HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 276, Issue 39, 36241-36250, September 28, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/39/36241    most recent M104319200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thirunavukkarasu, K. Articles by Onyia, J. E. Search for Related Content PubMed PubMed Citation Articles by Thirunavukkarasu, K. Articles by Onyia, J. E.

Stimulation of Osteoprotegerin (OPG) Gene Expression by Transforming Growth Factor- (TGF-)
MAPPING OF THE OPG PROMOTER REGION THAT MEDIATES TGF- EFFECTS^*

Kannan Thirunavukkarasu^¶§, Rebecca R. Miles^§¶, David L. Halladay^¶, Xuhao Yang^¶, Rachelle J. S. Galvin^¶, S. Chandrasekhar^¶, T. John Martin, and Jude E. Onyia^¶**

From ^¶ Gene Regulation, Bone and Inflammation Research, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana 46285 and  St. Vincent's Institute for Medical Research, Fitzroy, Victoria 3065, Australia

Transforming growth factor- (TGF-) regulates osteoclastogenesis and osteoclast survival, in part through the induction of osteoprotegerin (OPG), a protein known to inhibit osteoclast formation and function. To explore the molecular basis of TGF- regulation of OPG expression, we evaluated the effects of TGF- on osteoclast formation, OPG protein secretion, mRNA expression, and gene transcription. The marked inhibitory effect of TGF- on osteoclast differentiation was confirmed in a co-culture model utilizing murine stromal/osteoblastic BALC cells and bone marrow hematopoietic precursors. This inhibition in osteoclast differentiation was preceded by a decrease in RANKL mRNA expression (5-fold) and a reciprocal increase in OPG mRNA (6.1-fold) and protein (7.1-fold) expression in BALC cells. At the promoter/transcriptional level, TGF- treatment resulted in a 3-10-fold increase in reporter gene activity directed by a 5.9-kilobase fragment of the human OPG promoter in transfection assays performed in UMR106 cells. The effect of TGF- was mimicked by TGF-2 and -3 but not by BMP-4, suggesting a TGF- signal-specific effect. Deletion analysis revealed that a 183-base pair region (372 to 190) in the promoter was required for TGF- responsiveness, and this region was sufficient to confer TGF- inducibility to a heterologous (osteocalcin) minimal promoter. Substitution mutations that disrupted the Cbfa1- and/or Smad-binding elements present in the 183-base pair region resulted in a decrease in base-line expression and in the responsiveness to TGF- and Cbfa1. Collectively, these studies indicate the involvement and possible interaction of Cbfa1 and Smad proteins in mediating the effects of TGF- on OPG transcription.

This article has been cited by other articles:

				A. E. Kearns, S. Khosla, and P. J. Kostenuik Receptor Activator of Nuclear Factor {kappa}B Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease Endocr. Rev., April 1, 2008; 29(2): 155 - 192. [Abstract] [Full Text] [PDF]

				X. Tan, T. Weng, J. Zhang, J. Wang, W. Li, H. Wan, Y. Lan, X. Cheng, N. Hou, H. Liu, et al. Smad4 is required for maintaining normal murine postnatal bone homeostasis J. Cell Sci., July 1, 2007; 120(13): 2162 - 2170. [Abstract] [Full Text] [PDF]

				Y. Li, G. Toraldo, A. Li, X. Yang, H. Zhang, W.-P. Qian, and M. N. Weitzmann B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo Blood, May 1, 2007; 109(9): 3839 - 3848. [Abstract] [Full Text] [PDF]

				D. J. HADJIDAKIS and I. I. ANDROULAKIS Bone Remodeling Ann. N.Y. Acad. Sci., December 1, 2006; 1092(1): 385 - 396. [Abstract] [Full Text] [PDF]

				E. ABE Function of BMPs and BMP Antagonists in Adult Bone Ann. N.Y. Acad. Sci., April 1, 2006; 1068(1): 41 - 53. [Abstract] [Full Text] [PDF]

				J. E. Onyia, R. J. S. Galvin, Y. L. Ma, D. L. Halladay, R. R. Miles, X. Yang, T. Fuson, R. L. Cain, Q. Q. Zeng, S. Chandrasekhar, et al. Novel and Selective Small Molecule Stimulators of Osteoprotegerin Expression Inhibit Bone Resorption J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 369 - 379. [Abstract] [Full Text]

				M. A. Karsdal, P. Hjorth, K. Henriksen, T. Kirkegaard, K. L. Nielsen, H. Lou, J.-M. Delaisse, and N. T. Foged Transforming Growth Factor-{beta} Controls Human Osteoclastogenesis through the p38 MAPK and Regulation of RANK Expression J. Biol. Chem., November 7, 2003; 278(45): 44975 - 44987. [Abstract] [Full Text] [PDF]

				V. Viereck, C. Grundker, S. Blaschke, B. Niederkleine, H. Siggelkow, K.-H. Frosch, D. Raddatz, G. Emons, and L. C. Hofbauer Raloxifene Concurrently Stimulates Osteoprotegerin and Inhibits Interleukin-6 Production by Human Trabecular Osteoblasts J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4206 - 4213. [Abstract] [Full Text] [PDF]

				N. W. A. McGowan, H. MacPherson, K. Janssens, W. Van Hul, J. C. Frith, W. D. Fraser, S. H. Ralston, and M. H. Helfrich A Mutation Affecting the Latency-Associated Peptide of TGF{beta}1 in Camurati-Engelmann Disease Enhances Osteoclast Formation in Vitro J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3321 - 3326. [Abstract] [Full Text] [PDF]

				H. Enomoto, S. Shiojiri, K. Hoshi, T. Furuichi, R. Fukuyama, C. A. Yoshida, N. Kanatani, R. Nakamura, A. Mizuno, A. Zanma, et al. Induction of Osteoclast Differentiation by Runx2 through Receptor Activator of Nuclear Factor-{kappa}B Ligand (RANKL) and Osteoprotegerin Regulation and Partial Rescue of Osteoclastogenesis in Runx2-/- Mice by RANKL Transgene J. Biol. Chem., June 20, 2003; 278(26): 23971 - 23977. [Abstract] [Full Text] [PDF]

				H. Chagraoui, M. Tulliez, T. Smayra, E. Komura, S. Giraudier, T. Yun, N. Lassau, W. Vainchenker, and F. Wendling Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO Blood, April 15, 2003; 101(8): 2983 - 2989. [Abstract] [Full Text] [PDF]

				B. Arko, J. Prezelj, R. Komel, A. Kocijancic, P. Hudler, and J. Marc Sequence Variations in the Osteoprotegerin Gene Promoter in Patients with Postmenopausal Osteoporosis J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4080 - 4084. [Abstract] [Full Text] [PDF]

				V. Geoffroy, M. Kneissel, B. Fournier, A. Boyde, and P. Matthias High Bone Resorption in Adult Aging Transgenic Mice Overexpressing Cbfa1/Runx2 in Cells of the Osteoblastic Lineage Mol. Cell. Biol., September 1, 2002; 22(17): 6222 - 6233. [Abstract] [Full Text] [PDF]