Osteoporosis is a major public health problem among post-menopausal women and the elderly. It is characterized by a reduction in bone mass, and leads to fractures, skeletal deformities and chronic pain. Although the pathogenesis is complex, the fall in circulating estrogen levels at the time of menopause is an important etiologic factor. One effect of estrogen appears to be to protect the skeleton from the resorptive action of parathyroid hormone (PTH). Estrogen withdrawal at menopause thus increases the sensitivity of the skeleton to PTH, causing mobilization of calcium and bone loss. Therefore understanding the mechanism of bone-resorption, especially that induced by PTH, will be important to understanding the pathogenesis of osteoporosis. The cellular mechanisms of PTH-induced bone resorption are unclear. One hypothesis is that PTH-stimulated osteoblasts release cytokines which activate osteoclasts or osteoclast precursors. Although the nature of these cytokines is unknown, the colony stimulating factors (CSF's) may play an important role by stimulating proliferation of osteoclast precursors. Of the CSF's, only for colony stimulating factor-1 (CSF-1) is there convincing evidence supporting a role in bone remodelling. This evidence includes that deficiency of CSF-1 in vivo causes osteopetrosis in mice, - that CSF-1 stimulates osteoclast formation in vitro, and finally, our observation that CSF-1 is the principal colony stimulating activity secreted by osteoblasts in response to PTH. Although mounting evidence suggests a critical role for CSF-1 in osteoclast development, little is known about of its regulation and mechanism of action of bone. The goals of the present proposal are therefore: 1) to study the regulation of PTH-induced CSF-1 production in osteoblasts by examining the mechanism of PTH-induced up-regulation of CSF-1 gene expression, and by examining intra-cellular signalling mechanisms involved in CSF-1 secretion; 2) to examine CSF-1 production by osteoblasts in response to other bone-resorbing agents; 3) to determine the role of CSF-1 in bone resorption using organ culture systems; and 4) to characterize the expression of the CSF-1 receptor in osteoclasts, and examine its regulation by osteotropic agents. We expect that these studies will help clarify CSF-1's role in bone remodelling, which may be an important factor in the pathogenesis of osteoporosis.
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