Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks

In mammals, temporally coordinated daily rhythms of behaviour and physiology are generated by a multi-oscillatory circadian system, entrained through cyclic environmental cues (e.g. light). Presence of niche-dependent physiological time cues has been proposed, which would allow local tissues flexibility of adopting a different phase relationship if circumstances require. Up till now, such tissue-unique stimuli have remained elusive. Here we show that cycles of mechanical loading and osmotic stimuli within physiological range drive rhythmic expression of clock genes and reset clock phase and amplitude in cartilage and intervertebral disc tissues. Hyperosmolarity (and not hypo-osmolarity) resets clocks in young and ageing skeletal tissues through mTORC2-AKT-GSK3{beta} pathway, leading to genome-wide induction of rhythmic genes. These results suggest diurnal patterns of mechanical loading and consequent daily surges in extracellular osmolarity as a bona fide tissue niche-specific time cue to maintain skeletal circadian rhythms in sync. One-Sentence SummaryCircadian clocks in aneural skeletal tissues sense the passage of time through rhythmic patterns of loading and osmolarity.