Treatment of osteopenic disorders has relied, to-date, on anti-resorptive drugs such as estrogens and bisphosphonates. While these agents often retard progressive bone loss, they are not effective in reversing the established osteoporotic lesion, nor are they typically capable of curing patients already afflicted with the disease. The dramatic effect of parathyroid hormone as a potential clinical bone anabolic drug underscores the hypothesis that substantial enhancement of skeletal mass requires stimulation of bone formation. Thus, identification of molecules, which promote systemic osteogenesis, is a major focus of anti-osteoporosis research. We have made the surprising observation that the key osteoclastogenic cytokine, RANK ligand (RANKL), when administered subcutaneously as a GST-fusion protein, is a potent bone anabolic agent. This compound dramatically enhances osteoblastogenesis and, within one week, stimulates exuberant bone formation, as detected radiographically, histologically and densitometrically. Importantly, GST-RANKL, at doses inducing as much as a 25-fold increase in osteoblast (OB) number, does not promote osteoclastogenesis in vivo. We also have established that OBs, and their precursors, are direct targets of GST-RANKL and have shown that collagen type I synthesis, by these cells, is greatly accelerated when they are exposed to the fusion protein. These data position GST-RANKL, or its derivatives, as potential bone anabolic, anti-osteoporosis agents. We therefore hypothesize that (1) GST-RANKL enhances OBs function by distinct signal pathways; (2) GST-RANKL, transcriptionally and/or post-transcriptionally, induces collagen type I synthesis by OBs; and (3) GST-RANKL prevents and/or reverses osteoporosis.
Our Specific Aims are therefore to: (1) identify the signal pathways by which GST-RANKL enhances OB function; (2) identify the mechanism by which GST-RANKL induces collagen type I synthesis by OBs; and (3) determine if GST-RANKL prevents and/or reverses osteoporosis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Orthopedics and Musculoskeletal Study Section (ORTH)
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Sharrock, William J
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Washington University
Schools of Medicine
Saint Louis
United States
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Bush, Jason A; Kitaura, Hideki; Ma, Yuliang et al. (2012) Comparative proteomic analysis of a cytosolic fraction from ?3 integrin-deficient cells. Cancer Genomics Proteomics 9:1-13
Kim, Hyun-Ju; Zou, Wei; Ito, Yuji et al. (2010) Src-like adaptor protein regulates osteoclast generation and survival. J Cell Biochem 110:201-9
Bai, Shuting; Kopan, Raphael; Zou, Wei et al. (2008) NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem 283:6509-18
Zou, Wei; Kitaura, Hideki; Reeve, Jennifer et al. (2007) Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J Cell Biol 176:877-88
Sprague, Jennifer E; Kitaura, Hideki; Zou, Wei et al. (2007) Noninvasive imaging of osteoclasts in parathyroid hormone-induced osteolysis using a 64Cu-labeled RGD peptide. J Nucl Med 48:311-8
Teitelbaum, Steven L (2007) Osteoclasts: what do they do and how do they do it? Am J Pathol 170:427-35
Takeshita, Sunao; Faccio, Roberta; Chappel, Jean et al. (2007) c-Fms tyrosine 559 is a major mediator of M-CSF-induced proliferation of primary macrophages. J Biol Chem 282:18980-90
Feng, Yunfeng; Zhao, Haibo; Luderer, Hilary F et al. (2007) The LIM protein, Limd1, regulates AP-1 activation through an interaction with Traf6 to influence osteoclast development. J Biol Chem 282:39-48
Faccio, Roberta; Takeshita, Sunao; Colaianni, Graziana et al. (2007) M-CSF regulates the cytoskeleton via recruitment of a multimeric signaling complex to c-Fms Tyr-559/697/721. J Biol Chem 282:18991-9
Zhou, Ping; Kitaura, Hideki; Teitelbaum, Steven L et al. (2006) SHIP1 negatively regulates proliferation of osteoclast precursors via Akt-dependent alterations in D-type cyclins and p27. J Immunol 177:8777-84

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