Objectives The mechanisms driving onset of joint inflammation in arthritides such as rheumatoid arthritis and spondyloarthritis and the conversion to disease chronicity are poorly understood. We hypothesised mechanostrain could play an instrumental role herein by engaging local and/or systemic pathways, thereby attenuating disease course and outcome.
Methods The development of collagen antibody-induced arthritis (CAIA) in C57BL/6 mice was evaluated both clinically and histologically under different loading regimens: control, voluntary running or hindpaw unloading. Bone surface porosity was quantified by high-resolution µ-CT. Gene expression analyses were conducted by microarrays and qPCR on microdissected entheses, murine and human synovial tissues (both normal and inflamed). Serum cytokines and chemokines were measured by ELISA. The influence of complement activation and T regulatory (Treg) cell function on the induction and resolution phase of disease was studied by respectively pharmacological modulation and conditional Treg depletion.
Results Voluntary running strongly impacts the course of arthritis by impairing the resolution phase of CAIA, leading to more persistent inflammation and bone surface porosity. Mechanical strain induced local complement activation, increased danger-associated molecular pattern expression, activating Fcγ receptors as well as changes in fibroblast phenotype. Interestingly, complement C5a receptor blockade inhibited the enhanced joint pathology caused by voluntary running. Moreover, Treg depletion led to a loss of disease resolution in CAIA mice, which was not observed under voluntary running conditions.
Conclusions Running promotes onset and chronicity of arthritis by local upregulation of complement activators and hampering regulatory T cell feedback loops.
- transition to chronicity
- complement activation
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Handling editor Josef S Smolen
Correction notice This article has been corrected since it published Online First. The affiliation details have been corrected.
Contributors The project was designed, conceived and planned by IC, SL, RL, DE and KV and the experiments were performed by IC, NS, KV and DG. The data were analysed by IC, DG, KV and DE and the paper was written and edited by IC, DE and KV.
Funding DE is supported by FWO-Flanders, Fonds voor Wetenschappelijk Reumaonderzoek (FWRO), Council of Ghent University and interuniversity Attraction Pole grant Devrepair from Belspo Agency (project P7/07) and an FWO Excellence of Science (EOS) grant. RJUL is supported by FWO-Flanders, KU Leuven and interuniversity Attraction Pole grant Devrepair from Belspo Agency (project P7/07) and an FWO Excellence of Science (EOS) grant. KV is supported by FWO-Flanders and VLAIO. DG is supported by FWO-Flanders.
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval The ethical committee of the University Hospital of Leuven granted permission to perform this study with human samples. Animal experiments were approved by and conducted according to the guidelines of the Ethics Committee of Laboratory Animals Welfare of Ghent University
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The data that support the findings in this study are available from the corresponding author upon request.