The Role of the Circadian Clock in Rheumatoid Arthritis
The Role of the Circadian Clock in Rheumatoid Arthritis
The circadian clock is fundamental in the regulation of metabolic processes; controlling expression of genes involved in metabolic pathways but also responding to metabolic cues. Circadian disruption has detrimental effects on metabolism, and is an exacerbating factor in the incidence of metabolic syndrome, which itself is associated with the risk of developing RA. It is proposed that the link between metabolic syndrome and RA is due to the inflammatory milieu associated with metabolic syndrome, much of which is provided by the increased quantities of adipose tissue, which secretes elevated levels of cytokines (TNFα and IL-6) and adipokines. Adipokines are signalling molecules produced primarily by adipose tissue and include adiponectin, leptin, resistin and visfatin. White adipose tissue and its constituent adipocytes are both circadian rhythmic, and many adipokines exhibit 24-hour variation in plasma concentrations. Recent studies have identified clear associations between adipokines and the pathophysiology of rheumatic diseases. For example, visfatin (also known as nicotinamide phosphoribosyltransferase (NAMPT) or pre-B cell colony-enhancing factor (PBEF)) is released by visceral fat, macrophages, liver, skeletal muscle and leukocytes in a rhythmic manner to produce diurnal rhythms in circulating levels. Elevated levels of visfatin are associated with RA; furthermore, levels detected in serum and synovial fluid correlate with clinical disease severity. Visfatin is pro-inflammatory, and although the underlying mechanisms are not fully understood, it stimulates synovial fibroblasts and monocytes to release pro-inflammatory cytokines and matrix metalloproteinases. The well-established and complex relationship between the circadian clock and metabolic processes provides another link between the clock and the pathogenesis of RA.
Adipokines
The circadian clock is fundamental in the regulation of metabolic processes; controlling expression of genes involved in metabolic pathways but also responding to metabolic cues. Circadian disruption has detrimental effects on metabolism, and is an exacerbating factor in the incidence of metabolic syndrome, which itself is associated with the risk of developing RA. It is proposed that the link between metabolic syndrome and RA is due to the inflammatory milieu associated with metabolic syndrome, much of which is provided by the increased quantities of adipose tissue, which secretes elevated levels of cytokines (TNFα and IL-6) and adipokines. Adipokines are signalling molecules produced primarily by adipose tissue and include adiponectin, leptin, resistin and visfatin. White adipose tissue and its constituent adipocytes are both circadian rhythmic, and many adipokines exhibit 24-hour variation in plasma concentrations. Recent studies have identified clear associations between adipokines and the pathophysiology of rheumatic diseases. For example, visfatin (also known as nicotinamide phosphoribosyltransferase (NAMPT) or pre-B cell colony-enhancing factor (PBEF)) is released by visceral fat, macrophages, liver, skeletal muscle and leukocytes in a rhythmic manner to produce diurnal rhythms in circulating levels. Elevated levels of visfatin are associated with RA; furthermore, levels detected in serum and synovial fluid correlate with clinical disease severity. Visfatin is pro-inflammatory, and although the underlying mechanisms are not fully understood, it stimulates synovial fibroblasts and monocytes to release pro-inflammatory cytokines and matrix metalloproteinases. The well-established and complex relationship between the circadian clock and metabolic processes provides another link between the clock and the pathogenesis of RA.
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