Circadian rhythm disturbance induces osteoarthritis in mice: Involvement of Clock and Bmal1 dysregulation and Pdgfa inhibition

Abstract

Circadian rhythm disturbance (CRD) is likely associated with impaired bone development and the development of osteoarthritis (OA). This study investigates the functions of circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like 1 (Bmal1) in OA progression and explores the implicated molecular mechanisms. Mice were subjected to CRD for 70 d. This led to significant OA-like symptoms, accompanied by a reduction in the expression of Clock and Bmal1. Either Clock or Bmal1 upregulation reduced serum concentrations of inflammatory cytokines (interleukin [IL]-1β and IL-6) in mice, and it reduced cartilage erosion and extracellular matrix degradation in their knee joints, with parallel findings observed in the isolated chondrocytes in vitro. The Clock:Bmal1 heterodimer binds to the enhancer upstream of the Pdgfa promoter to enhance its transcription. Pdgfa knockdown reversed the protective effects of Clock and Bmal1 by inactivating the Pi3k/Akt and Erk1/2 cascade. By contrast, Pdgfa overexpression reduced chondrocyte damage, which was, however, negated by the Pi3k/Akt inhibitor LY294002. Collectively, this study validates that CRD is pertinent to the development of OA. Restoring Clock and Bmal1 levels may help ameliorate chondrocyte loss in CRD-associated OA by activating Pdgfa transcription and enhancing Pi3k/Akt and Erk1/2 signaling pathways.