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M existing therapies for the rheumatic diseases collagen in joint tissues in health and disease. In situ hybridization techniques have been used to measure relieve the pain and swelling associated with the disease, but have little effect on the underlying destruction collagenase gene expression in synovial and cartilage tissue from diseased joints [7–10]. Other studies have of tissue and the corresponding loss of function. Although Voltaire cynically stated that ‘The art of measured MMP protein in these tissues by immunohistochemistry [11]. MMPs have been extracted from medicine is the ability to keep the patient entertained whilst the disease runs its inevitable course’, rheumatodiseased tissues and assayed by activity or using immunoassays [12, 13]. Finally, the levels of MMP logists have long expressed the need for drugs that prevent joint damage. The second-line agents currently protein have been measured in synovial fluids and serum samples from patients [14, 15]. If these proin use, so-called disease-modifying drugs, have mainly been adapted for the rheumatic diseases from other teinases are involved in tissue destruction, then they could represent a new therapeutic target that would specialities and the mechanism and/or target of action is not always clear. Although some of these drugs do allow the prevention of tissue destruction. Any attempt to prevent tissue damage by targeting the MMPs could slow the progression of joint destruction [1], recent developments have increased our understanding of the follow a number of different strategies. These include blocking the production of MMPs, inhibiting the different disease mechanisms involved and led to the identification of new targets. There is a clear need for enzymes responsible for activation of proMMPs, increasing the amount of TIMPs available, thus new therapeutic approaches that block precise steps in the disease processes and some of these are in the early blocking MMP activity, or directly inhibiting the activated enzymes (reviewed in [16 ], [17]). stages of development [1]. The destruction of connective tissues such as cartilThe direct inhibition of MMPs as a therapeutic approach has been followed for a number of years. age and bone is the final stage of many diseases of the joint. Both the major proteins of cartilage, proteoThe antibiotic tetracycline shows some activity as an inhibitor of collagenase. Direct inhibitory activity is glycan and collagen, are degraded. In normal human cartilage, proteoglycan pulls water into the tissue and noted primarily against MMP-8 and the collagenases also autodegrade in the presence of this class of comswells against a type II collagen fibrillar network. This structure gives cartilage its tensile strength whilst pound. Greater activity is seen with some modified tetracyclines [18, 19] and collagenolysis is inhibited in allowing it to resist compression. Whilst proteoglycan can be readily replaced by the chondrocytes in cartilvivo and in vitro [20]. Recent data from animal models suggest that the levels of collagenase and gelatinase age, the loss of the collagen network leads to irreversible damage. This makes collagen breakdown a key are reduced, but with no overall reduction in bone and joint damage [21]. Patient studies have resulted in therapeutic target [2]. Of the four main classes of proteinases that can degrade proteins, the serine and contradictory findings, although they do suggest that, in combination with NSAIDs, these compounds prometalloproteinases act extracellularly at neutral pH and could therefore be responsible for the breakdown tect joints, and further studies are in progress with newer derivatives of these compounds [18, 22]. The of the extracellular matrix [3]. Collagen can be specifically cleaved by the collaobvious and clear advantage of this class of compounds is that they are already in clinical use and could give genases, members of a family of zinc-containing enzymes called the matrix metalloproteinases (MMPs). useful data on the inhibition of MMPs as a therapeutic strategy. The disadvantages are that they have a relaMMPs can degrade proteins of the extracellular matrix and often require specific stimuli to upregulate their tively low potency and, as they are licensed for a considerable period of time, the cost of extensive and production [4]. The pro-inflammatory cytokines upregulate many MMPs which are synthesized as prolengthy trials will be difficult to find. Other more targeted approaches have been followed. enzymes and require activation before substrate can be degraded [5]. The active forms of each enzyme can MMPs are related to the metallopeptidase angiotensin converting enzyme (ACE) and synthetic inhibitors be inhibited by tissue inhibitors of metalloproteinases (TIMPs), inhibitors that specifically block the action have been made that block the action of ACE. These inhibitors have a chelating group (hydroxamate) of this family of proteinases [6 ]. If the amount of active MMPs exceeds the locally available TIMPs, attached to a peptide mimic of the sequence of amino acids cleaved by the enzyme in angiotensin I. When then connective tissue turnover is the result. There are three human collagenases (MMP-1, these inhibitors were screened against MMPs, it was discovered that a stereoisomer, inactive against ACE, MMP-8 and MMP-13) and there is good evidence that these enzymes are closely involved in the turnover of gave significant inhibition. This early lead allowed the

Prevention of cartilage breakdown by matrix metalloproteinase inhibition--a realistic therapeutic target?