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

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.

Exercise Exacerbates the Transcriptional Profile of Hypoxia, Oxidative Stress and Inflammation in Rats with Adjuvant-Induced Arthritis

“…The molecular results of the PE effect are not easily comparable with previous studies due to the low number of reports, which had objectives aimed at particular aspects of the disease. However, we can distinguish that the negative effect of PE has also been reported in the two most recent and complete studies in this field [16,17]. The results of these studies suggest a direct link between the degree of mechanical stress to inflammation and tissue localization, which strengthens previous studies that propose biomechanical factors as potential determinants for the topographic pattern of joint disorders in arthritis [46].…”

“…Although the systemic benefits of PE in rheumatic patients are well recognized, the direct consequences of PE in active synovitis and the potential role of PE accelerating joint destruction are not clear. Some reports have shown that mechanical load influences the onset and worsens the progression of the disease in experimental animal models of arthritis [16,17]; therefore, the consequences of PE on inflamed joints remain a topic that should be addressed.…”

A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues

“…Additionally, increasing evidence suggests a potential role for TRPV4 in mediating cellular and tissue inflammation, and studies of chondrocyte-specific TRPV4-knockout mice report a decreased severity of age-associated OA (49). A load-induced mechanism of chondrocyte inflammation through TRPV4 may be a future target of ageassociated OA and other age-associated diseases (21,50,53). Our circuits here highlight the opportunities to target different responses through downstream pathway selection, namely using an NFKBr-circuit that is sensitive to IL-1a inflammation and a PTGS2r-circuit that is IL-1a-insensitive.…”

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

“…The enthesis, where muscles forces are concentrated and transmitted to the bone, is indeed a structure particularly subjected to mechanical stimulation. Moreover, even if no precise mechanism has been identified yet, the concept that mechanical strain drives both entheseal inflammation and abnormal bone formation in SpA has been evidenced in mouse models . Indeed, in a model of induced arthritis by TNF‐α overexpression, hind limb unloading reduces clinical signs, whereas voluntary running exacerbates the disease .…”

“…(8,9) Indeed, in a model of induced arthritis by TNF-α overexpression, hind limb unloading reduces clinical signs, whereas voluntary running exacerbates the disease. (7,9) In the present work, we have addressed the possibility that sphingosine1-phosphate (S1P) is a key molecule at the interface between bone biology, inflammation, and mechanical stress. S1P is a bioactive sphingolipid that regulates several cellular processes such as proliferation, survival, differentiation, migration, apoptosis, or inflammatory response.…”