Abstract Description Osteoarthritis (OA), the most prevalent chronic joint disease and a leading cause of disability, lacks effective treatments to slow its progression. This study elucidates the role of RORβ, an understudied nuclear receptor, in chondrogenesis and OA prevention. Stable expression of RORβ alters gene programs supportive of chondrogenesis and protective against OA development. RORβ modifies the expression ratio of FGFR1 and FGFR3, suppresses ERK1/2-MAPK signaling, and enhances AKT signaling. Using immunoprecipitation and cross-linking mass spectrometry, we identified p300 as a direct interacting protein of RORβ, binding to its DNA binding domain (DBD), hinge region, and ligand binding domain (LBD). Both p300 and SIRT1 influence RORβ’s turnover rate and transcriptional activity. P300-dependent acetylation sites were found in the DBD and hinge region of RORβ, which were deacetylated by SIRT1. Ubiquitination sites sensitive to proteasome inhibitors were also discovered. Notably, a constitutive acetylated mimic at K176 in the hinge region prevented ubiquitination of RORβ at distal sites. These findings elucidate the critical role of RORβ in chondrogenesis and provide insights into its regulatory mechanisms. Understanding RORβ’s protein interactions and post-translational modifications offers innovative approaches for osteoarthritis treatment, potentially addressing a significant unmet medical need in joint health. Funding Sources DK129535 and CA125123 Topic Categories Basic Autoimmunity (BA)
Chang et al. (Sat,) studied this question.