EFFECTS OF ORAL ESTRADIOL THERAPY ON OSTEOCLASTOGENESIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our understanding of the mechanisms by which estrogens regulate bone cells are incomplete. This process is important because estrogen loss by women after menopause and probably in hypogonadal men produces a relatively rapid decrease in bone mass and predisposes susceptible individuals to the development of the disease osteoporosis. This translational project is the result of a collaboration between basic and clinical scientists at the University of Connecticut Health Center (UCHC) whose work focuses on the identification of the mechanisms by which human beings develop the disease osteoporosis. Our specific goal in this pilot project is to examine the differences in cellular and molecular changes that occur in the bone marrow of sex steroid-replete and deficient older men and postmenopausal women in response to estrogen, as preliminary data in mice demonstrates the importance of this hormone. In preliminary work we have found that ovariectomy in mice is rapidly followed by an increase in the ability of bone marrow cells to differentiate into osteoclasts, the cells that mediate bone resorption. This finding suggests that regulates the ability of hematopoietic precursor cells to differentiate into osteoclasts, a process that has not been adequately examined. Since increased rates of bone resorption appear to be the earliest known effects of estrogen withdrawal on the human skeleton, a better understanding of this process may lead to more effective therapies for the treatment of osteoporosis in both men and women. Specific Aim 1:Examine the osteoclastogenic potential of each of these three groups of older men by evaluation of bone marrow aspirates both before and after treatment with Estrogen (E2). Specific Aim 2: Examine parameters of B-lymphocyte lineage development and osteoclast formation in cells from bone marrow including markers of B-lymphocyte lineage development, and the percentage of early and mature B-lymphocytes in the bone marrow before and after E2 treatment. These studies will also evaluate the ability of fractionated (CD19+ and CD19-) bone marrow cells to form osteoclasts-like cells in vitro with and without treatment with receptor activator of NF-kappa B-ligand (RANKL) and monocyte- colony stimulating factor (M-CSF). Specific Aim 3: Examine the expression in the bone marrow of factors known to influence osteoclast formation including messenger ribonucleic acid (RNA) for RANKL, receptor activator of NF-kappa B (RANK), osteoprotegerin (OPG), M-CSF and the M-CSF receptor (c-Fms). We will also measure protein levels of RANK and c-Fms by flow cytometry.