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J. Biol. Chem., Vol. 278, Issue 29, 26803-26809, July 18, 2003

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Parathyroid Hormone-induced E4BP4/NFIL3 Down-regulates Transcription in Osteoblasts^*

Ibrahim C. Ozkurt and Sotirios Tetradis 

From the Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, California 90095-1668

Parathyroid hormone (PTH), a major regulator of bone metabolism, activates the PTHR1 receptor on the osteoblast plasma membrane to initiate signaling and induce transcription of primary response genes. Subsequently, primary genes with transcriptional activity regulate expression of downstream PTH targets. We have identified the adenovirus E4 promoter-binding protein/nuclear factor regulated by IL-3 (E4bp4) as a PTH-induced primary gene in osteoblasts. E4BP4 is a basic leucine zipper (bZIP) transcription factor that represses or activates transcription in non-osteoblastic cells. We report here that PTH rapidly and transiently induced E4bp4 mRNA in osteoblastic cells and that this induction did not require protein synthesis. PTH also induced E4BP4 protein synthesis and E4BP4 binding to a consensus but not to a mutant E4BP4 response element (EBPRE). E4BP4 overexpression inhibited an EBPRE-containing promoter-reporter construct, whereas PTH treatment attenuated activity of the same construct in primary mouse osteoblasts. Finally, E4BP4 overexpression inhibited PTH-induced activity of a cyclooxygenase-2 promoter-reporter construct. Our data suggest a role for E4BP4 in attenuation of PTH target gene transcription in osteoblasts.

Received for publication, December 12, 2002 , and in revised form, May 9, 2003.

^* The research was supported by National Institutes of Health Grant R01-DE13316. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Diagnostic and Surgical Sciences, Rm. 53-068 CHS, UCLA, School of Dentistry, Los Angeles, CA 90095-1668. Tel.: 310-825-5712; Fax: 310-206-6485; E-mail: sotirist{at}dent.ucla.edu.

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