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We have previously found that elevated levels of H\u2010type vessels in subchondral bone correlate with OA and that focal adhesion kinase (FAK) is critical for H\u2010type vessel formation in osteoporosis. However, the potential role of FAK in OA remains unexplored. Here, we demonstrate that the p\u2010FAK level was dramatically elevated in subchondral bone following anterior cruciate ligament transection (ACLT) in rats. Specific inhibition of FAK signaling with Y15 in subchondral bone resulted in the suppression of subchondral bone deterioration and this effect was mediated by H\u2010type vessel\u2010induced ectopic bone formation. Further, articular cartilage degeneration was also alleviated after Y15 treatment. In vitro, the p\u2010FAK level was significantly elevated in mesenchymal stem cells (MSCs) from vehicle\u2010treated ACLT rats as compared to that in MSCs from sham controls and Y15\u2010treated ACLT rats. Elevated p\u2010FAK level in MSCs promoted vascular endothelial growth factor (VEGF) expression, as demonstrated from the high VEGF level in the blood, subchondral bone, and conditioned medium (CM) of MSCs from vehicle\u2010treated ACLT rats. The CM of MSCs from vehicle\u2010treated ACLT rats might promote the angiogenesis of endothelial cells and the catabolic response of chondrocytes through the FAK\u2010growth factor receptor\u2010bound protein 2\u2010mitogen\u2010activated protein kinase\u2010mediated expression of VEGF. The effect of the CM from MSCs of Y15\u2010treated ACLT rats or that treated with a VEGF\u2010neutralizing antibody on vessel formation and the catabolic response was lowered. Thus, the specific inhibition of FAK signaling may be a promising avenue for the prevention or early treatment of OA.<\/jats:p>","DOI":"10.1002\/jcp.29709","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T15:28:21Z","timestamp":1587655701000},"page":"8653-8666","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Specific inhibition of FAK signaling attenuates subchondral bone deterioration and articular cartilage degeneration during osteoarthritis pathogenesis"],"prefix":"10.1002","volume":"235","author":[{"given":"Hangtian","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Nanfang Hospital Southern Medical University  Guangzhou Guangdong China"},{"name":"Department of Orthopaedics, Guangdong Provincial Key Laboratory of Bone and Cartilage Regeneration Medicine Nanfang Hospital, Southern Medical University  Guangzhou Guangdong 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