WNT10A induces apoptosis of senescent synovial resident stem cells through Wnt/calcium pathway-mediated HDAC5 phosphorylation in OA joints

Recently, the accumulation of senescent cells (SnCs) within joints was found to promote osteoarthritis (OA) progression. Our previous study found that Wnt proteins, especially Wnt10a, have marked effects on cellular senescence and joint health. However, the effect of WNT10A on SnCs in OA joints remains unknown. In this study, we confirmed that the synovium was the first and most marked site of SnC accumulation in the OA joint, and synovial resident mesenchymal stem cells (SMSCs) seemed to be the main source of these SnCs. In synovium samples from OA patients, WNT10A level inversely correlated with the extent of SnCs accumulation. Therefore, we further explored the possible regulatory role and mechanism of WNT10A in intraarticular senescent SMSCs. In brief, we confirmed that WNT10A could specifically clear these senescent OA-SMSCs in vitro experiments and naturally occurring OA models via proapoptotic effects. Mechanistically, WNT10A activated noncanonical Wnt/calcium signaling in senescent OA-SMSCs, which in turn induced histone deacetylase 5 (HDAC5) phosphorylation and nuclear export via its downstream Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) to regulate cell fate. The regulation of this pathway significantly improved the regenerative microenvironment of OA, exhibiting its potential as a novel clinical disease-modifying OA drugs (DMOADs) target.