Matrix metalloproteinases and TIMPs: properties and implications for the rheumatic diseases

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Abstract

The matrix metalloproteinases (MMPs) are a unique family of metalloenzymes, which, once activated, can destroy all the components of cartilage. MMPs are found in resorbing cartilage, bone, rheumatoid and osteoarthritic synovial fluid, and adjacent soft tissues. The active enzymes are all inhibited by tissue inhibitors of metalloproteinases (TIMPs). The relative amounts of active MMPs and TIMPs are important in determining whether cartilage is broken down in joint diseases. Conventional treatments for arthritis do little to affect the underlying joint destruction, but new drugs are now available that can specifically block active MMPs. These potent inhibitors prevent the destruction of cartilage both in vitro and in animal models of arthritis. Future trials in patients will test their effectiveness in the prevention of cartilage destruction.

Section snippets

Cartilage matrix: structure and function

Collagen is the most common protein of the vertebrate body and has a unique structure[1]. Three coils of polypeptide form a rod-shaped triple-helical molecule with globular regions at either end. On leaving the cell, the globular regions are proteolytically removed and the collagen molecules align to produce a characteristic staggered arrangement. Crosslinks form between the collagen molecules, which increases stability. These self-aligned collagen molecules form the collagen fibres that give

How is connective tissue broken down?

Proteinases can be classified into four main groups according to the amino acid or chemical group at the catalytic centre of the enzyme[3]. Proteolytic pathways can be divided into: (1) intracellular pathways, catalysed by cysteine and aspartate proteinases, which cleave protein at low pH inside the cell; and (2) extracellular pathways, catalysed by serine and metalloproteinases, which act at neutral pH outside the cell.

These pathways all play a part in the turnover of collagen and

Cartilage and joint diseases

In diseases such as osteoarthritis and rheumatoid arthritis (Appendix A), cartilage is broken down. Rheumatoid disease is characterized by a proliferating synovial layer, which is infiltrated by inflammatory cells. This pannus tissue promotes the destruction of cartilage and bone, either directly or indirectly, by stimulating chondrocytes or bone cells to degrade connective tissue matrix[5]. Osteoarthritis is primarily a disease of cartilage; the underlying bone and the synovial membrane are

Matrix metalloproteinases: a unique family of proteinases

Collagen was thought to be totally resistant to proteolytic attack by enzymes from within the body until an enzyme was discovered, in resorbing tadpole tail, that specifically cleaves all three chains of collagen. Since this discovery of collagenase a family of closely related MMPs has been characterized that can destroy all the proteins of the extracellular matrix7, 8. MMPs have a number of common properties: (1) they contain common sequences of amino acids (Fig. 3); (2) they are secreted as

How are the MMPs controlled?

As the MMPs are so potent, they are carefully controlled at a number of key points: (1) various cytokines, growth factors and other agents can stimulate the synthesis and secretion of pro-MMPs[10]; (2) the pro-MMPs require activation[22]; and (3) the active enzymes can be inhibited by TIMPs, which are also regulated by growth factors. These control points are illustrated in Fig. 4.

Can we model cartilage breakdown?

Model systems that use cartilage in culture can provide important information on the mechanisms of cartilage breakdown. Initiation of proteoglycan breakdown can be induced with either IL-1 or retinoic acid, and the release of fragments can be followed in the presence or absence of inhibitors[33]. When IL-1 is added to cartilage in combination with the proinflammatory cytokine oncostatin M (a member of the IL-6 family of cytokines)[34], a rapid and reproducible loss of cartilage collagen occurs

Are synthetic inhibitors of MMPs clinically useful anti-arthritic drugs?

The future prospects for the prevention of connective tissue breakdown using synthetic MMP inhibitors as drugs look promising. Highly specific MMP inhibitors have been made36, 37, but there is some disagreement over the best strategy to employ. Some workers support the use of broad-spectrum inhibitors as these will test whether MMP inhibition is therapeutically effective. If successful, specific inhibitors targeted to individual enzymes could then be tested. If undiscovered MMPs are responsible

Glossary

α2-Macroglobulin—A large serum proteinase inhibitor that has the unique ability to inhibit serine, metallo-, cysteine and aspartate proteinases.

Aggrecan—The major proteoglycan of human cartilage, consisting of three globular domains and a highly sulphated linear polypeptide between the G2 and G3 domains. It associates with hyaluronan and link protein to form a highly charged aggregate that pulls water into the tissue.

Chondrocyte—A rounded cell sparsely distributed throughout the cartilage

The outstanding questions

  • Which enzyme is responsible for the breakdown of proteoglycan and can specific inhibitors be made that only block this activity?

  • Which collagenase(s) is/are responsible for the breakdown of collagen in osteoarthritis and rheumatoid arthritis, and would targeted inhibitors completely block tissue destruction in these diseases?

  • Will inhibition of matrix metalloproteinases (MMPs) block cartilage and bone destruction without causing unwanted side effects such as fibrosis or interference with wound

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