Importance of mechanical cues in regulating musculoskeletal circadian clock rhythmicity: Implications for articular cartilage.

The circadian clock, a collection of endogenous cellular oscillators with an approximate 24-h cycle, involves autoregulatory transcriptional/translational feedback loops to enable synchronization within the body. Circadian rhythmicity is controlled by a master clock situated in the hypothalamus; however, peripheral tissues are also under the control of autonomous clocks which are coordinated by the master clock to regulate physiological processes. Although light is the primary signal required to entrain the body to the external day, non-photic zeitgeber including exercise also entrains circadian rhythmicity. Cellular mechano-sensing is imperative for functionality of physiological systems including musculoskeletal tissues. Over the last decade, mechano-regulation of circadian rhythmicity in skeletal muscle, intervertebral disc, and bone has been demonstrated to impact tissue homeostasis. In contrast, few publications exist characterizing the influence of mechanical loading on the circadian rhythm in articular cartilage, a musculoskeletal tissue in which loading is imperative for function; importantly, a dysregulated cartilage clock contributes to development of osteoarthritis. Hence, this review summarizes the literature on mechano-regulation of circadian clocks in musculoskeletal tissues and infers on their collective importance in understanding the circadian clock and its synchronicity for articular cartilage mechanobiology.