{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:38:36Z","timestamp":1779892716280,"version":"3.53.1"},"reference-count":38,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T00:00:00Z","timestamp":1743724800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100007131","name":"Changzhou Municipal Science and Technology Bureau","doi-asserted-by":"publisher","award":["2024\u2010ZJ\u2010760"],"award-info":[{"award-number":["2024\u2010ZJ\u2010760"]}],"id":[{"id":"10.13039\/501100007131","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2025,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The tissue\u2010localized renin\u2010angiotensin system (tRAS) plays a pivotal role in the crosstalk between cardiovascular factors and osteoarthritis (OA). Semaphorin 6D (SEMA6D), a cardiovascular neuroeffector, may contribute to chondrocyte homeostasis; however, its cartilage\u2010specific functions remain unclear. Chondrocytes with altered SEMA6D expression were established via gene transfection. RNA sequencing was performed to identify SEMA6D\u2010related genes and pathways, with preliminary validation in human OA samples. Furthermore, biochemical methods were employed to investigate the role of the AGT\/AGTR1a\/IL\u20101\u03b2 axis in mediating SEMA6D\u2010associated extracellular matrix metabolism (ECM). An AAV5\u2010based lentiviral vector was used to generate OA rat models overexpressing SEMA6D, followed by radiological and histological analyses. SEMA6D overexpression significantly enhanced ECM homeostasis, marked by increased Aggrecan, COL2A1 and decreased COL10A1, MMP13, and Runx2 expression. These SEMA6D\u2010induced genes were enriched in the tRAS pathway, with AGT, AGTR1a, and IL\u20101\u03b2 identified as critical targets. Furthermore, the AGT\/AGTR1a\/IL\u20101\u03b2 axis activated ECM degradation in chondrocytes, while SEMA6D overexpression effectively suppressed this signaling. In the OA rat model, elevated SEMA6D expression significantly reduced cartilage degradation. SEMA6D confers chondroprotective effects in OA by modulating the tRAS pathway, likely through inhibition of the AGT\/AGTR1a\/IL\u20101\u03b2 axis, thereby regulating ECM metabolism and chondrocyte hypertrophy. These findings enhance our understanding of cardiovascular influences on cartilage health and reveal tissue\u2010specific regulatory mechanisms in OA.<\/jats:p>","DOI":"10.1096\/fj.202403120r","type":"journal-article","created":{"date-parts":[[2025,4,5]],"date-time":"2025-04-05T13:53:48Z","timestamp":1743861228000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>SEMA6D<\/scp>\n                    modulates extracellular matrix metabolism in osteoarthritis by inhibiting the\n                    <scp>AGT<\/scp>\n                    \/\n                    <scp>AGTR1a<\/scp>\n                    \/\n                    <scp>IL<\/scp>\n                    \u20101\u03b2 axis"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0016-6065","authenticated-orcid":false,"given":"Haoyu","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Orthopedics Wuxi Ninth People's Hospital Affiliated to Soochow University  Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2300-6117","authenticated-orcid":false,"given":"Xinjian","family":"Ye","sequence":"additional","affiliation":[{"name":"Key Laboratory of Oral Biomedical Research of Zhejiang Province School of Stomatology, Stomatology Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5267-933X","authenticated-orcid":false,"given":"JingJing","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second People's Hospital of Changzhou The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center  Changzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5807-1226","authenticated-orcid":false,"given":"Jiapei","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The Second People's Hospital of Changzhou The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center  Changzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1944-3656","authenticated-orcid":false,"given":"Yong","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The Second People's Hospital of Changzhou The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center  Changzhou 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