Estrogen (Es) plays a fundamental role in regulating the growth and maintenance of the skeleton. Es deficiency results in osteopenia and is an important contributing factor to the increased fracture risk in aging women. Es replacement therapy can reduce the fracture risk in postmenopausal women by preserving bone mass but the potential health risks of treatment include increased incidence of breast and uterine cancer. It may be possible to minimize the complications of Es replacement with tissue-specific partial Es agonists. The """"""""antiestrogen"""""""" tamoxifen (TAM) is an example of an Es analog that is an Es antagonist on the uterus under treatment conditions for which it is an agonist on the skeleton. The mechanism for the mixed Es agonist/antagonist effects of TAM are unknown. Furthermore, in spite of its important clinical manifestations, the mechanisms and even precise actions of Es on bone cells are unknown. We intend to test the hypothesis that the effects of Es to inhibit bone turnover are mediated by osteoblast-derived growth factors. Although Es may influence multiple growth factors, we will concentrate our efforts on insulin-like growth factor-I (IGF-I). IGF-I is produced by and has effects on bone cells and has been shown to mediate many of the effects of Es on normal uterine and liver cells as well as on breast cancer cells. The differences in the response of bone and uterus to TAM may result from the differential regulation of IGF-I expression in the respective tissues. Also, the pronounced opposing actions of Es and growth hormone (GH) on bone growth may be due to opposing regulation of IGF-I expression by the respective hormones. We will test these possibilities in rats by: 1) determining the effects of Es and TAM on IGF-I expression in bone and uterus, 2) localizing the cells that express IGF-I in bone, 3) establishing whether the pronounced inhibitory effects of Es and TAM on bone matrix synthesis are counteracted with IGF-I, and 4) determining whether Es and TAM interact with GH to regulate IGF-I expression. The results of the proposed studies are expected to increase our understanding of the mechanisms by which Es modulates numbers and activities of bone cells, information that could accelerate the rational design of innovative approaches for the prevention and/or treatment of postmenopausal bone loss.
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