HORMONAL CONTROL OF CYTOKINES IN BONE AND MARROW CELLS

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Work leading to this application indicates that the IL-6 gene is transcriptionally regulated by both classes of sex steroids and plays a critical role in the bone loss of gonadal function; that estrogens and androgens also downregulate the expression of the ligand-binding and the signal transducing components of the IL-6 receptor; and that their loss enhances the responsiveness of osteoclast precursors to IL-6 and IL-11, and upregulates osteoblast development. Based on this evidence, it is proposed that IL-6, and other members of the cytokine subfamily that share gp130 for the transduction of their signals, are capable of stimulating not only osteoclast, but also osteoblast, development. The production of IL-6, as well as the action of IL-6 and the action of other members of this cytokine subfamily, is under the inhibitory control of sex steroids. Removal of these inhibitory effects contributes to the increased bone remodeling and the bone loss associated with loss of gonadal function. To test this hypothesis, the mechanism(s) underlying the downregulating effects of estrogens and androgens on the transcription of the genes for IL-6, the ligand-binding subunit of the IL-6 receptor (gp80), and the signal transducing subunit (gp130) will be elucidated by identifying the cis-acting regulatory elements involved and their corresponding transcription factors. Further, the effects of sex steroids on the production of the soluble IL-6 receptor will be studied and cells expressing the mRNAs for IL-6, gp80 and gp130 in ex vivo murine bone marrow cultures and undecalcified cancellous bone sections from sex steroid replete and sex steroid deficient mice will be identified, using in situ RT-PCR in combination with immunohistochemistry. In addition, the role of the IL-6 subfamily of cytokines in the upregulation of osteoblast progenitor formation in the bone marrow following loss of sex steroids, and potential interactions between these cytokines and other growth factors on osteoblastogenesis will be investigated. Finally, chimeric constructs of the soluble IL-6 or CNTF receptor alpha, complexed with monoclonal antibodies recognizing cell surface markers, will be used to selectively direct the corresponding cytokines to either osteoclast or osteoblast progenitors; and investigate the effects of such manipulation on osteoclastogenesis and osteoblastogenesis.