Oral Presentation 1st Asia Pacific Herbert Fleisch Workshop 2025
Diurnal glucocorticoid rhythms play a critical role in the development of osteoarthritis during chronic disruption of circadian rhythms (#20)
Chronic disruption of circadian rhythms (CR) from shift work increases the risk of osteoarthritis, however, the underlying mechanisms are unknown. Endogenous glucocorticoid secretion follows a diurnal rhythm and regulates CR by synchronizing the body’s cellular clocks. We therefore asked whether glucocorticoid signaling in chondrocytes mediates the effects of CR disruption during osteoarthritis.
Eight-week-old male Col2a1CreT2/GRflox/flox (GRKO) mice and their wild-type (GRflox/flox) littermates were exposed to an established model of chronic CR disruption for 22 weeks. Mice were maintained on either a normal 12:12hr light-dark cycle (non-shifted) or exposed to weekly 12hr phase-shifts, equivalent to spending alternate weeks in America and Australia (shifted; Fig.1A). Shifted mice displayed pronounced disruption to sleep-wake cycles, feeding patterns, and were more active during resting periods compared to non-shifted mice (Fig.1B).
CR disruption abolished the diurnal rhythmicity of circulating glucocorticoids, characterized by a loss in the normal peak of serum corticosterone upon awakening in shifted mice (Fig.1C). Rhythmic expression of the major clock gene Bmal1 was abrogated in cartilage tissue of wild-type shifted mice but remained rhythmic in GRKO shifted mice. This indicates that blocking arrhythmic chondrocytic glucocorticoid signaling allows a self-sustaining rhythm in Bmal1 expression to persist in cartilage (Fig.1D).
Histological analysis revealed that CR disruption resulted in knee cartilage degradation in wild-type mice, but not in GRKO mice (Fig.1E). To further investigate the effects of CR disruption, we studied the progression of osteoarthritis by destabilization of the medial meniscus (DMM) four-weeks prior to harvest. In wild-type mice, CR disruption accelerated cartilage degradation, subchondral bone sclerosis, and induced synovial mast cell infiltration during the early stages of osteoarthritis. These features were significantly less pronounced in GRKO mice (Fig.1E).
Our findings, provide compelling in vivo evidence that chondrocyte glucocorticoid signaling is central to the development of osteoarthritis during chronic disruption of circadian rhythm.
