Regulation of chondrocyte differentiation by ADAMTS-12 metalloproteinase depends on its enzymatic activity |
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Authors: | X H Bai D W Wang Y Luan X P Yu C J Liu |
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Institution: | (1) Department of Developmental Biology, Center for Medical Biotechnology, University Duisburg-Essen, 45117 Essen, Germany; |
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Abstract: | ADAMTS-12, a metalloproteinase that belongs to ADAMTS family, is strongly upregulated during chondrogenesis and demonstrates
prominent expression in the growth plate chondrocytes. ADAMTS-12 potently inhibits chondrocyte differentiation, as revealed
by altered expression of both early and later genes critical for chondrogenesis. In addition, ADAMTS-12-mediated inhibition
of chondrogenesis depends on its enzymatic activity, since its point mutant lacking enzymatic activity completely loses this
activity. Furthermore, the C-terminal four thrombospondin motifs known to bind COMP substrate is necessary for its full proteolytic
activity and inhibition of chondrocyte differentiation. Mechanism studies demonstrate that ADAMTS-12 induces PTHrP, whereas
it inhibits IHH during chondrogenesis. Furthermore, PTHrP induces ADAMTS-12 and ADAMTS-12 is hardly detectable in PTHrP-/-growth
plate chondrocytes. Importantly, knocking down ADAMTS-12 mRNA levels or blocking ADAMTS-12 activity almost abolishes the PTHrP-mediated
inhibition of type X collagen expression. Collectively, these findings demonstrate that ADAMTS-12, a downstream molecule of
PTHrP signaling, is a novel regulator of chondrogenesis.
X. H. Bai, D.W. Wang: These two authors contributed equally to this work. |
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Keywords: | " target="_blank"> Chondrocyte differentiation ADAMTS-12 metalloproteinase PTHrP signaling |
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