The Role of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 in Antibody-Induced Arthritis

Abstract

Matrix metalloproteinases (MMPs) are a large group of enzymes responsible for matrix degradation. Among them, the family of gelatinases (MMP-2/gelatinase A and MMP-9/gelatinase B) is overproduced in the joints of patients with rheumatoid arthritis. Because of their degradative effects on the extracellular matrix, gelatinases have been believed to play an important role in progression and cartilage degradation in this disease, although their precise roles are yet to be defined. To clarify these roles, we investigated the development of Ab-induced arthritis, one of the murine models of rheumatoid arthritis, in MMP-2 or MMP-9 knockout (KO) mice. Surprisingly, the MMP-2 KO mice exhibited severe clinical and histologic arthritis than wild-type mice. The MMP-9 KO mice displayed milder arthritis. Recovery from exacerbated arthritis in the MMP-2 KO mice was possible by injection of wild-type fibroblasts. These results indicated a suppressive role of MMP-2 and a pivotal role of MMP-9 in the development of inflammatory joint disease.

Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

“…Rheumatoid arthritis, like OA, is characterized by the joint degeneration, but it occurs in a more aggressive manner. Experiments performed in MMP-2-knockout mice and in MMP-9-knockout mice revealed a reduction in the progression of arthritis only in the MMP-9-knockout mice (42). Hence, the much more significant involvement of MMP-9 than MMP-2 in the process of rheumatoid arthritis could also be of major importance in OA.…”

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

“…MMP-9 plays a critical role in the invasion of the synovial tissue, leading to cartilage destruction and bone erosion in RA (7,10,33,34). The importance of this enzyme in arthritis is highlighted by the finding that MMP-9-knockout mice display less severe antibodyinduced arthritis than do wild-type mice (10).…”

“…MMP-9 plays a critical role in the invasion of the synovial tissue, leading to cartilage destruction and bone erosion in RA (7,10,33,34). The importance of this enzyme in arthritis is highlighted by the finding that MMP-9-knockout mice display less severe antibodyinduced arthritis than do wild-type mice (10). MMP-9 is implicated in the degradation of basement membrane collagen, synovial membrane neovascularization, transfer of endothelial and hemopoietic stem cells from a quiescent to a proliferative state, and promotion of leukocyte migration from the vascular compartment to sites of inflammation (7,(35)(36)(37).…”

“…This action of MMP-2 was shown to result in not only blocking of the initiation of an in vivo inflammatory response, but also complete abrogation of preexisting inflammation in the paws of mice (15). Itoh et al (10) have proposed that although levels of MMP-2 are elevated in the arthritic joint, the matrix-degrading ability of MMP-2 appears to have little effect on the development of arthritis, but instead, it prevents inflammation by cleaving proinflammatory factors. Thus, APC has the potential to exert strong antiinflammatory effects first by inhibiting MMP-9 and second by promoting MMP-2 activity.…”

“…MMP-9-knockout mice show reduced severity of antibodyinduced arthritis (10). Although MMP-2 is elevated in the arthritic joint, MMP-2-knockout mice have exacerbated antibody-induced arthritis, indicating that MMP-2 may play a suppressive role in the progression of arthritis (10).…”