Cartilage breakdown in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a connective tissue disease characterized by destruction of the joint cartilage and subsequently of the underlying bone. Cartilage destruction is due to proteolysis by enzymes called metalloproteinases (MMPs), whose production and expression are regulated by numerous local mediators such as cytokines, growth factors, prostaglandins, oxygen species, and neuropeptides. MMP activation is largely due to a stimulatory effect of cytokines including IL-1beta and TNFalpha. When these cytokines bind to their membrane receptor, they set off signaling cascades, with activation of TGFbeta-activating kinase (TAK-1), of NF-kappaB by Ikappa-B kinase, of mitogen-activated protein kinases (MAP kinases), and finally of activator protein-1 (AP-1). Tissue inhibitors of MMPs (TIMPs) specifically inhibit MMPs. The interrelations between joint inflammation and joint destruction remain poorly understood. Experimental data suggest that IL-1 may be involved chiefly in joint destruction and TNF in joint inflammation. However, TNF antagonists are potent inhibitors of joint destruction in clinical practice. These results suggest that the mediators function as a network and that inhibition of a single mediator can affect the entire web. Insights gained into the innermost mechanisms of cartilage breakdown in patients with RA have led to major therapeutic breakthroughs. Thus, TNF antagonists have proved highly effective in RA. Future progress will no doubt stem from new knowledge about the extracellular mediators and intracellular signaling pathways that lead to the production and activation of enzymes responsible for cartilage degradation.
Rannou
François
F
Research Unit UMR-S 530-Inserm-Paris 5 University, France.
François
Mathias
M
Corvol
Marie-Thérèse
MT
Berenbaum
Francis
F
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D002358:Cartilage, Articular / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D045726:Metalloproteases / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D015415:Biomarkers; D019714:Tissue Inhibitor of Metalloproteinases; D045726:Metalloproteases