MMPs role in arthritic diseases

Matrix Metalloproteinases (MMPs) are enzymes considered to be responsible for cartilage bone damage. There are over 20 zinc-containing endopeptidases that include collagenases, gelatinases, stromelysins. MMPs are released as inactive but become active only when the propeptide is cleaved. MMPs have a key role in normal connective tissue remodeling and their activation, release, and inhibition (by TIMPs) is tightly regulated. Because they can degrade all components of the extracellular matrix, they have been implicated in numerous pathological conditions.The capacity of chondrocytes to degrade components of extracellular matrix depends on their ability to produce and secrete proteinases. They can be produced in response to IL-1, IL-17, IL18 and TNF which are found in excess in arthritic joints. Expression and production of proteinases (MMPs) is increased in OA and RA as well as other diseases.
In the article "Cytokines in the pathogenesis of rheumatoid arthritis" two mechanism lead to the disintegration of undifferentiated cartilage. Chondrocytes switch from an anabolic matrix-synthesizing state to a catabolic state. This state is chacterized by the formation of ADAMTs (a desintegrin and metalloproteinase) and MMPs that cleave the cartilage component of proteoglycan and collagen fivers. Synovial fibroblast also release MMPs, neutrophils and potentially mast cells, which are closely located to articular cartilage and can effect the damaging process.
IL-1β plays a central role in cartilage degradation through prevention of matrix synthesis as well as through induction of the matrix-degrading enzymes MMP1, MMP3, MMP8, MMP13, and MMP14.
IL-1-driven animal models of arthritis such as cartilage induced arthritis show rapid and extensive cartilage damage. Injection of IL-1 intra-articular led to PG loss, chondrocyte apoptosis and matrix degradation. Injection of IL-17 increased PG loss but did not progess to erosion and death of chondrocytes. Upon induction of CIA (cartilage induced arthritis), exogenous IL-17 worsened cartilage damage and led to erosion and death of chondrocytes. Therefore, IL-17 can act independently and synergistically with IL-1β and TNF to promote cartilage degradation. IL-18 also promotes cartilage degradation via IL-1 β.
In the article Molecular aspects of pathogenesis in osteoarthritis: the role of inflammation, higher concentrations of MMPs as well as elevated levels of tissue inhibitor of MMPs (TIMPs) were found in synovial fluid compared to healthy controls in an attempt by chondrocytes to balance excessive proteinase activity.
Overexpression of MMP-13 has been found in patients with OA. MMP-13 preferentially degrades collagen II. MMP-12 expression in macrophages significantly exacervate the development of experimental inflammatory arthritis in transgenic rabits.
Recent studies have shown the presence of selective collagenase inhibitors against MMP-13 and MMP-8 (in cultured OA) to halter the cleavage of collagen II. MMP-3 synthesis and inhibition of TIMP-1 production have been linked to apoptotic and antiproliferative catabolic effects. Very interesting studies are being done with MMP inhibitors. Some results have not been satisfactory mainly because of its toxic side effects and lack of enzyme specificity.

Other references:
MMP12, an Old Enzyme Plays a New Role in the Pathogenesis of RA?
Matrix metalloproteinase inhibitors in rheumatic diseases.
Matrix metalloproteinase 9 (MMP9) gene polymorphism and MMP-9 plasma levels in primary Sjogren's syndrome - did not discuss but very interesting.