The overall goal of this research is to extend our understanding of the mechanisms of action of hormones on bone. The approaches include a) biochemical studies of second messenger pathways in bone and changes in these pathways in response to calcemic hormones and b) pharmacological studies utilizing agents that affect these metabolic pathways in other tissues to determine their influence on bone resorption. The proposed studies would examine the functional significance of effects of parathyroid hormone (PTH) and other calcemic hormones on bone phospholipid metabolism. Studies to date indicate that concentrations of PTH and thrombin that are equieffective in stimulating resorption in vitro show marked differences their stimulation of inositol phosphate production, thrombin being the more effective agent. The proposed studies would further examine the effects of PTH and thrombin on bone phospholipid and calcium metabolism. Changes in inositol phosphates, inositol phospholipids, and diacylglycerol would be more fully characterizes in bone organ cultures, normal bone cells and osteosarcoma-derived cells. The cells would also be used to determine whether these agents differ in their effects on intracellular calcium. Possible bases for the observed differences in inositol phosphate production would be explored, including altered phosphatase activity, and the relative increases in cyclic AMP elicited by PTH and thrombin. The possibility that the changes in inositol phosphates are related to bone formation rather than resorption will be examined. Studies similar to those carried out with PTH and thrombin would be extended to other stimulators of resorption, including growth factors and cytokines. Pharmacological agents whose effects on resorption could be due to altered cellular calcium metabolism (e.g. tamoxifen, cyclosporine, and milrinone) will be tested for their effects on the Ca/phosphatidylinositol pathway. Agents shown to affect the pathways of phosphatidylinositol metabolism and protein kinase C (including RO 59 022 and bryostatin) will be examined for their effects on bone resorption and formation. Upgrading of presently available HPLC capabilities would permit measuremnt of newly recognized and potentially important inositol phosphate metabolites. The described studies should increase our understanding of the role of the calcium second messenger systems in the action of hormones on bone.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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General Medicine B Study Section (GMB)
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Northwestern University at Chicago
Schools of Dentistry
United States
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Wang, J; Stern, P H (2011) Dose-dependent differential effects of risedronate on gene expression in osteoblasts. Biochem Pharmacol 81:1036-42
Wang, J; Gilchrist, A; Stern, P H (2011) Antagonist minigenes identify genes regulated by parathyroid hormone through G protein-selective and G protein co-regulated mechanisms in osteoblastic cells. Cell Signal 23:380-8
Wang, Jun; Stern, Paula H (2010) Osteoclastogenic activity and RANKL expression are inhibited in osteoblastic cells expressing constitutively active G?(12) or constitutively active RhoA. J Cell Biochem 111:1531-6
Yoshida, Tomohiko; Clark, Mary F; Stern, Paula H (2009) The small GTPase RhoA is crucial for MC3T3-E1 osteoblastic cell survival. J Cell Biochem 106:896-902
Kazmers, Nikolas H; Ma, Sophia A; Yoshida, Tomohiko et al. (2009) Rho GTPase signaling and PTH 3-34, but not PTH 1-34, maintain the actin cytoskeleton and antagonize bisphosphonate effects in mouse osteoblastic MC3T3-E1 cells. Bone 45:52-60
Singh, A T K; Gilchrist, A; Voyno-Yasenetskaya, T et al. (2005) G alpha12/G alpha13 subunits of heterotrimeric G proteins mediate parathyroid hormone activation of phospholipase D in UMR-106 osteoblastic cells. Endocrinology 146:2171-5
Dossing, Debra A; Stern, Paula H (2005) Receptor activator of NF-kappaB ligand protein expression in UMR-106 cells is differentially regulated by parathyroid hormone and calcitriol. J Cell Biochem 95:1029-41
Singh, Amareshwar T K; Frohman, Michael A; Stern, Paula H (2005) Parathyroid hormone stimulates phosphatidylethanolamine hydrolysis by phospholipase D in osteoblastic cells. Lipids 40:1135-40
Radeff, Julie M; Nagy, Zsolt; Stern, Paula H (2004) Rho and Rho kinase are involved in parathyroid hormone-stimulated protein kinase C alpha translocation and IL-6 promoter activity in osteoblastic cells. J Bone Miner Res 19:1882-91
Radeff, Julie M; Singh, Amareshwar T K; Stern, Paula H (2004) Role of protein kinase A, phospholipase C and phospholipase D in parathyroid hormone receptor regulation of protein kinase Calpha and interleukin-6 in UMR-106 osteoblastic cells. Cell Signal 16:105-14

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