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Submitted on June 7, 2002
Accepted on September 9, 2002
1 Skeletal Biotechnology Laboratory, Hebrew University-Hadassah Medical Center, Jerusalem, Israel (S.Z., G.T., D.G.); University of California, San Francisco, CA USA (D.C.L.); University of Texas Health Science Center, San Antonio, TX USA (S.E.H.); Women's Health Research Institute, Wyeth Research, Collegeville, PA USA (B.S.K, P.V.N.B.)
* To whom correspondence should be addressed. E-mail: dgaz{at}cc.huji.ac.il.
Estrogens exert their physiological effects on target tissues by interacting with the estrogen receptors, ER
and ERß. Estrogen replacement is one the most common and effective strategies used to prevent osteoporosis in postmenopausal women. Whereas it was thought that estrogens work exclusively by inhibiting bone resorption, our previous results show that E2 increases mouse BMP-2 mRNA, suggesting that estrogens may also enhance bone formation. In this study, we used quantitative real-time RT-PCR analysis to demonstrate that estrogens increase BMP-2 mRNA in mouse Mesenchymal Stem Cells (MSCs). The SERMs, Tamoxifen, Raloxifene and ICI failed to enhance BMP-2 mRNA, whereas ICI inhibited E2 stimulation of expression. To investigate if estrogens increase BMP-2 expression by transcriptional mechanisms and if the response is mediated by ER and/or ERß, we studied the effects of estrogens on BMP-2 promoter activity in transient tranfected C3H10T1/2 cells. E2 produced a dose-dependent induction of the mouse -2712 BMP-2 promoter activity in cells cotransfected with ER and ERß. At a dose of 10 nM E2, ER induced mouse BMP-2 promoter luciferase activity 9-fold, while a 3-fold increase was observed in cells cotransfected with ERß. Tamoxifen and raloxifene were weak activators of the mouse BMP-2 promoter via ER, but not via ERß. ICI blocked the activation of BMP-2 promoter activity by E2 acting via both ER and ERß, indicating that mouse BMP-2 promoter activation is ER dependent. In contrast to E2 and SERMs, the phytoestrogen, genistein was more effective at activating the mouse BMP-2 promoter with ERß, compared with ER. Using a deletion series of the BMP-2 promoter we determined that AP-1 or Sp1 sites are not required for E2 activation. A mutation in a sequence at -415 to -402 (5'-GGGCCActcTGACCC-3') that resembles the classical ERE abolished the activation of the BMP-2 promoter in response to E2. Our studies demonstrate that E2 activation of mouse BMP-2 gene transcription requires ER or ERß acting via a variant ERE binding site in the promoter, with ER being the more efficacious regulator. Estrogenic compounds may enhance bone formation by increasing the transcription of the BMP-2 gene.
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