Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Rhythmic circulating glucocorticoid levels play a critical role in osteoarthritis driven by chronic disruption of circadian rhythms (#97)

Eugenie Macfarlane 1 , Lauryn Cavanagh 1 , Colette Fong-Yee 1 , Joseph Tannous 1 , Markus Seibel 1 2 , Hong Zhou 1
  1. Bone Research Program, ANZAC Research Institute, The University of Sydney, Concord, NSW, Australia
  2. Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Concord, NSW, Australia

Chronic disruption of circadian rhythms (CR) from shift work increases the risk of osteoarthritis (Zhou et al., 2020), however the underlying mechanisms are unknown. Endogenous glucocorticoid secretion follows a diurnal rhythm and regulates CRs by synchronizing the body’s cellular clocks. We therefore asked whether glucocorticoid signaling in chondrocytes mediates the effects of environmental CR disruption during osteoarthritis.

Eight-week-old male chondrocyte glucocorticoid receptor knockout mice (Col2a1CreERT2/GRflox/flox; GRKO) and their wild-type (GRflox/flox; WT) littermates were exposed to an established model of chronic CR disruption for 22 weeks. Mice were maintained on either normal 12:12-hr light-dark cycles (non-shifted) or exposed to weekly 12-hr phase-shifts, equivalent to spending alternate weeks in the UK and Australia (shifted; Fig.1A).

CR disruption abolished the diurnal rhythmicity of circulating glucocorticoids, characterized by a loss in the normal daily peak of serum corticosterone upon awakening in shifted mice (Fig.1B). Rhythmic expression of the major clock gene Bmal1 was abrogated in femoral cartilage tissue of WT shifted mice. In contrast, cartilaginous Bmal1 expression remained rhythmic in GRKO shifted mice, although in opposite phase to non-shifted animals. This indicates that blocking arhythmic chondrocytic glucocorticoid signaling allows a self-sustaining rhythm in Bmal1 expression to persist in cartilage.

Histological analysis revealed that chronic CR disruption resulted in knee joint cartilage degradation in WT but not in GRKO mice (Fig.1C). To further investigate the effects of chronic CR disruption on joint health we studied the progression of posttraumatic osteoarthritis by destabilization of the medial meniscus four weeks prior to harvest. In WT mice, chronic disruption of CR accelerated cartilage degradation, subchondral bone sclerosis, and induced synovial mast cell infiltration. These features were significantly less pronounced in GRKO mice.

Our findings provide compelling in vivo evidence that chondrocyte glucocorticoid signaling is central to the development of osteoarthritis during chronic disruption of circadian rhythm.

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  1. Zhou, M, Yang, S, Guo, Y, Wang, D, Qiu, W, Wang, B, Mu, G, Cao, L, Zhang, Z & Chen, W 2020, 'Shift work and the risk of knee osteoarthritis among Chinese workers: A retrospective cohort study', Scand J Work Environ Health, vol. 46, no. 2, pp. 152-160.