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 osteoblasts, cells that produce new bone, and osteoclasts, cells that break down bone. Osteoblasts 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 activate signaling pathways. Adenylyl cyclase and phospholipase C were previously recognized as signaling molecules activated by PTH-receptor interactions. Work from our laboratory has identified phospholipase D as an additional signaling intermediate for PTH in osteoblasts. We have found that the activation of phospholipase D by PTH occurs through the heterotrimeric proteins of the Galpha12 and Galpha13 family and the small G protein RhoA. We have shown that stimulation of the pathway by PTH in osteoblastic cells leads to activation of protein kinase C-alpha and increased IL-6. We also determined that RhoA is important for the survival of osteoblasts and for the maintenance of the actin cytoskeleton in the cells. Our ongoing studies are determining further roles of the pathway in osteoblasts and assessing the importance of the identified responses in the normal function and pathophysiology of bone. Another aspect of our osteoblast research addresses the question of why metastases from prostate cancer elicit abnormal and excessive bone formation. We have found that prostate cancer cells promote 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, in order to understand their function and to identify therapeutic targets. Osteoclasts are activated by the cytokine RANKL, resulting in resorption of bone. We observed that the resorption of bone in vitro is inhibited by cyclosporine A and FK506, inhibitors of the calcineurin-NFAT signaling pathway. In collaborative studies with Dr. Neil Clipstone, we found that ectopic expression of a constitutively active NFATc1 mutant in RAW 264.7 cells, a monocyte/macrophage precursor line, results in the rapid development of multinucleated cells having the phenotype of osteoclasts, including the ability to resorb a calcified substrate. We are interested in identifying factors in NFAT mutant cells that mediate the osteoclastogenesis. We are also interested in the role of the NFAT pathway in preventing apoptosis of the osteoclasts, since many of the currently used antiresorptive therapies induce osteoclast apoptosis.

In other studies we are investigating the effects of estrogen and androgen on osteoblasts and osteoclasts to determine whether there are sex-related differences in how the bone cells respond to each of these hormones.

Kazmers, N.H., Ma, S.A., Yoshida, T., Stern, P.H. 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, 4:52-60, 2009.

Yoshida, T., Clark, M.F., Stern, P.H. The small GTPase RhoA is crucial for MC3T3-E1 osteoblastic cell survival. J. Cell. Biochem. 106:896-902, 2009.

Singh, A.T.K., Gilchrist, A., Voyno-Yasenetskaya, T., Radeff-Huang, J.M., Stern, P.H. G(alpha)12/G(alpha)13 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 NF(kappa)B ligand protein expression in UMR-106 cells is differentially regulated by parathyroid hormone and calcitriol. J Cell. Biochem., 95:1029-1041, 2005.

Radeff, J.M., Nagy, Z., Stern, P.H. 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. 11:1882-1891, 2004.

Hirotani, H., Tuohy, N.A., Woo, J-T., Stern, P.H., Clipstone, N.A. The calcineurin/NFAT signaling pathway regulates osteoclastogenesis in RAW264.7 cells. J. Biol. Chem., 279:13984-13992, 2004.

Bhattacharyya, R.S. and Stern, P.H. IGF-I and MAP kinase involvement in the anabolic effects of LNCaP prostate cancer cell conditioned media on MC3T3-E1 osteoblastic cells. J. Cell. Biochem., 90 (5) 925-937, 2003.

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