The long term goal of this project is to elucidate the molecular mechanism by which cytokine and estrogen regulate bone modeling, as a means of understanding the pathophysiology of postmenopausal osteoporosis. Interleukin-1 (IL-1) and tumor necrosis factor (TNF), produced by several cell types including peripheral blood monocytes, stimulate the production of other cytokines including IL-6 by bone cells of the osteoblastic/stromal lineage. These cytokines promote bone resorption by mediating the differentiation of hematopoietic stem cells into monocytes and subsequently into multinucleated osteoclasts. Estrogen is believed to suppress cytokine synthesis or secretion, or both. The role of IL-6 in bone resorption has been confirmed in IL-6-deficient mice in which bone loss caused by estrogen depletion was prevented in the absence of IL-6. Little evidence is available to explain the molecular mechanisms that underlie the regulation of cytokine circuitry in bone cells, the transduction of the cytokine signals or the cross talk between cytokine and estrogen signals in bone cells. However, in other systems IL-6, IL-1 and TNF signals are convergently modulated by the interaction of NF-IL6, a transcription factor of the CCAAT/enhancer binding protein family, and the AP-1(Fos/Jun) family transcription factors. The interaction of NF-IL6 and Fos/Jun may be particularly significant for bone, since the absence of c-fos, a major member of the AP-1 family, results in osteopetrosis. The primary objectives of this proposal are to test a hypothesis in which the cross talk between NF-IL6 and AP-1 modulates signaling by IL-6, IL-1 and TNF in bone cells, and to elucidate the mechanism of estrogen action in bone cells. To accomplish these goals , we propose to: 1. Investigate the roles of NF-IL6 and Fos/Jun in the regulation of IL-6 synthesis in cells of the osteoblastic /stromal lineage, and determine the essential role of Fos in IL- I and TNF signaling using the fos-deficient mice. 2. Identify the sites and mechanisms of estrogen action bone cells, and 3. characterize the effects of estrogen depletion on cytokine production and cytokine signaling in humans, and their relationship to osteoporosis.
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