Circadian rhythms, endogenous glucocorticoids and skeletal health

Circadian rhythms are a hallmark of life. They are present in numerous physiological functions, including behavioural patterns such as sleep-wake cycles or feeding-fasting behaviour, hormonal secretion, core body temperature, cardiovascular and brain activity, cell regeneration and metabolic processes. Most organisms have developed evolutionarily conserved biological clock mechanisms that effectively react to cyclic changes in the photic environment to synchronize behaviour and physiological processes accordingly. These "pacemaker" like clocks are present in almost every cell and are intrinsically generated to maintain internal rhythms with a cycle frequency of approximately 24 hours. Chronic disruption of circadian rhythms, as in the case of shift work, frequent jet lag or sleep disorders, is increasingly being recognized as an important contributor to adverse health conditions such as cardiovascular disease, neurodegeneration, cancer, bone loss and joint degeneration. The effects of chronic disruption of circadian rhythms on musculoskeletal health are multifactorial, but endogenous glucocorticoids are likely to be involved given their critical role in numerous physiological processes, including bone and mineral homeostasis, systemic metabolism, and the inflammatory response. Of particular interest are the actions of endogenous glucocorticoids in the regulation of intrinsic circadian rhythms. It is well established that glucocorticoids act as a potent internal time signal to synchronize cell-autonomous clocks in peripheral tissues (such as bone and cartilage) with the central master clock in the suprachiasmatic nucleus. Furthermore, disruption to physiological glucocorticoid rhythms can disturb normal rhythms in gene expression, with deleterious effects on bone health. Understanding how glucocorticoids regulate skeletal molecular clocks and bone remodelling during disruption of circadian rhythms may provide opportunities to mitigate the effects of shift work on skeletal homeostasis. This review will focus on the interactions between circadian rhythms and glucocorticoid actions in bone and cartilage and their role in skeletal pathology.