The circadian regulator Bmal1 in joint mesenchymal cells regulates both joint development and inflammatory arthritis

Abstract

BackgroundThe circadian clock plays a crucial role in regulating physiology and is important for maintaining immune homeostasis and responses to inflammatory stimuli. Inflammatory arthritis often shows diurnal variation in disease symptoms and disease markers, and it is now established that cellular clocks regulate joint inflammation. The clock gene Bmal1 is critical for maintenance of 24-h rhythms and plays a key role in regulating immune responses, as well as in aging-related processes. Fibroblast-like synoviocytes (FLS) are circadian rhythmic joint mesenchymal cells which are important for maintenance of joint health and play a crucial role in the development of inflammatory arthritis. The aim of this study was to investigate the importance of the joint mesenchymal cell circadian clock in health and disease.MethodsMice were generated which lack Bmal1 in Col6a1-expressing cells, targeting mesenchymal cells in the ankle joints. Joints of these animals were assessed by X-ray imaging, whole-mount staining and histology, and the composition of the synovium was assessed by flow cytometry. Arthritis was induced using collagen antibodies.ResultsBmal1 deletion in joint mesenchymal cells rendered the FLS and articular cartilage cells arrhythmic. Targeted mice exhibited significant changes in the architecture of the joints, including chondroid metaplasia (suggesting a switch of connective tissue stem cells towards a chondroid phenotype), reductions in resident synovial macrophages and changes in the basal pro-inflammatory activity of FLS. Loss of Bmal1 in FLS rendered these resident immune cells more pro-inflammatory in response to challenge, leading to increased paw swelling, localised infiltration of mononuclear cells and enhanced cytokine production in a model of arthritis.ConclusionsThis study demonstrates the importance of Bmal1 in joint mesenchymal cells in regulating FLS and chondrocyte development. Additionally, we have identified a role for this core clock component for restraining local responses to inflammation and highlight a role for the circadian clock in regulating inflammatory arthritis.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1770-1) contains supplementary material, which is available to authorized users.

Regulatory T cells confer a circadian signature on inflammatory arthritis

“…1). As before two distinct macrophage populations, defined by MHC II expression 21,22 , were found in the joints (Fig. 1a).…”

“…Circadian variation in disease severity is frequent, but the mechanisms explaining this are undefined. Circadian disruption through genetic targeting of the core clock genes Cry1/2 or Bmal1 is associated with aggravated disease in the more simplistic mouse model of arthritis, collagen antibody-induced arthritis (CAIA) 22,33 , providing evidence for the role of the clock in restraining the pathogenesis of this disease. Analysis of joint-derived macrophages and neutrophils revealed significant dampening of intrinsic clocks in these inflammatory cells under arthritic conditions.…”

“…It is now established that FLS exist as multiple anatomically distinct subsets, each contributing differently to the inflammation and tissue damage associated with arthritis [45][46][47] . FLS are circadian rhythmic 22,35,38 and present as a candidate source for a locally derived rhythmic signal. Mechanisms driving Treg recruitment to arthritic joints are not well described.…”

Reconsidering the Role of Melatonin in Rheumatoid Arthritis

“…It is speculated that high melatonin concentrations in RA patients may modulate ROR activation [15]. ROR acts as a negative regulator of inflammation via the NF-κB signaling pathway and is essential in the activity of both melatonin and the clock gene Bmal1, which helps to maintain 24-h rhythms and regulate immune responses [15,37]. Moreover, ROR proteins bind into the promoter region and drive Bmal1 gene expression [38].…”

Resetting the clock on arthritis

“…A study by Haas et al demonstrated that FLS from OA and RA did express clock genes, but their expression was arrhythmic [10]. Hand and colleagues, however, were able to implicate FLS circadian rhythm in disease onset/progression by showing that FLS cells are indeed rhythmic and that the loss of circadian clock rhythm not only impacts their ability to regulate the inflammatory response, but also leads to worse disease progression in a model of arthritis [1]. However, given that Bmal1 was inactivated in all Col6a1-expressing cells throughout the development of the animal, it remains difficult to dissect what proportion of the observed effects were due to the loss of Bmal1 during developmental processes vs. post-induction of arthritis.…”