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Unfortunately, there are currently no effective treatments for OA, highlighting the need for novel therapeutic approaches. Thrombomodulin (TM), a glycoprotein expressed by chondrocytes and other cell types, has an unknown role in OA. Here, we investigated the function of TM in chondrocytes and OA using various methods, including recombinant TM (rTM), transgenic mice lacking the TM lectin-like domain (TMLeD\/LeD), and a microRNA (miRNA) antagomir that increased TM expression. Results showed that chondrocyte-expressed TM and soluble TM [sTM, like recombinant TM domain 1 to 3 (rTMD123)] enhanced cell growth and migration, blocked interleukin-1\u03b2 (IL-1\u03b2)-mediated signaling and protected against knee function and bone integrity loss in an anterior cruciate ligament transection (ACLT)-induced mouse model of OA. Conversely, TMLeD\/LeD mice exhibited accelerated knee function loss, while treatment with rTMD123 protected against cartilage loss even one-week post-surgery. The administration of an miRNA antagomir (miR-up-TM) also increased TM expression and protected against cartilage damage in the OA model. These findings suggested that chondrocyte TM plays a crucial role in counteracting OA, and miR-up-TM may represent a promising therapeutic approach to protect against cartilage-related disorders.<\/jats:p>","DOI":"10.3390\/ijms24119522","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T03:59:35Z","timestamp":1685505575000},"page":"9522","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Chondrocyte Thrombomodulin Protects against Osteoarthritis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2709-5604","authenticated-orcid":false,"given":"Lin","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704302, 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of Science and Technology, Pingtung 912, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0081-0305","authenticated-orcid":false,"given":"Edward M.","family":"Conway","sequence":"additional","affiliation":[{"name":"Centre for Blood Research, Faculty of Medicine, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua-Lin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Ling","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan"},{"name":"College of Professional Studies, National Pingtung University of Science and Technology, Pingtung 912, Taiwan"},{"name":"Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 800, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8485-2574","authenticated-orcid":false,"given":"Je-Ken","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Departments of Orthopaedics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Orthopaedic Research Center, Kaohsiung Medical University, 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