume":"11","author":"Little","year":"2022","journal-title":"Bone Jt. Res."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41572-025-00594-6","article-title":"Osteoarthritis","volume":"11","author":"Tang","year":"2025","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1080\/03008207.2025.2540950","article-title":"Cellular and molecular mechanisms underlying subchondral bone remodeling and associated pain in osteoarthritis","volume":"66","author":"Murphy","year":"2025","journal-title":"Connect. Tissue Res."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"100270","DOI":"10.1016\/j.ostima.2025.100270","article-title":"Imaging of osteoarthritis-related bone marrow lesions in clinical trials","volume":"5","author":"Moradi","year":"2025","journal-title":"Osteoarthr. Imaging"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/s41584-025-01305-x","article-title":"Novel approaches to the stratified management of knee osteoarthritis","volume":"21","author":"Fuggle","year":"2025","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s41584-025-01223-y","article-title":"The role of the immune system in osteoarthritis: Mechanisms, challenges and future directions","volume":"21","author":"Moulin","year":"2025","journal-title":"Nat. Rev. Rheumatol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5757\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T04:23:34Z","timestamp":1783139014000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5757"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":167,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135757"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135757","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]}}}