Circadian Regulation of Macrophages and Osteoclasts in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) represents one of the best examples of circadian fluctuations in disease severity. Patients with RA experience stiffness, pain, and swelling in afflicted joints in the early morning, which tends to become milder toward the afternoon. This has been primarily explained by the higher blood levels of pro-inflammatory hormones and cytokines, such as melatonin, TNFα, IL-1, and IL-6, in the early morning than in the afternoon as well as insufficient levels of anti-inflammatory cortisol, which rises later in the morning. Clinical importance of the circadian regulation of RA symptoms has been demonstrated by the effectiveness of time-of-day-dependent delivery of therapeutic agents in chronotherapy. The primary inflammatory site in RA is the synovium, where increased macrophages, T cells, and synovial fibroblasts play central roles by secreting pro-inflammatory cytokines, chemokines, and enzymes to stimulate each other, additional immune cells, and osteoclasts, ultimately leading to cartilage and bone erosion. Among these central players, macrophages have been one of the prime targets for the study of the link between circadian rhythms and inflammatory activities. Gene knockout experiments of various core circadian regulators have established that disruption of any core circadian regulators results in hyper- or hypoactivation of inflammatory responses by macrophages when challenged by lipopolysaccharide and bacteria. Although these stimulations are not directly linked to RA etiology, these findings serve as a foundation for further study by providing proof of principle. On the other hand, circadian regulation of osteoclasts, downstream effectors of macrophages, remain under-explored. Nonetheless, circadian expression of the inducers of osteoclastogenesis, such as TNFα, IL-1, and IL-6, as well as the knockout phenotypes of circadian regulators in osteoclasts suggest the significance of the circadian control of osteoclast activity in the pathogenesis of RA. More detailed mechanistic understanding of the circadian regulation of macrophages and osteoclasts in the afflicted joints could add novel local therapeutic options for RA.