Those afflicted with inflammatory arthritis, such as rheumatoid and psoriatic, dread getting out of bed more than most. However, their morning dismay stems from more than just the lack of caffeine and the thought of facing the daily commute. Inflammation symptoms—such as joint stiffness—for sufferers from inflammatory arthritis are generally worse during waking hours. Now, a new study from investigators at the University of Manchester in the U.K. is seeking to find the connection between the circadian clock and various inflammatory pathways.
The British researchers discovered that a protein created by the body's “biological clock”—called CRYPTOCHROME—actively represses inflammatory pathways within affected limbs during the night. Previous research on this protein has described its anti-inflammatory properties in vitro and could represent potential new opportunities for the development of drugs that may be used to treat inflammatory diseases and conditions, such as arthritis.
“By understanding how the biological clock regulates inflammation, we can begin to develop new treatments, which might exploit this knowledge,” explained senior study author Julie Gibbs, Ph.D., lecturer at the Centre for Endocrinology and Diabetes at the Institute of Human Development within the University of Manchester. “Furthermore, by adapting the time of day at which current drug therapies are administered, we may be able to make them more effective.”
The research team harvested cells from joint tissue of healthy mice and humans. These cells, called fibroblast-like synoviocytes (FLSs), are important in the pathology that underlies inflammatory arthritis. Each of these cells keeps a 24-hour rhythm, and when this rhythm was disrupted by knocking out the cryptochrome gene there was an increased inflammatory response
“To investigate mechanistic links between the biological clock and pathways underlying inflammatory arthritis, mice were administered collagen (or saline as a control) to induce arthritis,” the authors wrote. “The treatment provoked an inflammatory response within the limbs, which showed robust daily variation in paw swelling and inflammatory cytokine expression. Inflammatory markers were significantly repressed during the dark phase.”
The findings from this study were published recently in The FASEB Journal in an article entitled “The Circadian Clock Regulates Inflammatory Arthritis.”
The scientists’ data suggested that the cryptochrome gene product, the CRYPTOCHROME protein, had significant anti-inflammatory effects. Thus, the research team was interested in testing this hypothesis, so they administered drugs designed to activate the protein to determine if protection against inflammation could be achieved—which proved successful.
“The results show that the core clock proteins CRYPTOCHROME 1 and 2 repressed inflammation within the FLSs, and provide novel evidence that a CRYPTOCHROME activator has anti-inflammatory properties in human cells,” the authors penned. “We conclude that under chronic inflammatory conditions, the clock actively represses inflammatory pathways during the dark phase. This interaction has exciting potential as a therapeutic avenue for treatment of inflammatory disease.”
“This study reminds us that inflammation, typically thought of as chronic and brittle, can, in fact, be nuanced—In this case, under the influence of the brain's suprachiasmatic nucleus, which controls the body's circadian physiology,” noted Thoru Pederson, Ph.D., editor-in-chief of The FASEB Journal. “The clinical implications are far-reaching.”