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The injured joint of C57BL\/6J mice received biweekly intraarticular injections of a soluble EphA4-binding ligand (EfnA4-fc) at 1\u00a0day after the tibial plateau injury or at 5\u2009weeks post-injury. The animals were euthanized 5\u2009weeks later. The injured right and contralateral uninjured left joints were analyzed for hallmarks of OA by histology. Relative severity was determined by a modified Mankin OA scoring system and serum COMP and CTX-II levels. Tibial plateau injury caused more severe OA in Epha4 null mice than in wild-type (WT) littermates, suggesting a protective role of EphA4 signaling in OA. A prototype strategy of an EphA4 signaling-based strategy involving biweekly injections of EfnA4-fc into injured joints was developed and was shown to be highly effective in preventing OA\/PTOA when it was administered at 1 day post-injury and in treating OA\/PTOA when it was applied after OA has been established. The efficacy of this prototype was dose- and time-dependent. The effects were not caused by the Fc moiety of EfnA4-fc. Other soluble EfnA ligands of EphA4, ie, EfnA1-fc and EfnA2-fc, were also effective. A prototype of a novel EphA4 signaling-based therapy was developed for OA\/PTOA that not only reduces the progressive destruction of articular cartilage but may also promote regeneration of the damaged cartilage. \u00a9 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.<\/jats:p>","DOI":"10.1002\/jbmr.4500","type":"journal-article","created":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T03:54:17Z","timestamp":1641441257000},"page":"660-674","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Novel EphA4 Signaling-Based Therapeutic Strategy for Osteoarthritis in Mice"],"prefix":"10.1093","volume":"37","author":[{"given":"Virginia M","family":"Stiffel","sequence":"first","affiliation":[{"name":"Musculoskeletal Disease Center (151) Jerry L. Pettis Memorial VA Medical Center Loma Linda CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles H","family":"Rundle","sequence":"additional","affiliation":[{"name":"Department of Medicine Loma Linda University School of Medicine Loma Linda CA USA"},{"name":"Musculoskeletal Disease Center (151) Jerry L. 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