Melatonin attenuates clock gene Cryptochrome1, which may aggravates mouse anti-type II collagen antibody-induced arthritis

Abstract

Very recently, the circadian rhythm was proved to play an important role in the pathogenesis of arthritis. The role of melatonin in the development and progress of rheumatoid arthritis has been implicated for decades. This study was aimed to investigate the effect of melatonin on the expression of circadian clock genes in mouse anti-type II collagen antibody-induced arthritis (CIA). Mice were divided into 3 groups: control, CIA, and CIA + melatonin treatment (MLT). Both mRNA and protein levels of circadian clock gene Cryptochrome1 (Cry1) were markedly decreased in CIA + MEL group compared with those in control and CIA groups. MLT increased paw thickness. Histologic and X-ray assessment also revealed increased infiltration of inflammatory cells, synovial hyperplasia, and the destruction of articular cartilage and bone by MLT. The concentrations of anti-type II collagen antibody in CIA + MEL group mice were significantly higher than those in control and CIA groups (P < 0.05). Serum concentrations of TNF-α (P < 0.005) and IL-6 (P < 0.05) in CIA + MLT group were also increased. Taken together, these results implicate that clock gene Cry1 may be involved in the aggravation of MLT-mediated arthritis in mice anti-type II collagen antibody-induced arthritis.

Disruption of rhythms of molecular clocks in primary synovial fibroblasts of patients with osteoarthritis and rheumatoid arthritis, role of IL-1β/TNF

“…The authors found CLOCK upregulated after mechanical stress which identifies CLOCK as a possible mechanosensitive gene [29]. Another report demonstrated that melatonin inhibited Cryptochrome 1 in a mouse model of experimental arthritis [30]. However, no functional tests were performed to understand the link between melatonin, cryptochrome 1 and proinflammatory mechanisms [30].…”

“…Another report demonstrated that melatonin inhibited Cryptochrome 1 in a mouse model of experimental arthritis [30]. However, no functional tests were performed to understand the link between melatonin, cryptochrome 1 and proinflammatory mechanisms [30]. …”

Involvement of the Circadian Rhythm and Inflammatory Cytokines in the Pathogenesis of Rheumatoid Arthritis

“…Consistently, expression of CRY 1 was markedly decreased by administration of melatonin, subsequently aggravated in mouse antitype ΙΙ collagen antibody-induced arthritis [48]. Further, a phase and amplitude of the clock genes were different between osteoarthritis fibroblast-like synovial cells (OA-FLS) and RA-FLS cells [49].…”

Modulation by Melatonin of the Pathogenesis of Inflammatory Autoimmune Diseases

“…As melatonin is the major product of the pineal gland, this result suggests that unlike the other autoimmune diseases we discuss in this article, melatonin may have a promoting effect in the development of RA. Although one study found that melatonin possesses dose-dependent (from 1 to 100 μg/kg) prophylactic and therapeutic effects in an adjuvant-induced arthritis rat model [97], a recent study documented that melatonin treatment (10 mg/kg) increased the severity of CIA, probably via attenuation of the expression of cryptochrome 1 [98]. These contrasting observations may result from the different dosages or different models (DBA/1 mouse vs. rat) used in these studies.…”