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Published on: July 24, 2018
Local Circadian Clocks Are Desynchronized From the Central Circadian Pacemaker in a Mouse Model of Inflammatory
Lance A Riley1, Luke E Springer2, Sandra Paola Cárdenas-García1
1Department of Biology, Washington University, St. Louis, Missouri.
Objective:
Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting joints marked by daily and intermittent surges in inflammatory cytokine levels that result in "flares" of disease activity. Because circadian proteins regulate inflammatory responses in arthritis, continuous behavioral- and tissue-level monitoring may clarify therapeutic dynamics. Using the K/BxN serum transfer arthritis (STA) mouse model, we tested whether locomotor activity and circadian clock gene expression track RA progression from onset through symptom resolution.
Methods:
C57BL/6NJ and PER2::luciferase mice (8-10 weeks) received 180 μL K/BxN serum via retroorbital injection. Uninjected littermates served as controls. We measured daily ankle thickness and continuously monitored open-field locomotion from singly housed mice, a subset of which received dexamethasone (DEX) at dusk daily for 6 days. PER2::luciferase bioluminescence from paw, suprachiasmatic nuclei (SCNs), and femoral heads explants from mice treated with or without DEX were compared during STA.
Results:
Total daily locomotion decreased alongside ankle swelling approximately 2 days following K/BxN STA. STA altered the timing of daily PER2 peak expression in arthritic paws but not in the SCN or nonarthritic joints. By day 22, total daily locomotion, ankle thickness, and paw circadian phase had resolved. In vivo DEX reduced circadian phase disruption in arthritic paws, accelerated the resolution of ankle swelling, and increased total daily locomotion without altering locomotor timing.
Conclusion:
Locomotor activity is a real-time, noninvasive supplement for measuring RA onset and resolution. Altered PER2 expression indicates that local circadian synchrony in arthritic joints is impaired. DEX may aid recovery by resynchronizing circadian rhythms in arthritic tissues.
