Chrono-mechanobiology: The complex interactions between mechanotransduction and circadian rhythms in the intervertebral disc and articular cartilage, in health and disease

• Mechanical stress is transduced into biochemical signals in intervertebral disc and articular cartilage via direct and indirect pathways, shaping transcriptional programs that govern extracellular matrix homeostasis and the balance between tissue maintenance and degeneration. • Circadian clocks in intervertebral disc and articular cartilage coordinate rhythmic regulation of extracellular matrix turnover, nutrient transport, metabolism, and inflammation, while their disruption predisposes tissues to degeneration. • Mechanical cues act as potent zeitgebers that entrain circadian rhythms, whereas circadian clocks modulate mechanosensitivity, aligning cellular responses with daily cycles of loading and rest. • The bidirectional crosstalk between mechanotransduction and circadian rhythms emerges as a central determinant of intervertebral disc and articular cartilage health, and its disruption contributes to intervertebral disc degeneration and osteoarthritis. • Chrono-informed and mechanobiology-based strategies provide promising opportunities to prevent or treat intervertebral disc and articular cartilage degeneration through optimized timing of interventions. The intervertebral disc (IVD) and the articular cartilage (AC) are specialized, load-bearing tissues critical for spinal flexibility and joint mobility, respectively. Both tissues are characterized by their avascular nature and abundant extracellular matrix (ECM). They heavily rely on precisely regulated anabolic and catabolic processes to maintain structural integrity and functional performance. Disturbances can contribute to IVD degeneration and osteoarthritis that represent leading global causes of disability and pose substantial challenges to healthcare systems worldwide. One of the key regulators of IVD and AC homeostasis is mechanotransduction, the process through which mechanical cues are translated into biological responses. More recently, daily oscillations of genes and proteins implicated in mechanotransduction-related intracellular pathways started to gain attention. Such oscillations are driven by circadian rhythms and seem to affect the IVD and AC in health and degeneration. Circadian rhythms regulate the oscillatory expression of genes essential for matrix homeostasis, including those involved in nutrient transport, inflammation control, and cellular metabolism. Alterations of these rhythms, due to aging, inflammation, or lifestyle, might impair tissue homeostasis. Mechanotransduction and circadian rhythms interact reciprocally, as daily patterns of mechanical stimuli can entrain circadian rhythms, and circadian rhythms modulate cellular mechanosensitivity, optimizing responses to daily activity-rest cycles. This review synthesizes recent advances in understanding these intertwined mechano-circadian interactions within IVD and AC. It discusses the implications for degenerative disease progression and highlights potential therapeutic strategies leveraging chronotherapeutics and mechanobiology to preserve tissue function and improve the management of musculoskeletal disorders.