Parathyroid hormone (PTH) plays a central role in regulation of calcium metabolism but also appears to act through single receptor on the osteoblast to elicit all of its skeletal effects. In this process, PTH causes a change in osteoblastic gene expression. For instance, in response to PTH, mRNA levels for collagen and osteopontin decline while those for interleukin-6 and collagenase are markedly elevated. All of these effects are mediated by events at the transcriptional level and many have been shown to be secondary responses caused by changes in cAMP. However, the signal transduction pathway for PTH to cause these changes is not completely elucidated in any case. We and other have shown that c-fos ( a member of the activator protein-1 family of transcription factors) appears to be a primary gene regulated by PTH and cAMP which may, in turn regulate other genes. In fact, we have shown that the activator protein-1 site in the rat collagenase gen is a participant in basal and PTH-regulated promoter activity. Nevertheless, over-expression of Fos in the viral or cellular form lead to deranged, uninhibited growth of osteoblastic cells. Since PTH can be anabolic for bone, we have hypothesized that PTH-mediated changes in FOs lead to regulation of a range of genes, some involved in growth, others devoted to more differentiated phenotypes. Thus, the overall goal of the present proposal is to delineate the role of PTH-regulated Fos expression in osteoblastic cells. To test the foregoing hypothesis, we will : 1) determine whether low does of PTH stimulate growth of osteoblastic cells and if this is mediated by G(beta, gamma,i) 2) ascertain whether of growth stimulatory doses of PTH activate the mitogen-activated protein kinases, ERKs, in osteoblastic cells, 3) determine whether low doses of PTH are acting through stimulation of the serum-response element of the c-fos promoter in osteoblastic cells, 4) assess whether PTH is able to stimulate growth in the absence of Fos, 5) determine whether known PTH-regulated genes are affected by the absence of Fos, 6) identify other PTH-regulated genes requiring Fos expression. The results of this work will provide insight into one of the key pathways of regulation of the osteoblast. In so doing, the data will also provide new perspectives into treatment of disorders of calcium metabolism.
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