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

Abstract

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.