During bone resorption, an osteoclast generates and, as a consequence, becomes exposed to millimolar Ca2+ levels. The goal of the present study is to define pathways through which changes in extracellular Ca2+, and corresponding changes in intracellular Ca2+, are transduced first into changes in intranuclear Ca2+, and then into alterations in gene expression. Notably, the osteoclast plasma membrane represents a unique site for the location of a ryanodine receptor. Ryanodine receptors are Ca2+-permeable channels that normally reside in microsomal membranes. However, in the osteoclast, a plasma membrane-resident, type II, ryanodine receptor isoform serves to sense changes in extracellular Ca2+, hence the term Ca2+ sensor. It has been shown recently that ryanodine receptors are also located in nuclear membranes at which site they gate the flux of Ca2_+ into the nucleoplasm. By making separate measurement of nuclear envelope and nucleoplasmic Ca2+ levels, as well as by performing confocal microscopic studies using epitope-specific antisera, we first propose to determine whether Ca2+ transport across the osteoclast nuclear membrane occurs through ryanodine receptor-gated Ca2+ channels. Such studies are particularly relevant to recent observations showing that nuclear Ca2+ levels regulate gene expression directly. Thus, by applying the in situ reverse transcriptase polymerase chain reaction (RT=PCR) to isolated single osteoclasts, we propose to investigate whether Ca2+ modulates expression of the gene for the osteoclast cytokine, interleukin-6, as well as that of its receptor. Finally, we will also assess whether the secreted interleukin-6 attenuates Ca2+ sensing, a phenomenon that, we believe, should allow a resorbing osteoclast 'escape' (or recover) from Ca2+-induced inhibition. Important therapeutic implications should follow from a better understanding of mechanisms that underlie extracellular Ca2+ sensing by, and Ca2+ homeostasis in, the osteoclast.
| Sun, Li; Yang, Guozhe; Zaidi, Mone et al. (2008) TNF-induced oscillations in combinatorial transcription factor binding. Biochem Biophys Res Commun 371:912-6 |
| Iqbal, Jameel; Zaidi, Mone (2008) TNF-induced MAP kinase activation oscillates in time. Biochem Biophys Res Commun 371:906-11 |
| Sun, Li; Vukicevic, Slobodan; Baliram, Ramkumarie et al. (2008) Intermittent recombinant TSH injections prevent ovariectomy-induced bone loss. Proc Natl Acad Sci U S A 105:4289-94 |
| Sun, Li; Yang, Guozhe; Zaidi, Mone et al. (2008) TNF-induced gene expression oscillates in time. Biochem Biophys Res Commun 371:900-5 |
| Iqbal, Jameel; Kumar, Kevin; Sun, Li et al. (2006) Selective upregulation of the ADP-ribosyl cyclases CD38 and CD157 by TNF but not by RANK-L reveals differences in downstream signaling. Am J Physiol Renal Physiol 291:F557-66 |
| Hase, Hidenori; Ando, Takao; Eldeiry, Leslie et al. (2006) TNFalpha mediates the skeletal effects of thyroid-stimulating hormone. Proc Natl Acad Sci U S A 103:12849-54 |
| Iqbal, Jameel; Sun, Li; Kumar, T Rajendra et al. (2006) Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation. Proc Natl Acad Sci U S A 103:14925-30 |
| Huang, C L H; Sun, L; Moonga, B S et al. (2006) Molecular physiology and pharmacology of calcitonin. Cell Mol Biol (Noisy-le-grand) 52:33-43 |
| Iqbal, Jameel; Zaidi, Mone (2006) TNF regulates cellular NAD+ metabolism in primary macrophages. Biochem Biophys Res Commun 342:1312-8 |
| Zaidi, Mone (2005) Neural surveillance of skeletal homeostasis. Cell Metab 1:219-21 |
Showing the most recent 10 out of 32 publications
