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[摘要]：Osteoblasts are controlled by the individual and combined effects of systemic and local growth regulators. Here we show functional and physical interactions between estradiol (17 beta E) and Wnt activated pathways in osteoblasts. 17 beta E increased gene promoter activity by the Wnt pathway transcriptional effector T cell factor (TCF) in an estrogen receptor (ER) dependent way. This occurred independently of its activity through traditional estrogen response elements and was not replicated by androgen receptor activation. 17 beta E also increased the stimulatory effect of LiCl on TCF activity, LiCl increased the stimulatory effect of 17 beta E through estrogen response elements, and both were further enhanced by a noncanonical Wnt receptor agonist (WAg) that functions independently of beta-catenin stabilization. In contrast to LiCl, WAg increased DNA synthesis and reduced relative collagen synthesis and alkaline phosphatase activity in otherwise untreated or 17 beta E stimulated cells. In addition, WAg suppressed Runx2, osterix, and alkaline phosphatase mRNA levels, and potently induced osteoprotegerin mRNA, whereas LiCl was ineffective alone and inhibitory in combination with 17 beta E. A definitive intersection between the 17 beta E and Wnt pathways occurred at the protein level, where ER alpha physically associated with TCF-4 independently of its beta-catenin binding domain. This interaction required ligand-dependent exposure of a TCF binding region that mapped to ER alpha domain E and was further enhanced by Wnt pathway activation. Our studies reveal highly focused co-regulatory effects between the 17 beta E and Wnt pathways in osteoblasts that involve activated ER alpha and TCF-4 and downstream changes in gene expression, osteoblast proliferation, and differentiated cell function. (C) 2011 Elsevier B.V. All rights reserved. |
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