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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG014917-03
Application #
2855846
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Sharrock, William J
Project Start
1997-01-15
Project End
1999-08-31
Budget Start
1999-01-01
Budget End
1999-08-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Mcp Hahnemann University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19102
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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
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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
Zaidi, Mone (2005) Neural surveillance of skeletal homeostasis. Cell Metab 1:219-21

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