Matrix Metalloproteinase Knockout Studies and the Potential Use of Matrix Metalloproteinase Inhibitors in the Rheumatic Diseases

Abstract

The matrix metalloproteinases (MMPs) comprise a family of enzymes that collectively can degrade all components of the extracellular matrix (ECM). MMPs play an important role in many physiological processes such as embryonic development and growth, tissue remodelling and repair. Overexpression and activation of MMPs contributes to many pathologies, including arthritis, cardiovascular disease, tumour progression and lung disease. Targeted mutagenesis has allowed investigators to examine the contribution of MMPs to these physiological and pathologic processes. In this manuscript, we will present an up-to date review of these studies. Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic diseases that result in cartilage degradation and loss of joint function. MMPs have been implicated in the collagen breakdown that contributes to joint destruction. Current available drugs to treat arthritis are predominantly directed towards the control of pain and/or the inflammation associated with joint synovitis but they do little to reduce joint destruction. Synthetic MMP inhibitors have been developed and in animal models of OA and/or RA, these agents have shown chondroprotective effects. However, results from clinical trials in RA have been equivocal, with some studies being terminated because of lack of efficacy or safety concerns. Increased understanding of the structure, regulation and function of individual MMPs may lead to more effective strategies. Approaches aimed at multiple steps of the pathogenesis of arthritis may be needed to break the chronic cycle of joint destruction. In the future, it will be important to have drugs that prevent the structural damage caused by bone and cartilage breakdown.

Expression, pharmacology, and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages

“…The fact that in our system, SRIF-14 had a detectable effect on IL-8 but not on MCP-1 secretion or cell viability suggests that sst 1 /sst 2 -induced inhibition of IL-8 secretion involves highly efficient coupling between receptor and effector and that a small degree of G protein activation is required to obtain a significant inhibition (see also above). Conversely, we also showed that the immunoregulatory role of the SRIF system in human macrophages did not involve MMP-9, a major secretory product of macrophages, which constitutes a prototypical example of the regulation of immune functions by proteolysis [57][58][59]. Indeed, the application of SRIF-14 and SRIF receptor-selective agonists did not affect the secretion of proMMP-9 by LPS-activated macrophages.…”

“…MMP-9 (also known as gelatinase B) is a major secretory product of macrophages and plays an important role in inflammatory processes [57][58][59]. In LPS-activated macrophages, we used zymography to measure the secretion of MMP-9 24 h after the application of SRIF analogs.…”

Local overexpression of interleukin-1 family, member 6 relates to the development of tubulointerstitial lesions

“…16 IL-1b has been found to be produced by macrophages, T-cells, fibroblasts, and chondrocytes in articular cavities of rheumatic patients; it also participates in local inflammation and tissue remodeling via MMPs. 16,[18][19][20][21][22] Of the recently studied IL-1 members, IL-1F8 has been associated with the pathogenesis of rheumatism by increasing IL-6 and IL-8 expression in synovial fibroblasts and chondrocytes. 16,23 In renal diseases, it was reported that some IL-1 members aggravated renal fibrosis.…”

Regulation of matrix metalloproteinase gene expression by a retinoid X receptor–specific ligand

“…The destruction of joint tissues that is a hallmark of rheumatoid arthritis (RA) and osteoarthritis (OA) is mediated largely by members of the matrix metalloproteinase (MMP) family of enzymes (1)(2)(3). At low expression levels, these zinc-dependent endopeptidases maintain connective tissue homeostasis in a wide range of biologic functions (4).…”

“…MMP-1 is expressed by a range of cell types, including chondrocytes and fibroblasts, and is most effective against type III collagen. MMP-13 is expressed mainly by articular chondrocytes, and it preferentially cleaves type II collagen as well as aggrecan, a proteoglycan important for the resiliency of normal articular cartilage (1)(2)(3). MMP-8 has its greatest activity against type I collagen, although its expression level in joints is quite low (6).…”