Both AP-1 and Cbfa1-like factors are required for the induction of interstitial collagenase by parathyroid hormone

Oncogene. 1999 Jan 21;18(3):667-78. doi: 10.1038/sj.onc.1202333.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Collagenases / biosynthesis*
  • Collagenases / genetics
  • Core Binding Factor Alpha 1 Subunit
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins*
  • Enzyme Induction
  • Gene Expression Regulation, Enzymologic
  • Matrix Metalloproteinase 13
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Proteins*
  • Parathyroid Hormone / pharmacology*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins*
  • Rats
  • Response Elements
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation
  • Tumor Cells, Cultured

Substances

  • Core Binding Factor Alpha 1 Subunit
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Parathyroid Hormone
  • Proto-Oncogene Proteins
  • Runx1 protein, mouse
  • Runx1 protein, rat
  • Transcription Factor AP-1
  • Transcription Factors
  • Collagenases
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • Mmp13 protein, rat