Inhibiting the REV-ERBα expression protects against mechanical overloading-induced cartilage clock disruption and osteoarthritis progression.

Background: The circadian clock maintains homeostasis in peripheral tissues, including articular cartilage. Cartilage as a highly mechanical loaded tissue experiences diurnal rhythmic mechanical loading activity/rest cycle patterns, which gives external time cue on chondrocytes. Given the cartilage clock driven by loading patterns, we hypothesize that abnormal mechanical loading, a major risk factor for osteoarthritis (OA), can disrupt the cartilage clock, further contributing to OA progression. Methods: We used both noninvasive Results: Excessive mechanical loading disrupted the circadian rhythm of articular cartilage. The core clock molecule REV-ERBα was increased in OA cartilage and knockdown of Conclusions: REV-ERBα is a key factor in the association between mechanical overloading-induced circadian disruption and OA pathology. This study illustrates the essential mechanism of impaired circadian rhythm under overloading and provides a possibly impactful therapeutic approach for the treatment of OA. The Translational Potential of this Article: Inhibition REV-ERBα expression by clock-based therapeutic drug SR8278 or MAPK-MYC pathway inhibitors could ameliorate mechanical overloading-induced circadian disruption of cartilage and OA degeneration, indicating a clinical conversion potential for OA treatment.