This Article Full Text Full Text (PDF) 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 Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hill, P. A. Articles by Meikle, M. C. Search for Related Content PubMed PubMed Citation Articles by Hill, P. A. Articles by Meikle, M. C.

Multiple Extracellular Signals Promote Osteoblast Survival and Apoptosis¹

Department of Orthodontics and Pediatric Dentistry, United Medical and Dental Schools of Guy’s and St. Thomas’ Hospitals, University of London, London, United Kingdom SE1 9RT

Address all correspondence and requests for reprints to: Dr. Peter A. Hill, Department of Orthodontics and Pediatric Dentistry, United Medical and Dental Schools of Guy’s and St. Thomas’ Hospitals, London Bridge, London, United Kingdom SE1 9RT.

Programed cell death (PCD) or apoptosis is a naturally occurring cell suicide pathway induced in a variety of cell types. In many cases, PCD apparently arises as a result of competition for limiting amounts of survival signals. In this study, we have investigated the potential role of growth factors (GF), cytokines, and osteotropic hormones on osteoblast survival in vitro. Our results indicate that in the absence of any of these factors, osteoblasts rapidly undergo PCD, as determined by cell morphology, mitochondrial function, and nuclei fragmentation. Osteoblast survival was promoted by insulin-like growth factor I (IGF-I), IGF-II, insulin, and basic fibroblast growth factor (bFGF). Platelet-derived growth factor had no effect on osteoblast survival, but this GF potentiated the survival-promoting effects of IGF-I, IGF-II, and insulin. A similar effect occurred when bFGF was added in combination with either of the IGFs or insulin. The effects of the IGFs were blocked by IR-3, an antibody to the type I IGF receptor, whereas the effects of insulin were only partially blocked. This antibody blocked the potentiating effects of platelet-derived growth factor on IGF-I-mediated osteoblast survival, but only partially blocked those of bFGF. Although a 100% survival of osteoblasts was seen in the presence of 2% FCS, the highest level attained by any of the above GF combinations was 75%. The monocyte-derived factor, tumor necrosis factor- (TNF) was the only agent that enhanced PCD in this study. These results suggest that osteoblast survival is promoted by those GFs sequestrated in bone matrix and that the type I, but not the type II, IGF receptor is involved in the response. Our data also indicate that other unidentified GFs or components of the extracellular matrix may be involved in promoting osteoblast survival and that TNF may abrogate their effects in vivo. We propose that these GFs may be released from bone matrix during phases of bone resorption and promote osteoblast survival, thereby playing an important role in bone remodeling, and that PCD induced by TNF may contribute to the bone loss in inflammatory bone disease.

This article has been cited by other articles:

				Y. Goga, M. Chiba, Y. Shimizu, and H. Mitani Compressive Force Induces Osteoblast Apoptosis via Caspase-8 Journal of Dental Research, March 1, 2006; 85(3): 240 - 244. [Abstract] [Full Text] [PDF]

				K. Janssens, P. ten Dijke, S. Janssens, and W. Van Hul Transforming Growth Factor-{beta}1 to the Bone Endocr. Rev., October 1, 2005; 26(6): 743 - 774. [Abstract] [Full Text] [PDF]

				L. C. Gilbert, J. Rubin, and M. S. Nanes The p55 TNF receptor mediates TNF inhibition of osteoblast differentiation independently of apoptosis Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E1011 - E1018. [Abstract] [Full Text] [PDF]

				A. Grey, Q. Chen, X. Xu, K. Callon, and J. Cornish Parallel Phosphatidylinositol-3 Kinase and p42/44 Mitogen-Activated Protein Kinase Signaling Pathways Subserve the Mitogenic and Antiapoptotic Actions of Insulin-Like Growth Factor I in Osteoblastic Cells Endocrinology, November 1, 2003; 144(11): 4886 - 4893. [Abstract] [Full Text] [PDF]

				M. Zhang, S. Xuan, M. L. Bouxsein, D. von Stechow, N. Akeno, M. C. Faugere, H. Malluche, G. Zhao, C. J. Rosen, A. Efstratiadis, et al. Osteoblast-specific Knockout of the Insulin-like Growth Factor (IGF) Receptor Gene Reveals an Essential Role of IGF Signaling in Bone Matrix Mineralization J. Biol. Chem., November 8, 2002; 277(46): 44005 - 44012. [Abstract] [Full Text] [PDF]

				D. M. Ornitz and P. J. Marie FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease Genes & Dev., June 15, 2002; 16(12): 1446 - 1465. [Full Text] [PDF]

				N. Akeno, J. Robins, M. Zhang, M. F. Czyzyk-Krzeska, and T. L. Clemens Induction of Vascular Endothelial Growth Factor by IGF-I in Osteoblast-Like Cells Is Mediated by the PI3K Signaling Pathway through the Hypoxia-Inducible Factor-2{alpha} Endocrinology, February 1, 2002; 143(2): 420 - 425. [Abstract] [Full Text] [PDF]

				A. M. Delany, D. Durant, and E. Canalis Glucocorticoid Suppression of IGF I Transcription in Osteoblasts Mol. Endocrinol., October 1, 2001; 15(10): 1781 - 1789. [Abstract] [Full Text] [PDF]

				U. K. MESSMER, V. A. BRINER, and J. PFEILSCHIFTER Basic Fibroblast Growth Factor Selectively Enhances TNF-{alpha}--Induced Apoptotic Cell Death in Glomerular Endothelial Cells: Effects on Apoptotic Signaling Pathways J. Am. Soc. Nephrol., December 1, 2000; 11(12): 2199 - 2211. [Abstract] [Full Text]

				L. Gilbert, X. He, P. Farmer, S. Boden, M. Kozlowski, J. Rubin, and M. S. Nanes Inhibition of Osteoblast Differentiation by Tumor Necrosis Factor-{alpha} Endocrinology, November 1, 2000; 141(11): 3956 - 3964. [Abstract] [Full Text] [PDF]

				G. Zhao, M.-C. Monier-Faugere, M. C. Langub, Z. Geng, T. Nakayama, J. W. Pike, S. D. Chernausek, C. J. Rosen, L.-R. Donahue, H. H. Malluche, et al. Targeted Overexpression of Insulin-Like Growth Factor I to Osteoblasts of Transgenic Mice: Increased Trabecular Bone Volume without Increased Osteoblast Proliferation Endocrinology, July 1, 2000; 141(7): 2674 - 2682. [Abstract] [Full Text] [PDF]

				A. Mansukhani, P. Bellosta, M. Sahni, and C. Basilico Signaling by Fibroblast Growth Factors (FGF) and Fibroblast Growth Factor Receptor 2 (FGFR2)-activating Mutations Blocks Mineralization and Induces Apoptosis in Osteoblasts J. Cell Biol., June 12, 2000; 149(6): 1297 - 1308. [Abstract] [Full Text] [PDF]

				R. Globus, S. Doty, J. Lull, E Holmuhamedov, M. Humphries, and C. Damsky Fibronectin is a survival factor for differentiated osteoblasts J. Cell Sci., January 5, 1998; 111(10): 1385 - 1393. [Abstract] [PDF]

				T. Bellido, M. Huening, M. Raval-Pandya, S. C. Manolagas, and S. Christakos Calbindin-D28k Is Expressed in Osteoblastic Cells and Suppresses Their Apoptosis by Inhibiting Caspase-3 Activity J. Biol. Chem., August 18, 2000; 275(34): 26328 - 26332. [Abstract] [Full Text] [PDF]

				C. S. Adams, K. Mansfield, R. L. Perlot, and I. M. Shapiro Matrix Regulation of Skeletal Cell Apoptosis. ROLE OF CALCIUM AND PHOSPHATE IONS J. Biol. Chem., June 1, 2001; 276(23): 20316 - 20322. [Abstract] [Full Text] [PDF]

				E. Hay, J. Lemonnier, O. Fromigue, and P. J. Marie Bone Morphogenetic Protein-2 Promotes Osteoblast Apoptosis through a Smad-independent, Protein Kinase C-dependent Signaling Pathway J. Biol. Chem., July 27, 2001; 276(31): 29028 - 29036. [Abstract] [Full Text] [PDF]