PARATHYROID HORMONE-OSTEOBLAST MODULATED BONE RESORPTION

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Osteopenia is a major cause of morbidity and mortality in an aging population, yet its precise pathophysiology remains unclear. Since bone resorption increases as individuals age, the mechanism of control of the osteoclast, the primary resorbing cell of the skeleton, is of tremendous importance. Despite these observations, the mechanisms by which bone seeking agents, such as parathyroid hormone (PTH), activate osteoclasts are unknown. Such agents can theoretically stimulate resorption by 1) a direct interaction with osteoclasts, 2) enhancement of differentiation of osteoclast precursors or 3) interaction with an intermediary (modulator) cell which can in turn stimulate osteoclastic activity and/or promote osteoclast differentiation. Available evidence suggests that parathyroid hormone enhances resorption via modulator cells. We propose that osteoblasts have the capacity to modulate parathyroid hormone induced bone absorption because 1) they produce agents which stimulate osteoclasts, 2) osteoblasts bind parathyroid hormone and are responsive to the hormone and 3) bone resorption by isolated macrophages (surrogate osteoclasts) is not stimulated by the PTH unless osteoblasts are also present. This proposal is directed toward examining the mechanisms by which parathyroid hormone stimulates osteoblast modulated bone resorption. The initial studies will address the isolation of the factor produced by osteoblasts in response to parthyroid hormone which is capable of increasing bone resorption. Other studies will address the mechanisms by which this effect takes place both at a biochemical and cellular level. The studies will also address the modulation of this response in osteoblasts by other hormones as well as the modulation of the response of the resorbing cell. These experiments will focus on the properties of the various cell types which are known to enhance their capacity to degrade bone matrix. These properties include a) enhance differentiation of immature macrophages, b) enhancement of the capacity of resorptive macrophages to bind the bone, c) enhanced multinucleation of macrophages and d) increased macrophage number.