Pathogenesis of Joint Destruction in Rheumatoid Arthritis

Abstract

Synovial mesenchymal cells, matrix metalloproteinases (MMPs), and osteoclasts are the three major players directly responsible for the pathogenesis of rheumatoid joint destruction. First, synovial mesenchymal cells, internally driven by a transcription factor c-Fos/AP-1, not only directly invade cartilage and bone as a granulation tissue called "pannus" but also release inflammatory cytokine interleukin (IL)-1β. IL-1β induces MMPs and activates osteoclasts. Synovial cells can also present antigen to T cells to drive antigen-specific immune responses. Second, cartilaginous joint matrix can only be degraded after the first attack of collagen fibrils by MMPs, and importantly, most of the MMPs are under the control of c-Fos/AP-1 and IL-1β as well. Third, differentiation of osteoclast is driven internally by NFATc1, where NFATc1 is under the control of TRAF6, c-Fos/AP-1 and osteoclastogenic signaling complex. IL-1β has been shown to induce osteoclastogenesis directly and also indirectly via signaling through RANKL. Therefore, IL-1β and c-Fos/AP-1 influence each other's gene expression and activity, resulting in an orchestrated cross-talk that is crucial to arthritic joint destruction, and thus, blockade of IL-1β and/or c-Fos/AP-1 can be most promising as a therapeutic target, and in fact, a selective inhibition of c-Fos/AP-1 does resolve arthritic joint destruction.

Aryl hydrocarbon receptor antagonism mitigates cytokine-mediated inflammatory signalling in primary human fibroblast-like synoviocytes

“…The progression of RA is a well-orchestrated process involving chronic inflammation and pannus formation, followed by joint destruction 35 36. RA pathogenesis progresses within the multi-cell type environment of RA synovium 37.…”

Juvenile idiopathic arthritis characteristics: Etiology and pathophysiology

“…65 That c-Fos/AP-1 is an important transcription factor was shown as inhibition of c-Fos/AP-1 not only reduces arthritis but also resolves arthritic joint destruction as the main enzyme for tissue destruction, the matrix metalloproteinases (MMPs), are controlled by c-Fos/AP-1. 66,67 The effects of MMPs are inhibited by their physiological inhibitors tissue inhibitor of metalloproteinases (TIMP) and if the ratio between MMPs and TIMPs increases as in arthritic conditions, the MMPs will be overrepresented leading to tissue destruction. 67 Some of the most important degrading MMPs are produced in the synovial lining cells and are up-regulated by proinflammatory cytokines (e.g., TNF-α and IL-1β) and are present in large amounts in the pannus causing cartilage destruction.…”

“…66,67 The effects of MMPs are inhibited by their physiological inhibitors tissue inhibitor of metalloproteinases (TIMP) and if the ratio between MMPs and TIMPs increases as in arthritic conditions, the MMPs will be overrepresented leading to tissue destruction. 67 Some of the most important degrading MMPs are produced in the synovial lining cells and are up-regulated by proinflammatory cytokines (e.g., TNF-α and IL-1β) and are present in large amounts in the pannus causing cartilage destruction. 68 MMP-3 is expressed in both JIA and normal synovial tissue, in synovial fluid, and its expression correlates with the degree of inflammation.…”

Tissue Engineering von Knorpelersatzgewebe – Mechanische Stimulation in der In-vitro-Kultivierung von humanen Chondrozyten

“…Rahmen von Erkrankungen des rheumatischen Formenkreises, durch progressive Knochen-und Knorpelerosion und -zerstörung gekennzeichnet (Shiozawa et al, 2011).…”