Metalloproteinase inhibitors and the prevention of connective tissue breakdown.
The primary agents responsible for cartilage and bone destruction in joint diseases are active proteinases degrading collagen and proteoglycan. All four main classes of proteolytic enzymes are involved in either the normal turnover of connective tissue or its pathological destruction. These proteinases are made by different cells found within the joints. Both extracellular and intracellular pathways exist, and individual enzymes can be inhibited by specific proteinaceous inhibitors that block their activity. Recent research has implicated the matrix metalloproteinases in many of the processes involved in joint diseases. Conventional treatments do little to affect the underlying disease processes, and recently, the use of proteinase inhibitors has been suggested as a new therapeutic approach. A large variety of different synthetic approaches have been used and highly effective metalloproteinase inhibitors have been designed, synthesised and tested. These metalloproteinase inhibitors can prevent the destruction of animal cartilage in model systems and slow the progression of human tumours. Future patient trials will test the effectiveness of these compounds in vivo for the treatment of joint diseases.
Cawston
T E
TE
Rheumatology Research Unit, Addenbrookes Hospital, Cambridge, UK.
D000595:Amino Acid Sequence; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000494:pharmacology; D003238:Connective Tissue / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007592:Joint Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D011509:Proteoglycans / Q000378:metabolism
D011509:Proteoglycans; D003094:Collagen; D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3