The Role of Endogenous Glucocorticoids and Circadian Rhythm Disruption in Osteoarthritis and Bone Loss

Abstract

Glucocorticoids regulate numerous cellular processes in nearly all body systems, including skeletal homeostasis, inflammation, and circadian rhythms. Previous work from our group indicates that glucocorticoid signaling in bone cells promotes the development of murine osteoarthritis. However, whether glucocorticoid signaling in chondrocytes also affects osteoarthritis is unknown. Furthermore, studies suggest that chronic disruption of circadian rhythms contributes to osteoarthritis and poor skeletal health. While glucocorticoids are potent synchronisers of circadian rhythms throughout the body, the role of endogenous glucocorticoid signaling in mediating the effects of chronic disruption of circadian rhythms on joints and bones has not been investigated.

To address these questions, two mouse lines were used in which the glucocorticoid receptor was selectively deleted in either chondrocytes or osteoblasts/osteocytes. These mice were examined in three disease settings: i) osteoarthritis, ii) bone loss induced by disruption of circadian rhythm and iii) osteoarthritis during circadian rhythm disruption.

i.In murine osteoarthritis, deletion of the glucocorticoid receptor in chondrocytes attenuated synovial activation, chondrocyte senescence and cartilage loss.

ii.Chronic disruption of circadian rhythm induced bone loss in wild-type mice. In contrast, osteoblast/osteocyte glucocorticoid receptor knockout mice were protected from this phenotype, displaying increased bone volume.

iii.Chronic disruption of circadian rhythm accelerated osteoarthritic cartilage loss in wild-type and osteoblast/osteocyte glucocorticoid receptor knockout mice. Conversely, in mice with deletion of the chondrocyte glucocorticoid receptor, osteoarthritic cartilage loss was mitigated.

These novel findings establish endogenous glucocorticoid signaling as a critical mediator of the deleterious effects of osteoarthritis and skeletal pathologies associated with chronic disruption of circadian rhythm.