IL-6 AND ESTROGEN AND PTH INDUCED BONE RESORPTION

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DESCRIPTION (Taken from the applicant's Abstract): Osteoporosis is an important disease of aging. The age-specific incidence of Osteoporosis is an important disease of aging. The age-specific incidence of the disease is table or increasing, and when this is coupled with the greater number of older Americans in the at risk population, it is clear that the prevalence of this disease will rise for the foreseeable future. Already nearly one million fractures occur annually in persons over the age of 65, and the vast majority of these are due to osteoporosis. Osteoporosis is due to the permanent loss of otherwise normal bone from the skeleton. Of the various subtypes of this disease, postmenopausal osteoporosis is by far the most common. Increased bone resorption is the principle mechanism for bone loss in postmenopausal osteoporosis, and recent evidence indicates that rates of bone resorption are important predictors of bone mass in older individuals. Parathyroid hormone (PTH) is the principle regulator of bone resorption on a day to day basis, and increasing sensitivity to PTH may underlie the increased bone resorption seen in osteoporosis. We have demonstrated that the pro-resorptive cytokine, IL-6, is regulated by PTH in vitro and in vivo and plays a crucial role in mediating the resorptive actions of PTH. Thus we have recently shown that circulating levels of IL-6 are elevated in states of parathyroid excess, are low in hypoparathyroidism, and correlate strongly with markers of bone resorption in patients with primary hyperparathyroidism. In experimental animals, we have demonstrated that PTH infusions cause serum IL-6 levels to rise and that neutralizing antisera to IL-6 block PTH-induced increases in bone resorption. Finally, in both cultured bone cells and mice, we have demonstrated that estrogen withdrawal increases IL-6 production in response to PTH. We hypothesize that IL-6 is an important mediator of PTH's resorptive actions in bone and that in the estrogen deficient state, PTH-dependent IL-6 production increases. To test this hypothesis: (1) We will examine the response of postmenopausal women to an infusion of PTH, before and after estrogen replacement, to determine if estrogen affects PTH-induced changes in IL-6. (2) We will determine whether neutralizing IL-6 in vivo blocks PTH-induced bone loss in mice and whether IL-6 knock-out mice do not lone bone in response to PTH, we will also examine if ovariectomy augments PTH-induced bone loss and PTH-induce increases in circulating IL-6 in mice. (3) We will study the molecular mechanism of the PTH-induced increase in IL-6 production by bone cells and the modulating effect of estrogen on this process.