Osteoarthritis OA is the most common joint disease, affecting articular cartilage of Ageing boot joints, with currently no cure.
Age is a major risk factor for OA, Ageing boot despite significant advances made in the OA research field, how ageing contributes to OA is still not well understood. In this review, we will focus on one particular aspect of chondrocyte biology, i. Disruptions to Ageing boot clocks have been linked to various diseases.
Our recent work demonstrates autonomous clocks in chondrocytes which regulate key pathways implicated in OA. The cartilage rhythm dampens with age and clock gene expression changes during the initiation stage of OA development in an experimental mouse OA model.
There is currently Ageing boot cure, Ageing boot treatments limited to painkillers and eventual joint replacement. OA primarily affects the articular cartilage lining the ends of long bones. Articular cartilage consists of abundant extracellular matrix ECMsparsely populated by chondrocytes. Isolated from the vasculature and lacking innervations, chondrocytes control cartilage tissue homeostasis by maintaining a fine balance between anabolic and catabolic activities.
OA is characterised by a Ageing boot in chondrocyte homeostasis to a scenario in which catabolic Ageing boot outweighs anabolic activity, resulting in gradual degeneration of articular cartilage van der Kraan The precise molecular mechanisms underlying disease initiation are unknown. OA is commonly referred to as a multifactorial disorder.
Age is the single biggest risk factor for disease development; however OA is not inevitable in the elderly. The SCN integrates inputs from various external time-cues, predominantly light, in order to transmit temporal information to almost every cell and tissue in the body, and regulate genes controlling rhythmic tissue physiology Takahashi et al. The molecular basis of circadian rhythm generation is increasingly well understood.
Components of the molecular circadian clock control various target genes Ageing boot controlled Ageing boot CCGs through response elements such as ROREs and E-boxes in their regulatory sequences. Molecular mechanism of the mammalian circadian clock.
Autonomous clocks have been demonstrated in most peripheral tissues and cultured cells Yoo et al. The SCN is proposed Ageing boot a master synchroniser of rhythms in peripheral tissues, ensuring their coordinated activity Fig. The precise nature of the SCN-controlled signal orchestrating peripheral clocks is an area of debate. Glucocorticoid signalling has been suggested as a candidate systemic entrainment factor, Ageing boot rhythms in peripheral tissues of adrenalectomized Ageing boot demonstrating phase changes Ageing boot desynchrony Pezuk et al.
There is also evidence that feeding signals entrain peripheral clocks, such as those in liver, colon and gut Damiola et al.
It is likely that a number of signals act together to entrain peripheral clocks, perhaps with different signals being differentially salient to different tissues.
They showed that while the liver followed the phase entrainment of food cues, other tissues responded to corticosterone injection. The master clock in the SCN controls rhythms in peripheral tissues to Ageing boot physiology and pathology.
Schematic representing rhythms in the SCN and peripheral tissues; multiple factors transmit timekeeping information from the SCN to set the phase of peripheral tissues; Ageing boot of Ageing boot clocks leads to changes in tissue specific outputs and causes a wide variety of health disorders.
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The circadian clock directs tissue physiology though control of tissue specific sets of CCGs. Circadian genes are tissue specific Yan et al. The importance of circadian clocks in peripheral tissues has been highlighted in studies in which local clocks are conditionally ablated.
Despite the intact Ageing boot and SCN rhythm, these mice developed a diabetes mellitus-like disorder, in which insulin release and glucose tolerance was impaired. Similarly, tissue specific disruption of the circadian clock in the liver led to hypoglycemia and increased glucose clearance Lamia et al.
Further, mice with conditional Bmal1 disruption in the retina responded abnormally to light Storch et al. One caveat of these studies is that some phenotypes may be Ageing boot to loss of one specific clock gene rather than due to arrhythmicity.
This suggests possible clock-independent functions for at least some of the core clock transcription factors. Despite this, these studies underline the overall importance of circadian rhythms to tissue Ageing boot. Until recently, evidence for a functional circadian clock in cartilage tissue capable of driving downstream CCGs has been largely circumstantial.