Running promotes chronicity of arthritis by local modulation of complement activators and impairing T regulatory feedback loops

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.status: publishe

Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis

Mechanical loading is an important factor in musculoskeletal health and disease. Tendons and ligaments require physiological levels of mechanical loading to develop and maintain their tissue architecture, a process that is achieved at the cellular level through mechanotransduction-mediated fine tuning of the extracellular matrix by tendon and ligament stromal cells. Pathological levels of force represent a biological (mechanical) stress that elicits an immune system-mediated tissue repair pathway in tendons and ligaments. The biomechanics and mechanobiology of tendons and ligaments form the basis for understanding how such tissues sense and respond to mechanical force, and the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. The role of mechanical stress in 'overuse' injuries, such as tendinopathy, has long been known, but mechanical stress is now also emerging as a possible trigger for some forms of chronic inflammatory arthritis, including spondyloarthritis and rheumatoid arthritis. Thus, seemingly diverse diseases of the musculoskeletal system might have similar mechanisms of immunopathogenesis owing to conserved responses to mechanical stress.status: publishe

Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis

Many pro-inflammatory pathways leading to arthritis have global effects on the immune system rather than only acting locally in joints. The reason behind the regional and patchy distribution of arthritis represents a longstanding paradox. Here we show that biomechanical loading acts as a decisive factor in the transition from systemic autoimmunity to joint inflammation. Distribution of inflammation and erosive disease is confined to mechano-sensitive regions with a unique microanatomy. Curiously, this pathway relies on stromal cells but not adaptive immunity. Mechano-stimulation of mesenchymal cells induces CXCL1 and CCL2 for the recruitment of classical monocytes, which can differentiate into bone-resorbing osteoclasts. Genetic ablation of CCL2 or pharmacologic targeting of its receptor CCR2 abates mechanically-induced exacerbation of arthritis, indicating that stress-induced chemokine release by mesenchymal cells and chemo-attraction of monocytes determines preferential homing of arthritis to certain hot spots. Thus, mechanical strain controls the site-specific localisation of inflammation and tissue damage in arthritis.status: publishe