Abstract

Bone remodeling is controlled by two cell types, the osteoblast and the osteoclast, that regulate matrix deposition and mineral resorption, respectively. Together, these two cell types control bone growth, shape, mass and strength. The intricate balance between rates of deposition and resorption is a key element in the regulation of bone remodeling and systemic Ca+2 homeostasis, both of which impact directly on the mineralized tissues of the oral cavity. Preliminary data obtained using metabolites/analogs of 1,25(OH)2D3 indicates that there are at least two separate pathways for modulation of osteoblast function by the calcitropic hormone 1,25(OH)2D3 during bone growth and remodeling including both rapid-plasma membrane-mediated events as well as slower nuclear receptor-mediated events. 1-Deoxy analogs have been identified that bind very poorly to the nuclear receptor but can activate Ca+2 channels present in the plasma membrane of the osteoblast. OUR HYPOTHESIS IS THAT BOTH RAPID MEMBRANE EFFECTS AND LONG TERM GENE ACTIVATION ARE REQUIRED TO EXPLAIN THE EFFECTS OF 1,25(OH)2D3 ON BONE CELL FUNCTION. This proposal outlines a variety of biochemical, pharmacological, electrophysiological, ion flux, and molecular biological approaches designed to dissect the regulation of osteoblast function by 1,25(OH)2D3.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE010318-02
Application #
3223840
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1992-09-01
Project End
1996-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
University of Texas Health Science Center Houston
Department
Type
Schools of Dentistry
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225

  Publications

Farach-Carson, M C; Ridall, A L (1998) Dual 1,25-dihydroxyvitamin D3 signal response pathways in osteoblasts: cross-talk between genomic and membrane-initiated pathways. Am J Kidney Dis 31:729-42
Duncan, R L; Akanbi, K A; Farach-Carson, M C (1998) Calcium signals and calcium channels in osteoblastic cells. Semin Nephrol 18:178-90
Nemere, I; Farach-Carson, M C (1998) Membrane receptors for steroid hormones: a case for specific cell surface binding sites for vitamin D metabolites and estrogens. Biochem Biophys Res Commun 248:443-9
Meszaros, J G; Farach-Carson, M C (1997) Assay of direct effect of 1,25-dihydroxyvitamin D3 on calcium ion influx into cultured osteoblasts. Methods Enzymol 282:236-43
Li, W; Duncan, R L; Karin, N J et al. (1997) 1,25 (OH)2D3 enhances PTH-induced Ca2+ transients in preosteoblasts by activating L-type Ca2+ channels. Am J Physiol 273:E599-605
Norman, A W; Okamura, W H; Hammond, M W et al. (1997) Comparison of 6-s-cis- and 6-s-trans-locked analogs of 1alpha,25-dihydroxyvitamin D3 indicates that the 6-s-cis conformation is preferred for rapid nongenomic biological responses and that neither 6-s-cis- nor 6-s-trans-locked analogs are preferred for ge Mol Endocrinol 11:1518-31
Meszaros, J G; Karin, N J; Akanbi, K et al. (1996) Down-regulation of L-type Ca2+ channel transcript levels by 1,25-dihyroxyvitamin D3. Osteoblastic cells express L-type alpha1C Ca2+ channel isoforms. J Biol Chem 271:32981-5
Meszaros, J G; Karin, N J; Farach-Carson, M C (1996) Voltage-sensitive calcium channels in osteoblasts: mediators of plasma membrane signalling events. Connect Tissue Res 35:107-11
Khoury, R S; Weber, J; Farach-Carson, M C (1995) Vitamin D metabolites modulate osteoblast activity by Ca+2 influx-independent genomic and Ca+2 influx-dependent nongenomic pathways. J Nutr 125:1699S-1703S
Liu, R; Farach-Carson, M C; Karin, N J (1995) Effects of sphingosine derivatives on MC3T3-E1 pre-osteoblasts: psychosine elicits release of calcium from intracellualr stores. Biochem Biophys Res Commun 214:676-84

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