Osteoporosis is a major women's health problem in the postmenopausal period and also in extreme old age. Estrogen prevents bone loss, with recent data suggesting that estrogens directly suppress cytokine-mediated osteoclast differentiation and bone resorption. Circulating estrogen levels, however, do not distinguish normal postmenopausal from osteoporotic women, but there are data showing that serum levels of the adrenal steroidal precursor, dehydroepiandrosterone sulfate (DHEAS) are lower in osteoporotics.Increased body weight and fat, moreover, are protective of bone after menopause. In postmenopausal women, adipose tissue is the main site of estrogen production.It is possible that fat in marrow as well may provide a source of estrogen that exerts a paracrine effect on bone metabolism. The overall goal of this proposal is to determine whether differences in marrow biology play a role in the pathophysiology of osteoporosis. The applicants have established a new cell culture system using bone marrow harvested from discarded femurs at the time of total hip replacement. Marrow biosynthesis of estrogen, aromatase expression, cytokine production, and osteoclastogenesis will be assessed in vitro for normal (traumatic fracture) and osteoporotic women who come to surgery.Trabecular bone samples taken from the surgical site will be examined for osteoclast number. Subjects will be characterized for bone mineral density (BMD), body fat, and serum steroid levels, and will be controlled for risk factors associated with osteopenia.
Specific Aim I will test the hypothesis that women with reduced bone density or osteoporotic fractures will show low estrogen production by marrow. The investigators will measure aromatase mRNA expression and estrogen synthesis in marrow from osteoporotic and age-matched, nonosteoporotic women who present for surgery. They will relate substrate availability, [DHEAS], to these measures. They will also determine whether there are correlations between marrow estrogen production and BMD or body fat.
In Specific Aim II the applicants will test the hypothesis that cytokine production and osteoclastogenesis in vitro are elevated in marrow from osteoporotic women and are correlated with BMD and body fat composition, marrow estrogen biosynthesis, and osteoclast count in trabecular bone.
In Specific Aim III they will test the hypothesis that cytokine production and osteoclastogenesis can be modulated by estrogen, DHEA[S], or androgen in vitro. The resulting information would represent a major step in understanding the pathogenesis of osteoporosis and why some women do to not show increased bone loss and fractures with age.
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