Molecular Circuits Regulating Joint Destruction

Daily rhythms in mammalian behavior and physiology are generated by a multi-oscillator circadian system that is entrained by environmental cues such as light and feeding. Prior studies have demonstrated that disruption of the circadian clock leads to degeneration of articular cartilage and intervertebral disc (IVD) in mice, and that night shift work is associated with an increased risk of osteoarthritis (OA) and lower back pain in humans.

In this study, we investigated the role of daily patterns of mechanical loading in regulating circadian rhythms in skeletal tissues. Explants of the central clock (suprachiasmatic nucleus), femoral head cartilage, IVD, and primary chondrocytes and IVD cells were isolated from PER2::LUC mice. A treadmill model was used to assess the effects of timed mechanical loading on both central and peripheral clocks in vivo. Tissues and cells were exposed to mechanical loading or changes in osmolarity at specific phases of the circadian cycle. Bioluminescence from explants and cells was recorded in real-time, while RNA sequencing and qPCR were employed to assess gene expression changes.

Our results demonstrate that mechanical loading—and the associated osmotic changes within physiological ranges—can reset the circadian clock phase and amplitude in cartilage and IVD tissues both in vivo and in explant cultures. Notably, we found that dampened circadian rhythms in the aging skeletal system can be resynchronized through daily cycles of mechanical loading or hyperosmotic challenge.

These findings reveal that diurnal mechanical loading and the resulting daily oscillations in osmolarity act as bona fide, tissue niche-specific time cues to maintain synchronized skeletal circadian rhythms. Furthermore, they suggest that time-prescribed physical exercise may serve as an effective intervention to slow skeletal tissue aging and restore homeostasis in osteoarthritic joints or degenerate IVDs by enhancing circadian-regulated pathways.