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. 2005 Nov;64(Suppl 4):iv44–iv47. doi: 10.1136/ard.2005.042465

What are the roles of metalloproteinases in cartilage and bone damage?

G Murphy, M Lee
PMCID: PMC1766921  PMID: 16239386

Abstract

A role for metalloproteinases in the pathological destruction in diseases such as rheumatoid arthritis and osteoarthritis, and the irreversible nature of the ensuing cartilage and bone damage, have been the focus of much investigation for several decades. This has led to the development of broad spectrum metalloproteinase inhibitors as potential therapeutics. More recently it has been appreciated that several families of zinc dependent proteinases play significant and varied roles in the biology of the resident cells in these tissues, orchestrating development, remodelling, and subsequent pathological processes. They also play key roles in the activity of inflammatory cells. The task of elucidating the precise role of individual metalloproteinases is therefore a burgeoning necessity for the final design of metalloproteinase inhibitors if they are to be employed as therapeutic agents.

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Figure 1.

Figure 1

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 Three metzincin families, matrix metalloproteinases (MMPs), disintegrin metalloproteinases (ADAMs), and disintegrin metalloproteinases with thrombospondin repeats (ADAM TSs) have been identified as having roles in the biology and pathology of cartilage and bone. They have in common the zinc containing catalytic domain which is rendered inactive in the presence of an N-terminal propeptide. Activation is usually effected by the proteolytic removal of the propeptide at cellular sites specific to individual proteinases. Most of these metalloproteinases have other domains conferring specificity with respect to substrate cleavage or cellular or ECM localisation. Some members of the MMP family and all the ADAM family are membrane associated.

Figure 2.

Figure 2

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 Modification of the metalloproteinase binding ridge of tissue inhibitors of metalloproteinases (TIMPs) to generate potent inhibitors of TACE. Based on any of the four TIMP basic scaffolds a tight binding inhibitor of the disintegrin metalloproteinase (ADAM) tumour necrosis factor α converting enzyme (TACE) can be made by the modification of four positions on the active site binding ridge. (1) a leucine residue on the EF ß strand loop; (2) a leucine residue on the CD ß strand loop; (3) a threonine residue at the P1' binding site; hand (4) a proline-phenylalanine-glycine triad at the tip of the AB ß strand loop. Adapted from Lee et al.20

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