Gα₁₂/Gα₁₃ subunits of heterotrimeric G proteins mediate parathyroid hormone activation of phospholipase D in UMR-106 osteoblastic cells.
Endocrinology, 146:2171-2175,2005.


Dossing, D.A., Stern, P.H.
Receptor activator of NFkB ligand protein expression in UMR-106 cells is differentially regulated by parathyroid hormone and calcitriol.
J Cell. Biochem., 95:1029-1041,2005.

   Paula H. Stern

The research interests of my laboratory are in bone cell biology/endocrine pharmacology. The maintenance of bone involves a delicate balance between the actions of systemic hormones, local cytokines and growth factors, and physical forces. Disorders that interfere with, amplify, or mimic the effects of these factors can result in abnormal bone remodeling and elicit pathological conditions that result in increased susceptibility to fracture. The research in my laboratory seeks to define the pathways that lead to the responses to these factors, in order to identify new potential targets for therapy. Studies are being carried out in both osteoblasts, cells that produce new bone, and osteoclasts, cells that break down bone. Osteoblasts can also activate osteoclasts through production of local factors that promote osteoclast formation, activity and survival.
Our studies on osteoblasts have focused on parathyroid hormone (PTH) signaling. PTH can promote both the formation and resorption of bone. Intermittent stimulation by PTH promotes bone formation, likely through the local production of growth factors. Continuous stimulation by PTH promotes resorption through the local production of the osteoclast-stimulatory cytokines RANKL and interleukin-6 (IL-6). PTH acts through specific receptors to initially increase signaling molecules. Increased adenylyl cyclase and increased phospholipase C have been recognized as pathways activated by PTH-receptor interactions. Work from our laboratory has identified phospholipase D as an additional signaling pathway for PTH in osteoblasts. We have shown that activation of phospholipase D by PTH leads to activation of protein kinase C-alpha and increased IL-6 in osteoblastic cells. We have also found that the upstream activation of phospholipase D by PTH occurs through the small G protein Rho A and heterotrimeric proteins of the G-alpha 12 and G-alpha 13 family. We are currently investigating the role of this newly-recognized pathway in PTH-stimulated anabolic effects of PTH on bone.
Another aspect of our osteoblast research addresses the question of why metastases from prostate cancer promote abnormal and excessive bone formation. We have found that prostate cancer cells produce factors that cause osteoblast proliferation through the growth factor, insulin-like growth factor and through the MAP kinase signaling pathway.
We are also carrying out studies on signaling in osteoclasts. RANKL activates osteoclasts, resulting in resorption of bone. We observed that the resorption of bone in vitro could be inhibited by cyclosporine A and FK506, which inhibitors of the calcineurin-NFAT signaling pathway. In collaborative studies with Dr. Neil Clipstone, we have found that ectopic expression of a constitutively active NFATc1 mutant in the RAW 264.7 cell line, a monocyte/macrophage precursor line, results in the rapid development of multinucleated cells with the phenotype of osteoclasts, including the presence of the marker TRAP, calcitonin receptor mRNA, and the ability to resorb a calcified substrate. In ongoing studies we are determining factors produced by the cells expressing the NFAT mutant that might mediate the osteoclastogenesis. We are also determining the role of the NFAT pathway in preventing apoptosis of the osteoclasts, since many of the currently used antiresorptive therapies induce osteoclast apoptosis.


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