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Abstract
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.
Highlights
Many pro-inflammatory pathways leading to arthritis have global effects on the immune system rather than only acting locally in joints
Mechano-stimulation of mesenchymal cells induces the production of CXCL1 and CCL2 and recruitment of classical monocytes that may differentiate into bone-resorbing osteoclasts
Arthritis incidence of hind paws of control mice steadily increased throughout the experiment (Fig. 1a)
Summary
Many pro-inflammatory pathways leading to arthritis have global effects on the immune system rather than only acting locally in joints. Distribution of inflammation and erosive disease is confined to mechanosensitive regions with a unique microanatomy This pathway relies on stromal cells but not adaptive immunity. Key pro-inflammatory molecular pathways identified to induce arthritis such as TNFα, IL-1, IL-6, and IL-17/23 rather act systemically in triggering the onset and progression of the disease but give little hint why arthritis affects certain joints more often than others[1]. Excess mechanical load by voluntary running accelerates the onset of arthritis induced by passive transfer of anti-collagen specific antibodies. This mechano-sensitive pathway for induction of arthritis does not rely on adaptive immunity. Our data implicate a crucial role for mechanostress as a driver for the conversion of the autoimmune to tissue localisation of arthritis and explain the particular anatomical pattern of bone disease in arthritis
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