Abstract
Members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family are known to influence development, angiogenesis, coagulation and progression of arthritis. As proteinases their substrates include the von Willebrand factor precursor and extracellular matrix components such as procollagen, hyalectans (hyaluronan-binding proteoglycans including aggrecan), decorin, fibromodulin and cartilage oligomeric matrix protein. ADAMTS levels and activities are regulated at multiple levels through the control of gene expression, mRNA splicing, protein processing and inhibition by TIMP (tissue inhibitor of metalloproteinases). A recent screen of human cartilage has shown that multiple members of the ADAMTS family may be important in connective tissue homeostasis and pathology.
Highlights
ADAMTS proteinases are a group of secreted enzymes; many of them have been found to be expressed in cartilage [1]
The purpose of this review is to summarise the structure, function and regulation of the entire ADAMTS group of proteinases and to emphasise areas of potential relevance with regard to the homeostasis and pathology of connective tissues
Evidence suggests that the synthesis of these proteinases is regulated at the level of both expression and translation and that their structures and activities are regulated through mRNA splicing and post-translationally through protein processing and endogenous inhibitors
Summary
ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases are a group of secreted enzymes; many of them have been found to be expressed in cartilage [1]. In contrast to ADAM proteins, in which the CRD is followed by epidermal growth factor (EGF)-like repeats, a transmembrane domain and Cterminal cytosolic region, all ADAMTS proteinases possess instead a cysteine-free ‘spacer’ region This domain varies in length and contains several conserved hydrophobic residues in the N-terminal portion and an extremely variable C-terminal portion. A recent study of truncated recombinant forms of ADAMTS-4 indicated that the presence of the CRD was required for maximal aggrecanase activity, whereas the inclusion of the spacer region prevented cleavage of aggrecan at the IGD site [27]. The requirement of the CRD for optimal cleavage of glycosylated aggrecan compared with its negligible influences on the cleavage of non-proteoglycan substrates suggests that this domain promotes hyalectan cleavage by mediating interactions with sulphated glycosaminoglycan, in a similar manner to that proposed for the activation by heparan sulphate of growth-factor-receptor signalling [87]. These data suggest that many members of the ADAMTS subfamily might possess important roles in both the homeostasis and pathology of connective tissues and are worthy of further investigation
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