{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:01:20Z","timestamp":1787238080645,"version":"build-2736575974"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":22,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K27717"],"award-info":[{"award-number":["23K27717"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23H05484"],"award-info":[{"award-number":["23H05484"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K27718"],"award-info":[{"award-number":["23K27718"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-026-39416-4","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T15:24:40Z","timestamp":1770650680000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Loss of mechanical stress induces synovitis, fibrosis and articular cartilage degeneration via distinct synovial cell subsets"],"prefix":"10.1038","volume":"16","author":[{"given":"Hisatoshi","family":"Ishikura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yota","family":"Kin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Chijimatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Higuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Miyahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naohiro","family":"Tachibana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosei","family":"Nagata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asuka","family":"Terashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiko","family":"Yano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunori","family":"Omata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahide","family":"Seki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Baron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakae","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"39416_CR1","doi-asserted-by":"publisher","first-page":"1779","DOI":"10.1136\/ard.2009.121426","volume":"69","author":"K Baker","year":"2010","unstructured":"Baker, K. et al. Relation of synovitis to knee pain using contrast-enhanced MRIs. Ann. Rheum. Dis. 69, 1779\u20131783. https:\/\/doi.org\/10.1136\/ard.2009.121426 (2010).","journal-title":"Ann. Rheum. Dis."},{"key":"39416_CR2","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/j.joca.2015.09.013","volume":"24","author":"DT Felson","year":"2016","unstructured":"Felson, D. T. et al. Synovitis and the risk of knee osteoarthritis: the MOST study. Osteoarthr. Cartil. 24, 458\u2013464. https:\/\/doi.org\/10.1016\/j.joca.2015.09.013 (2016).","journal-title":"Osteoarthr. Cartil."},{"key":"39416_CR3","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.joca.2021.04.020","volume":"30","author":"KD Allen","year":"2022","unstructured":"Allen, K. D., Thoma, L. M. & Golightly, Y. M. Epidemiology of osteoarthritis. Osteoarthr. Cartil. 30, 184\u2013195. https:\/\/doi.org\/10.1016\/j.joca.2021.04.020 (2022).","journal-title":"Osteoarthr. Cartil."},{"key":"39416_CR4","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.berh.2018.10.007","volume":"32","author":"TW O\u2019Neill","year":"2018","unstructured":"O\u2019Neill, T. W., McCabe, P. S. & McBeth, J. Update on the epidemiology, risk factors and disease outcomes of osteoarthritis. Best Pract. Res. Clin. Rheumatol. 32, 312\u2013326. https:\/\/doi.org\/10.1016\/j.berh.2018.10.007 (2018).","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"39416_CR5","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1038\/s41467-019-09491-5","volume":"10","author":"SH Chang","year":"2019","unstructured":"Chang, S. H. et al. Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-kappaB pathway. Nat. Commun. 10, 1442. https:\/\/doi.org\/10.1038\/s41467-019-09491-5 (2019).","journal-title":"Nat. Commun."},{"key":"39416_CR6","doi-asserted-by":"publisher","first-page":"2516","DOI":"10.1002\/art.20378","volume":"50","author":"S Hinterwimmer","year":"2004","unstructured":"Hinterwimmer, S. et al. Cartilage atrophy in the knees of patients after seven weeks of partial load bearing. Arthritis Rheum. 50, 2516\u20132520. https:\/\/doi.org\/10.1002\/art.20378 (2004).","journal-title":"Arthritis Rheum."},{"key":"39416_CR7","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1097\/MRR.0b013e3283532736","volume":"35","author":"H Tunc","year":"2012","unstructured":"Tunc, H. et al. Ultrasonographic measurement of the femoral cartilage thickness in hemiparetic patients after stroke. Int. J. Rehabil Res. 35, 203\u2013207. https:\/\/doi.org\/10.1097\/MRR.0b013e3283532736 (2012).","journal-title":"Int. J. Rehabil Res."},{"key":"39416_CR8","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1038\/sc.2015.151","volume":"54","author":"B Yilmaz","year":"2016","unstructured":"Yilmaz, B., Demir, Y., Ozyoruk, E., Kesikburun, S. & Guzelkucuk, U. The effect of knee joint loading and immobilization on the femoral cartilage thickness in paraplegics. Spinal Cord. 54, 283\u2013286. https:\/\/doi.org\/10.1038\/sc.2015.151 (2016).","journal-title":"Spinal Cord"},{"key":"39416_CR9","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1007\/s00223-021-00836-1","volume":"110","author":"T Rolvien","year":"2022","unstructured":"Rolvien, T. & Amling, M. Disuse osteoporosis: clinical and mechanistic insights. Calcif Tissue Int. 110, 592\u2013604. https:\/\/doi.org\/10.1007\/s00223-021-00836-1 (2022).","journal-title":"Calcif Tissue Int."},{"key":"39416_CR10","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1186\/s12891-019-2521-4","volume":"20","author":"H Chen","year":"2019","unstructured":"Chen, H. et al. The effects of a home-based exercise intervention on elderly patients with knee osteoarthritis: a quasi-experimental study. BMC Musculoskelet. Disord. 20, 160. https:\/\/doi.org\/10.1186\/s12891-019-2521-4 (2019).","journal-title":"BMC Musculoskelet. Disord"},{"key":"39416_CR11","doi-asserted-by":"publisher","first-page":"3165","DOI":"10.1080\/09638288.2018.1493160","volume":"41","author":"MB de Braghin","year":"2019","unstructured":"de Braghin, M. B. The effect of low-level laser therapy and physical exercise on pain, stiffness, function, and Spatiotemporal gait variables in subjects with bilateral knee osteoarthritis: a blind randomized clinical trial. Disabil. Rehabil. 41, 3165\u20133172. https:\/\/doi.org\/10.1080\/09638288.2018.1493160 (2019).","journal-title":"Disabil. Rehabil"},{"key":"39416_CR12","doi-asserted-by":"publisher","first-page":"853","DOI":"10.3233\/THC-161234","volume":"24","author":"AO Ojoawo","year":"2016","unstructured":"Ojoawo, A. O., Olaogun, M. O. & Hassan, M. A. Comparative effects of proprioceptive and isometric exercises on pain intensity and difficulty in patients with knee osteoarthritis: A randomised control study. Technol. Health Care. 24, 853\u2013863. https:\/\/doi.org\/10.3233\/THC-161234 (2016).","journal-title":"Technol. Health Care"},{"key":"39416_CR13","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1038\/s41586-021-03549-5","volume":"593","author":"MB Buechler","year":"2021","unstructured":"Buechler, M. B. et al. Cross-tissue organization of the fibroblast lineage. Nature 593, 575\u2013579. https:\/\/doi.org\/10.1038\/s41586-021-03549-5 (2021).","journal-title":"Nature"},{"key":"39416_CR14","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1038\/s41586-019-1471-1","volume":"572","author":"S Culemann","year":"2019","unstructured":"Culemann, S. et al. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature 572, 670\u2013675. https:\/\/doi.org\/10.1038\/s41586-019-1471-1 (2019).","journal-title":"Nature"},{"key":"39416_CR15","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1161\/CIRCRESAHA.117.312509","volume":"122","author":"C Cochain","year":"2018","unstructured":"Cochain, C. et al. Single-Cell RNA-Seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. 122, 1661\u20131674. https:\/\/doi.org\/10.1161\/CIRCRESAHA.117.312509 (2018).","journal-title":"Circ. Res."},{"key":"39416_CR16","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1016\/j.cell.2019.08.008","volume":"178","author":"JC Martin","year":"2019","unstructured":"Martin, J. C. et al. Single-Cell analysis of crohn\u2019s disease lesions identifies a pathogenic cellular module associated with resistance to Anti-TNF therapy. Cell 178, 1493\u20131508e1420. https:\/\/doi.org\/10.1016\/j.cell.2019.08.008 (2019).","journal-title":"Cell"},{"key":"39416_CR17","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1038\/s41591-020-0939-8","volume":"26","author":"S Alivernini","year":"2020","unstructured":"Alivernini, S. et al. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat. Med. 26, 1295\u20131306. https:\/\/doi.org\/10.1038\/s41591-020-0939-8 (2020).","journal-title":"Nat. Med."},{"key":"39416_CR18","doi-asserted-by":"publisher","first-page":"10868","DOI":"10.1038\/s41598-020-67730-y","volume":"10","author":"CH Chou","year":"2020","unstructured":"Chou, C. H. et al. Synovial cell cross-talk with cartilage plays a major role in the pathogenesis of osteoarthritis. Sci. Rep. 10, 10868. https:\/\/doi.org\/10.1038\/s41598-020-67730-y (2020).","journal-title":"Sci. Rep."},{"key":"39416_CR19","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1038\/s41590-019-0378-1","volume":"20","author":"F Zhang","year":"2019","unstructured":"Zhang, F. et al. Defining inflammatory cell States in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol. 20, 928\u2013942. https:\/\/doi.org\/10.1038\/s41590-019-0378-1 (2019).","journal-title":"Nat. Immunol."},{"key":"39416_CR20","first-page":"755","volume":"58","author":"H Li","year":"2012","unstructured":"Li, H. et al. Levels of metalloproteinase (MMP-3, MMP-9), NF-kappaB ligand (RANKL), and nitric oxide (NO) in peripheral blood of osteoarthritis (OA) patients. Clin. Lab. 58, 755\u2013762 (2012).","journal-title":"Clin. Lab."},{"key":"39416_CR21","doi-asserted-by":"publisher","first-page":"14811","DOI":"10.4238\/2015.November.18.46","volume":"14","author":"GQ Zeng","year":"2015","unstructured":"Zeng, G. Q., Chen, A. B., Li, W., Song, J. H. & Gao, C. Y. High MMP-1, MMP-2, and MMP-9 protein levels in osteoarthritis. Genet. Mol. Res. 14, 14811\u201314822 (2015).","journal-title":"Genet. Mol. Res."},{"key":"39416_CR22","doi-asserted-by":"publisher","first-page":"721258","DOI":"10.3389\/fgene.2021.721258","volume":"12","author":"S Li","year":"2021","unstructured":"Li, S. et al. COL3A1 and MMP9 serve as potential diagnostic biomarkers of osteoarthritis and are associated with immune cell infiltration. Front. Genet. 12, 721258. https:\/\/doi.org\/10.3389\/fgene.2021.721258 (2021).","journal-title":"Front. Genet."},{"key":"39416_CR23","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1016\/j.molimm.2006.05.003","volume":"44","author":"JW Rhee","year":"2007","unstructured":"Rhee, J. W. et al. Regulation of matrix metalloproteinase-9 gene expression and cell migration by NF-kappa B in response to CpG-oligodeoxynucleotides in RAW 264.7 cells. Mol. Immunol. 44, 1393\u20131400. https:\/\/doi.org\/10.1016\/j.molimm.2006.05.003 (2007).","journal-title":"Mol. Immunol."},{"key":"39416_CR24","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s13075-017-1296-y","volume":"19","author":"T Saito","year":"2017","unstructured":"Saito, T. & Tanaka, S. Molecular mechanisms underlying osteoarthritis development: Notch and NF-kappaB. Arthritis Res. Ther. 19, 94. https:\/\/doi.org\/10.1186\/s13075-017-1296-y (2017).","journal-title":"Arthritis Res. Ther."},{"key":"39416_CR25","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1101\/gad.14.2.163","volume":"14","author":"Q Yu","year":"2000","unstructured":"Yu, Q. & Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163\u2013176 (2000).","journal-title":"Genes Dev."},{"key":"39416_CR26","doi-asserted-by":"publisher","first-page":"e20190103","DOI":"10.1084\/jem.20190103","volume":"217","author":"N Frangogiannis","year":"2020","unstructured":"Frangogiannis, N. Transforming growth factor-\u03b2 in tissue fibrosis. J. Exp. Med. 217, e20190103. https:\/\/doi.org\/10.1084\/jem.20190103 (2020).","journal-title":"J. Exp. Med."},{"key":"39416_CR27","doi-asserted-by":"publisher","first-page":"13763","DOI":"10.1074\/jbc.M114.622274","volume":"290","author":"C Dayer","year":"2015","unstructured":"Dayer, C. & Stamenkovic, I. Recruitment of matrix Metalloproteinase-9 (MMP-9) to the fibroblast cell surface by Lysyl hydroxylase 3 (LH3) triggers transforming growth Factor-beta (TGF-beta) activation and fibroblast differentiation. J. Biol. Chem. 290, 13763\u201313778. https:\/\/doi.org\/10.1074\/jbc.M114.622274 (2015).","journal-title":"J. Biol. Chem."},{"key":"39416_CR28","doi-asserted-by":"publisher","unstructured":"Xu, D., Mu, R. & Wei, X. The Roles of IL-1 Family Cytokines in the Pathogenesis of Systemic Sclerosis. Front Immunol 10, (2025). https:\/\/doi.org\/10.3389\/fimmu.2019.02025 (2019).","DOI":"10.3389\/fimmu.2019.02025"},{"key":"39416_CR29","doi-asserted-by":"publisher","unstructured":"Meli, V. S. et al. YAP-mediated mechanotransduction tunes the macrophage inflammatory response. Sci. Adv. 6 https:\/\/doi.org\/10.1126\/sciadv.abb8471 (2020).","DOI":"10.1126\/sciadv.abb8471"},{"key":"39416_CR30","doi-asserted-by":"publisher","first-page":"1044729","DOI":"10.3389\/fcell.2022.1044729","volume":"10","author":"M Lee","year":"2022","unstructured":"Lee, M., Du, H., Winer, D. A., Clemente-Casares, X. & Tsai, S. Mechanosensing in macrophages and dendritic cells in steady-state and disease. Front. Cell. Dev. Biol. 10, 1044729. https:\/\/doi.org\/10.3389\/fcell.2022.1044729 (2022).","journal-title":"Front. Cell. Dev. Biol."},{"key":"39416_CR31","doi-asserted-by":"publisher","unstructured":"Gilbert, S. J., Bonnet, C. S. & Blain, E. J. Mechanical cues: bidirectional reciprocity in the extracellular matrix drives Mechano-Signalling in articular cartilage. Int. J. Mol. Sci. 22 https:\/\/doi.org\/10.3390\/ijms222413595 (2021).","DOI":"10.3390\/ijms222413595"},{"key":"39416_CR32","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1172\/JCI22263","volume":"115","author":"DK Rhee","year":"2005","unstructured":"Rhee, D. K. et al. The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth. J. Clin. Invest. 115, 622\u2013631. https:\/\/doi.org\/10.1172\/JCI22263 (2005).","journal-title":"J. Clin. Invest."},{"key":"39416_CR33","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s12969-016-0093-5","volume":"14","author":"B Peters","year":"2016","unstructured":"Peters, B. et al. Protein-losing enteropathy in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome. Pediatr. Rheumatol. Online J. 14, 32. https:\/\/doi.org\/10.1186\/s12969-016-0093-5 (2016).","journal-title":"Pediatr. Rheumatol. Online J."},{"key":"39416_CR34","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1101\/gad.231969.113","volume":"28","author":"H Ogawa","year":"2014","unstructured":"Ogawa, H., Kozhemyakina, E., Hung, H. H., Grodzinsky, A. J. & Lassar, A. B. Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways. Genes Dev. 28, 127\u2013139. https:\/\/doi.org\/10.1101\/gad.231969.113 (2014).","journal-title":"Genes Dev."},{"key":"39416_CR35","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1002\/jbmr.4226","volume":"36","author":"Y Maenohara","year":"2021","unstructured":"Maenohara, Y. et al. Lubricin contributes to homeostasis of articular cartilage by modulating differentiation of superficial zone cells. J. Bone Min. Res. 36, 792\u2013802. https:\/\/doi.org\/10.1002\/jbmr.4226 (2021).","journal-title":"J. Bone Min. Res."},{"key":"39416_CR36","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1038\/s41586-019-1263-7","volume":"570","author":"AP Croft","year":"2019","unstructured":"Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246\u2013251. https:\/\/doi.org\/10.1038\/s41586-019-1263-7 (2019).","journal-title":"Nature"},{"key":"39416_CR37","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/s41467-018-02892-y","volume":"9","author":"F Mizoguchi","year":"2018","unstructured":"Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789. https:\/\/doi.org\/10.1038\/s41467-018-02892-y (2018).","journal-title":"Nat. Commun."},{"key":"39416_CR38","doi-asserted-by":"publisher","first-page":"97","DOI":"10.3389\/fimmu.2019.00097","volume":"10","author":"M Papadaki","year":"2019","unstructured":"Papadaki, M. et al. New insights for RANKL as a Proinflammatory modulator in modeled inflammatory arthritis. Front. Immunol. 10, 97. https:\/\/doi.org\/10.3389\/fimmu.2019.00097 (2019).","journal-title":"Front. Immunol."},{"key":"39416_CR39","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1053\/joca.2000.0368","volume":"9","author":"AC Bakker","year":"2001","unstructured":"Bakker, A. C. et al. Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layer-dependent chondro-osteophyte formation. Osteoarthr. Cartil. 9, 128\u2013136. https:\/\/doi.org\/10.1053\/joca.2000.0368 (2001).","journal-title":"Osteoarthr. Cartil."},{"key":"39416_CR40","doi-asserted-by":"publisher","first-page":"507","DOI":"10.4049\/jimmunol.169.1.507","volume":"169","author":"A Scharstuhl","year":"2002","unstructured":"Scharstuhl, A. et al. Inhibition of endogenous TGF-beta during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. J. Immunol. 169, 507\u2013514. https:\/\/doi.org\/10.4049\/jimmunol.169.1.507 (2002).","journal-title":"J. Immunol."},{"key":"39416_CR41","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1111\/nyas.13000","volume":"1376","author":"L Xie","year":"2016","unstructured":"Xie, L. et al. Systemic neutralization of TGF-beta attenuates osteoarthritis. Ann. N Y Acad. Sci. 1376, 53\u201364. https:\/\/doi.org\/10.1111\/nyas.13000 (2016).","journal-title":"Ann. N Y Acad. Sci."},{"key":"39416_CR42","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1177\/0022034513513034","volume":"93","author":"K Jiao","year":"2014","unstructured":"Jiao, K. et al. Overexpressed TGF-beta in subchondral bone leads to mandibular condyle degradation. J. Dent. Res. 93, 140\u2013147. https:\/\/doi.org\/10.1177\/0022034513513034 (2014).","journal-title":"J. Dent. Res."},{"key":"39416_CR43","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/j.ajpath.2013.06.005","volume":"183","author":"T Tsukui","year":"2013","unstructured":"Tsukui, T. et al. Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis. Am. J. Pathol. 183, 758\u2013773. https:\/\/doi.org\/10.1016\/j.ajpath.2013.06.005 (2013).","journal-title":"Am. J. Pathol."},{"key":"39416_CR44","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/nrrheum.2010.196","volume":"7","author":"M Kapoor","year":"2011","unstructured":"Kapoor, M., Martel-Pelletier, J., Lajeunesse, D., Pelletier, J. P. & Fahmi, H. Role of Proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat. Rev. Rheumatol. 7, 33\u201342. https:\/\/doi.org\/10.1038\/nrrheum.2010.196 (2011).","journal-title":"Nat. Rev. Rheumatol."},{"key":"39416_CR45","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41584-020-00533-7","volume":"17","author":"PR Coryell","year":"2021","unstructured":"Coryell, P. R., Diekman, B. O. & Loeser, R. F. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat. Rev. Rheumatol. 17, 47\u201357. https:\/\/doi.org\/10.1038\/s41584-020-00533-7 (2021).","journal-title":"Nat. Rev. Rheumatol."},{"key":"39416_CR46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1139\/cjpp-2013-0063","volume":"92","author":"MA Khan","year":"2014","unstructured":"Khan, M. A. et al. Nonsurgically induced disuse muscle atrophy and neuromuscular dysfunction upregulates alpha7 acetylcholine receptors. Can. J. Physiol. Pharmacol. 92, 1\u20138. https:\/\/doi.org\/10.1139\/cjpp-2013-0063 (2014).","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"39416_CR47","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1007\/s00774-020-01115-z","volume":"38","author":"K Yokota","year":"2020","unstructured":"Yokota, K. et al. Deterioration of bone microstructure by aging and menopause in Japanese healthy women: analysis by HR-pQCT. J. Bone Min. Metab. 38, 826\u2013838. https:\/\/doi.org\/10.1007\/s00774-020-01115-z (2020).","journal-title":"J. Bone Min. Metab."},{"key":"39416_CR48","first-page":"561","volume":"26","author":"MA Cake","year":"2008","unstructured":"Cake, M. A. et al. Synovial pathology in an ovine model of osteoarthritis: effect of intraarticular hyaluronan (Hyalgan). Clin. Exp. Rheumatol. 26, 561\u2013567 (2008).","journal-title":"Clin. Exp. Rheumatol."},{"key":"39416_CR49","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1002\/jor.1100100107","volume":"10","author":"JA van der Sluijs","year":"1992","unstructured":"van der Sluijs, J. A. et al. The reliability of the Mankin score for osteoarthritis. J. Orthop. Res. 10, 58\u201361. https:\/\/doi.org\/10.1002\/jor.1100100107 (1992).","journal-title":"J. Orthop. Res."},{"key":"39416_CR50","doi-asserted-by":"publisher","unstructured":"Rajthala, S. et al. Combined in situ hybridization and immunohistochemistry on archival tissues reveals stromal microRNA-204 as prognostic biomarker for oral squamous cell carcinoma. Cancers (Basel). 13. https:\/\/doi.org\/10.3390\/cancers13061307 (2021).","DOI":"10.3390\/cancers13061307"},{"key":"39416_CR51","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1186\/s12859-018-2486-6","volume":"19","author":"SX Ge","year":"2018","unstructured":"Ge, S. X., Son, E. W. & Yao, R. iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data. BMC Bioinform. 19, 534. https:\/\/doi.org\/10.1186\/s12859-018-2486-6 (2018).","journal-title":"BMC Bioinform."},{"key":"39416_CR52","unstructured":"R Core Team. R: A Language and Environment for Statistical Computing, Version 4.4.1. Vienna, Austria (2024). https:\/\/www.r-project.org\/"},{"key":"39416_CR53","doi-asserted-by":"crossref","unstructured":"Wickham, H. ggplot2: Elegant Graphics for Data AnalysisSpringer New York, (2009).","DOI":"10.1007\/978-0-387-98141-3"},{"key":"39416_CR54","doi-asserted-by":"publisher","unstructured":"Gu, Z. Complex heatmap visualization. Imeta 1 (e43). https:\/\/doi.org\/10.1002\/imt2.43 (2022).","DOI":"10.1002\/imt2.43"},{"key":"39416_CR55","unstructured":"Kuhn, M. et al. corrr: Correlations in R (2025). https:\/\/github.com\/tidymodels\/corrr"},{"key":"39416_CR56","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.1038\/s41592-023-02014-7","volume":"20","author":"AS Castanza","year":"2023","unstructured":"Castanza, A. S. et al. Extending support for mouse data in the molecular signatures database (MSigDB). Nat. Methods. 20, 1619\u20131620. https:\/\/doi.org\/10.1038\/s41592-023-02014-7 (2023).","journal-title":"Nat. Methods"},{"key":"39416_CR57","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","volume":"30","author":"A Kramer","year":"2014","unstructured":"Kramer, A., Green, J., Pollard, J. Jr. & Tugendreich, S. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 30, 523\u2013530. https:\/\/doi.org\/10.1093\/bioinformatics\/btt703 (2014).","journal-title":"Bioinformatics"},{"key":"39416_CR58","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1007\/s11914-024-00861-7","volume":"22","author":"H Okada","year":"2024","unstructured":"Okada, H., Chung, U. I., Hojo, H. & Correction Practical compass of Single-Cell RNA-Seq analysis. Curr. Osteoporos. Rep. 22, 299. https:\/\/doi.org\/10.1007\/s11914-024-00861-7 (2024).","journal-title":"Curr. Osteoporos. Rep."},{"key":"39416_CR59","doi-asserted-by":"publisher","unstructured":"Kaminow, B. et al. STARsolo: accurate, fast and versatile mapping\/quantification of single-cell and single-nucleus RNA-seq data. Preprint at (2021). https:\/\/doi.org\/10.1101\/2021.05.05.442755","DOI":"10.1101\/2021.05.05.442755"},{"key":"39416_CR60","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13059-017-1382-0","volume":"19","author":"FA Wolf","year":"2018","unstructured":"Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15. https:\/\/doi.org\/10.1186\/s13059-017-1382-0 (2018).","journal-title":"Genome Biol."},{"key":"39416_CR61","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41587-021-01206-w","volume":"40","author":"A Gayoso","year":"2022","unstructured":"Gayoso, A. et al. A python library for probabilistic analysis of single-cell omics data. Nat. Biotechnol. 40, 163\u2013166. https:\/\/doi.org\/10.1038\/s41587-021-01206-w (2022).","journal-title":"Nat. Biotechnol."},{"key":"39416_CR62","doi-asserted-by":"publisher","first-page":"vbac016","DOI":"10.1093\/bioadv\/vbac016","volume":"2","author":"IMP Badia","year":"2022","unstructured":"Badia, I. M. P. et al. DecoupleR: ensemble of computational methods to infer biological activities from omics data. Bioinform Adv. 2, vbac016. https:\/\/doi.org\/10.1093\/bioadv\/vbac016 (2022).","journal-title":"Bioinform Adv."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-39416-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-39416-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-39416-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T23:01:45Z","timestamp":1772578905000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-39416-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,9]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["39416"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-39416-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,9]]},"assertion":[{"value":"1 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All mouse experiments were authorized to be approved by the Animal Care and Use Committee of the University of Tokyo (approval number M-P17-091). All methods were carried out in accordance with the relevant guidelines and regulations. All methods are reported in accordance with the ARRIVE guidelines (\n                      \n                      ).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8007"}}