The transcriptional coactivator YAP1 is overexpressed in osteoarthritis and promotes its progression by interacting...

Osteoarthritis (OA) constitutes the most common disease of degenerative joints, with chondrocytes playing an important role in disease progression. However, the underlying pathobiological mechanisms have not been fully characterized. In this study, we investigated the role of Yes-associated protein 1 (YAP1)-regulated autophagy in chondrocyte proliferation, apoptosis, and differentiation. The data showed that YAP1, a transcriptional coactivator, was overexpressed in OA tissues from a murine model of OA, as analyzed by real time PCR and western blot. Overexpression of YAP1 significantly suppressed ATDC5 chondrogenic cell proliferation and decreased the expression of differentiation-related genes including Runx2, osteocalcin, and collagen I, and elevated cell apoptosis, whereas these cellular processes were reversed by knockdown of YAP1. Immunofluorescence analysis demonstrated that YAP1 co-localized with the autophagy regulator beclin1. Co-immunoprecipitation experiments indicated that this interaction was enhanced in OA tissues. In contrast, YAP1 lacking the internal WW domains failed to interact with beclin1 and was unable to inhibit beclin1 ubiquitination. This resulted in upregulated autophagy, which significantly improved OA by increasing chondrocyte proliferation and differentiation. Notably, YAP1 expression was significantly downregulated by various anti-OA drugs. Finally, the Yap1 promoter was activated by transcriptional factors AP2α and SP1, whereas its 3'UTR was targeted by miR-5624-5p, miR-33-3p, and miR-6918-5p. In conclusion, inhibition of YAP1 could facilitate beclin1-regulated autophagy in OA, suggesting a potential therapeutic approach to combat OA.