Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021
Endogenous glucocorticoid signalling plays an important role in surgically induced murine osteoarthritis which is accelerated by chronic disruption of circadian rhythm (#20)
Recent evidence suggests chronic disruption of circadian rhythms such as shift work increases the risk of osteoarthritis (OA). Endogenous glucocorticoid secretion follows a diurnal rhythm and is known to regulate circadian clock expression. We aimed to investigate if endogenous glucocorticoid signalling mediates the effects of environmental circadian rhythm disruption at early stages of OA development using a surgically-induced model of OA in wild-type (WT) and tamoxifen-inducible chondrocyte glucocorticoid receptor knockout (chGRKO) mice.
Eight-week-old WT and chGRKO littermates were maintained for 22 weeks on either a normal 12 hour:12 hour light-dark cycle (non-shifted) or exposed to weekly alternating 12 hour phase shifts (shifted, Fig.1A). Four weeks prior to harvest, all mice underwent surgical destabilization of the medial meniscus (DMM) with the contralateral limb used as SHAM control (n=8-12/group).
Gene expression analysis confirmed that compared to non-shifted mice, clock genes were significantly disrupted in the long bones of shifted mice. Histological scoring showed a trend towards worse cartilage damage in shifted WT-DMM compared to non-shifted WT-DMM mice. Histomorphometry revealed that the medial tibial (MTP) hyaline cartilage area was reduced in shifted WT-DMM compared to non-shifted WT-DMM mice (2,494 vs. 3,015μm2 p=0.0036; Fig.1B,C). At the medial femur condyle (MFC), hyaline cartilage area was also reduced in shifted WT-DMM compared to non-shifted WT-DMM mice (1,446 vs. 1,846μm2 p=0.0004; Fig.1D). In chGRKO mice, hyaline cartilage area was only reduced at the MFC in shifted compared to non-shifted DMM mice (1,519 vs. 1,740μm2 p=0.0371; Fig.1E,F). Both micro-CT and histomorphometry analysis revealed that only shifted WT-DMM mice developed subchondral bone sclerosis suggesting these animals developed OA at an accelerated rate compared to all other groups at this early timepoint.
Our results indicate that chronic disruption of circadian rhythms may accelerate OA, mediated via changes in tissue-specific (chrondrocytic) glucocorticoid signalling.
