The major focus of this application will be to use cultured normal human osteoblast-like (hOB) cells as a model system for understanding the regulation of normal osteoblast function and to provide insights on abnormal cell function in osteoporosis. Studies to develop a defined, serum-free medium for optimal cell growth will be continued since this medium should 1) enhance the production of these cells which are slow growing, labor intensive and costly, and 2) permit more accurate assessment of the effects of individual growth related agents on these cells. Our present data demonstrate the presence of estrogen receptors in hOB cells with indications of the presence of androgen and progesterone receptors. We plan to continue our analyses of the functional sex steroid receptors in the hOB cells and selected osteosarcoma lines using a nuclear binding assay, a charcoal assay, Northern blot (mRNA), and Western blot (protein) analyses. We have obtained cDNA probes to a variety of mRNAs for bone proteins, growth factors, proto-oncogenes and other steroid regulated genes including steroid receptors. We plan to screen these cDNA probes to select those which display optimal estrogen regulation. Then, using these cDNAs, we will assess in greater detail the effects of estrogens, androgens and progestins on the mRNA levels in hOB cells and in selected osteosarcoma cell lines. Studies of steroid agonism and antagonism with other sex steroids and other hormones (PTH, 1,25 dihydroxyvitamin D3, and glucocorticoids) will be performed in hOB cells. The steroid action on the levels of bone proteins will be measured in the instance the steroid regulation of the expression of these important genes occurs at the level of translation/post-translation. Finally, we plan to continue our investigations on the effects of sex steroids on the production of the transforming growth factors (TGF-a, TGF-b) and insulin-like growth factors (IGF-I adn IGF-II) in hOB cells at the level of mRNA, protein, and activity. Collaborations with Dr. Greg Mundy and coworkers, University of Texans at San Antonio, will involve studies of the interactions of estrogens with our sex steroids and with PTH to influence TGF-B production. Also in the same collaboration, the effects of conditioned media from estrogen treated hOB cells on osteoclast cell function (bone resorption) will be investigated. It is hoped that the above investigations will yield insights into bone regulatory pathways and ultimately into abnormalities of these [pathways in involutional osteoporosis resulting in better strategies for its treatment.
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