Tissue physiology revolving around the clock: circadian rhythms as exemplified by the intervertebral disc

Abstract

Circadian clocks in the brain and peripheral tissues temporally coordinate local physiology to align with the 24 hours rhythmic environment through light/darkness, rest/activity and feeding/fasting cycles. Circadian disruptions (during ageing, shift work and jet-lag) have been proposed as a risk factor for degeneration and disease of tissues, including the musculoskeletal system. The intervertebral disc (IVD) in the spine separates the bony vertebrae and permits movement of the spinal column. IVD degeneration is highly prevalent among the ageing population and is a leading cause of lower back pain. The IVD is known to experience diurnal changes in loading patterns driven by the circadian rhythm in rest/activity cycles. In recent years, emerging evidence indicates the existence of molecular circadian clocks within the IVD, disruption to which accelerates tissue ageing and predispose animals to IVD degeneration. The cell-intrinsic circadian clocks in the IVD control key aspects of physiology and pathophysiology by rhythmically regulating the expression of ~3.5% of the IVD transcriptome, allowing cells to cope with the drastic biomechanical and chemical changes that occur throughout the day. Indeed, epidemiological studies on long-term shift workers have shown an increased incidence of lower back pain. In this review, we summarise recent findings of circadian rhythms in health and disease, with the IVD as an exemplar tissue system. We focus on rhythmic IVD functions and discuss implications of utilising biological timing mechanisms to improve tissue health and mitigate degeneration. These findings may have broader implications in chronic rheumatic conditions, given the recent findings of musculoskeletal circadian clocks.

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

“…The mammalian skeletal system, especially the articular cartilage in joints and intervertebral disc (IVDs) in the spine, provides a unique model to resolve this question. Cartilage and IVDs are among the most highly loaded tissues in the body, experiencing a diurnal loading cycle associated with daily rest/activity patterns ( 12 ). They experience a prolonged period of compression of 2-3.5 MPa during the activity phase, followed by a period of low-load recovery during resting phase (down to 0.1 MPa).…”

“…Taken together, we have identified daily cycles of mechanical loading and associated rhythmic changes of osmolarity within the physiological range as bona fide entrainment cues for skeletal circadian clocks. These time cues are particularly important for tissues such as the IVD and cartilage because they are isolated from vascular, lymphatic and nervous systems, yet their circadian rhythms are sensitive to age-related dampening ( 12 ). We show that repeated daily osmotic cycles lead to resynchronisation of circadian rhythm in ageing tissue explants, supporting a hypothesis that reduced rest/activity patterns in ageing individuals could contribute to skeletal clock disruptions in vivo .…”

“…Genetic disruption of the cartilage and IVD clocks results in imbalance of anabolic and catabolic processes which subsequently leads to accelerated tissue ageing and degeneration (13)(14)(15)(16)(17). The aneural and avascular nature of articular cartilage and IVDs makes them less amenable to conventional systemic time cues conveyed through nerves or hormones (12). Therefore, it remains unknown how these skeletal clocks are entrained under physiological conditions.…”

“…With the onset of the activity phase mouse cartilage and IVD tissues experience roughly 12 hours of loading within a 24-hour day, leading to increased osmolarity (20). Having determined that the acute increase in osmolarity is a clock synchronising factor, we next used a protocol to approximate the diurnal osmotic cycles experienced by skeletal tissues by exposing cartilage and IVD explants to 12 hours hyperosmotic condition and returning them to 12 hours of iso-osmotic medium.…”

Single-cell transcriptome profiling reveals multicellular ecosystem of nucleus pulposus during degeneration progression

“…Nucleus pulposus cells (NPCs) are the main cell type residing in the NP, and they are responsible for maintaining tissue homeostasis 8 . NPCs proliferate slowly and lack self-regeneration capacity adding to the intractability of the disease.…”