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TIMP‐3 is an Inhibitor of ADAMTS‐2
Author(s) -
Wang Mandy,
Ge Gaoxiang,
Greenspan Dan
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a516-a
Subject(s) - adamts , matrix metalloproteinase , protein precursor , procollagen peptidase , metalloproteinase , extracellular matrix , chemistry , disintegrin , endogeny , phenotype , tissue inhibitor of metalloproteinase , type i collagen , microbiology and biotechnology , biochemistry , thrombospondin , enzyme , biology , gene , endocrinology
The metalloproteinase ADAMTS‐2 is capable of cleaving N‐propeptides of major fibrillar collagen types I, II and III. Mutations in the ADAMTS‐2 gene in dermatosparaxis and Ehlers‐Danlos syndrome VIIC cause incomplete processing of procollagen I and III, which contribute to a phenotype marked by extreme fragility of the skin. Endogenous factors responsible for regulating N‐propeptide processing of fibrillar collagens have not been previously been reported, although such factors could be important modulators of the deposition of collagenous extracellular matrix. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that regulate the activity of matrix metalloproteinases (MMPs) and of some ADAMs (A Disintegrin And Metalloproteinase) proteinase family members. There are four TIMPS, and the inhibitory activity of each resides in the N‐terminal portion of the protein. Here we demonstrate that both full‐length TIMP‐3 and the isolated N‐terminal domain of TIMP‐3 can inhibit ADAMTS‐2 activity with Ki‘s in the nM range. In contrast, TIMP‐3 had no observable effect on the activity of BMP‐1 (bone morphogenetic protein 1), the proteinase responsible for cleaving the C‐propeptides of collagens I–III. Discovery of that TIMP‐3 is an effective inhibitior of ADAMTS‐2 demonstrates a previously unrecognized control point for collagen deposition in tissue, and also provides a potentially useful therapeutic agent for blocking the excess collagen deposition associated with the fibroses.