Nmp4/CIZ regulation of matrix metalloproteinase 13 (MMP-13) response to parathyroid hormone in osteoblasts

Rita Shah, Marta Alvarez, Daniel R. Jones, Kitti Torrungruang, Andrew J. Watt, Nagarajan Selvamurugan, Nicola C. Partridge, Cheryl O. Quinn, Fred M. Pavalko, Simon J. Rhodes, Joseph P. Bidwell

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Parathyroid hormone (PTH) regulation of matrix metalloproteinase-13 (MMP-13) expression in osteoblasts contributes to normal bone turnover. The PTH response region of the rat MMP-13 gene spans nucleotides (nt) -148 to -38 and supports binding of numerous transcription factors, including Runx2, necessary for osteoblast differentiation, c-Fos/c-Jun, and Ets-1. These trans-acting proteins mediate hormone induction via incompletely defined combinatorial interactions. Within this region, adjacent to the distal Runx2 site, is a homopolymeric(dA:dT) element (-119/-110 nt) that conforms to the consensus site for the novel transcription factor nuclear matrix protein-4/cas interacting zinc finger protein (Nmp4/CIZ). This protein regulates bone cell expression of type I collagen and suppresses BMP2-enhanced osteoblast differentiation. The aim of this study was to determine whether Nmp4/CIZ contributes to MMP-13 basal transcription and PTH responsiveness in osteoblasts. Electrophoretic mobility shift analysis confirms Nmp4/ CIZ binding within the MMP-13 PTH response region. Mutation of the Nmp4/CIZ element decreases basal activity of an MMP-13 promoter-reporter construct containing the first 1329 nt of the 5′-regulatory region, and overexpression of Nmp4/CIZ protein enhances the activity of the wild-type promoter. The same mutation of the homopolymeric(dA:dT) element enhances the MMP-13 response to PTH and PGE 2. Overexpression of Nmp4/CIZ diminishes hormone induction. Mutation of both the homopolymeric(dA:dT) element and the adjacent Runx2 site further augments the PTH response. On the basis of these data and previous studies, we propose that Nmp4/CIZ is a component of a multiprotein assemblage or enhanceosome within the MMP-13 PTH response region and that, within this context, Nmp4/ CIZ promotes both basal expression and hormonal synergy.

Original languageEnglish (US)
Pages (from-to)E289-E296
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume287
Issue number2 50-2
DOIs
StatePublished - Aug 2004

Keywords

  • Bone
  • Collagen
  • Collagenase
  • Endocrine

ASJC Scopus subject areas

  • Physiology
  • Endocrinology
  • Biochemistry

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