Osteoporosis affects almost 40% of the postmenopausal white women and much of the osteoporosis morbidity and mortality is caused by proximal femur fractures. It is estimated that 347,000 hip fractures will occur annually due to the demographic changes in the US population and the annual expenditure will reach 31 to 62 billion dollars by the year of 2020. Hence, there is an urgent need to enhance our understanding of the pathogenesis of osteoporosis at a molecular level and to provide effective treatments for people who are affected. It was shown that mice that received ovariectomy had a dramatic increase in osteoclast activity and this increase was found to be caused by overexpression of interleukin6 (IL-6), a member of the pro- inflammatory cytokine family. In addition, estrogen was shown to suppress the IL6 promoter activity induced by transcriptional activator NFkB in vitro, although estrogen does not act the IL-6 promoter directly. It was recently shown that ER binds to the p65 subunit of the NFkB and this physical association prevents NFkB from binding to the kB motifs in the IL promoter region. NFkB is kept in an inactive state in the cytoplasm by its inhibitor I beta kappa alpha. Upon extracellular stimulation, I kappa beta alpha is degraded rapidly and freed Nf kappa beta translocates into the nucleus to activate responsive genes, such as IL-6. The depleted I kappa B alpha is replenished quickly since NFkB also actives the transcription of its inhibitor. Our preliminary results showed that estrogen inhibited the signal-induced protein degradation of I kappa beta alpha. In addition, estrogen inhibited the signal-induced upregulation of I kappa beta alpha transcription. Based on our results and the current understanding of the NF kappa beta/I kappa beta alpha signal transduction pathway, we hypothesize that estrogen/ER bind to the I kappa beta alpha/NF kappa beta complex in cytoplasm and this association prevents phosphorylation and ubiquitination of I kappa beta alpha, which are prerequisites for its proteolysis. At the transcriptional level, estrogen/ER may Inhibit I kappa beta alpha transcription by binding to NFKappa beta and inhibiting its DNA binding activity. To test our hypotheses, we propose to determine 1) if estrogen inhibits the phosphorylation and ubiquitination of II kappa beta alpha and 2) if estrogen mediates its effect on the stability of I kappa beta alpha protein and its mRNA level through a protein-protein interaction. We hope that our research will provide an explanation for the estrogen effect on bone resorption and that our findings may translate into potential clinical application for osteoporosis.
| Sun, W H; Keller, E T; Stebler, B S et al. (1998) Estrogen inhibits phorbol ester-induced I kappa B alpha transcription and protein degradation. Biochem Biophys Res Commun 244:691-5 |
