Both AP-1 and Cbfa1-like factors are required for the induction of interstitial collagenase by parathyroid hormone.
PTH is a major regulator of calcium homeostasis by mobilizing calcium through bone resorption. We show that the expression of collagenase-3 (MMP-13), a member of the family of matrix metalloproteinases, required for the cleavage of collagens in the bone, is increased upon PTH injection in mice. A cis-acting element in the collagenase-3 promoter was identified which, together with AP-1, is required for induction by PTH. This element contains CCACA motifs which are required for binding of the 65 kDa osteoblast-specific splice variant of Cbfal. Introduction of mutations in this binding site that interfere with protein interaction also eliminates PTH inducibility and transactivation by Cbfa/ Runt proteins. While DNA binding activity of AP-1 is increased upon PTH treatment, high basal level of Cbfa/Runt binding activity is detectable in untreated cells which is not further increased by PTH, suggesting that AP-1 and Cbfal contribute to transcriptional activation through different mechanisms. In agreement with the critical role of both proteins defined in tissue culture cells, expression of collagenase-3 is reduced in mice lacking c-fos and is completely absent in cbfa1-/-embryos. These data provide the first evidence for a critical role of Cbfal, a major regulator of bone development, in PTH-dependent processes such as bone resorption.
Porte
D
D
Deutsches Krebsforschungszentrum, Abteilung Signaltransduktion und Wachstumskontrolle, Heidelberg, Germany.
Tuckermann
J
J
Becker
M
M
Baumann
B
B
Teurich
S
S
Higgins
T
T
Owen
M J
MJ
Schorpp-Kistner
M
M
Angel
P
P
D000818:Animals; D001665:Binding Sites; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic; D053509:Matrix Metalloproteinase 13; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D051381:Rats; D020218:Response Elements; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured