|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 276, Issue 31, 29028-29036, August 3, 2001
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Laboratory of Osteoblast Biology and Pathology, INSERM U
349, Affiliated CNRS, Lariboisière Hospital,
75475 Cedex 10 Paris, France
Bone morphogenetic protein-2 (BMP-2), a member of
the transforming growth factor-
Bone Morphogenetic Protein-2 Promotes Osteoblast Apoptosis
through a Smad-independent, Protein Kinase C-dependent
Signaling Pathway*
,
(TGF-) family, regulates
osteoblast differentiation and bone formation. Here we show a novel
function of BMP-2 in human osteoblasts and identify a signaling pathway
involved in this function. BMP-2 promotes apoptosis in primary human
calvaria osteoblasts and in immortalized human neonatal calvaria
osteoblasts, as shown by terminal deoxynucleotidyl transferase-mediated
nick end labeling analysis. In contrast, TGF-2 inhibits apoptosis in
human osteoblasts. Studies of the mechanisms of action showed that
BMP-2 increases the Bax/Bcl-2 ratio, whereas TG-2 has a negative
effect. Moreover, BMP-2 increases the release of mitochondrial cytochrome c to the cytosol. Consistent with these results,
BMP-2 increases caspase-9 and caspase-3, -6, and -7 activity, and an anti-caspase-9 agent suppresses BMP-2-induced apoptosis. Overexpression of dominant-negative Smad1 effectively blocks BMP-2-induced expression of the osteoblast transcription factor Runx2 but not the activation of
caspases or apoptosis induced by BMP-2, indicating that the Smad1
signaling pathway is not involved in the BMP-2-induced apoptosis. The
proapoptotic effect of BMP-2 is PKC-dependent, because
BMP-2 increases PKC activity, and the selective PKC inhibitor
calphostin C blocks the BMP-2-induced increased Bax/Bcl-2, caspase
activity, and apoptosis. In contrast, the cAMP-dependent
protein kinase A inhibitor H89, the p38 MAPK inhibitor SB203580, and
the MEK inhibitor PD-98059 have no effect. The results show that BMP-2 uses a Smad-independent, PKC-dependent pathway to promote
apoptosis via a Bax/Bcl-2 and cytochrome
c-caspase-9-caspase-3, -6, -7 cascade in human osteoblasts.
*
This work was supported in part by a GIP Fonds de Recherche
Hoechst Marion Roussel grant (GIP/HMR/INSERM).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a grant from Genset France.
§
To whom correspondence should be addressed. Tel.: 33-1-49-95-63-58;
Fax: 33-1-49-95-84-52; E-mail:
pierre.marie@inserm.lrb.ap-hop-paris.fr.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Dufour, X. Holy, and P. J. Marie Transforming growth factor-{beta} prevents osteoblast apoptosis induced by skeletal unloading via PI3K/Akt, Bcl-2, and phospho-Bad signaling Am J Physiol Endocrinol Metab, April 1, 2008; 294(4): E794 - E801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. J. Lee, Y. Ji, S. Paul, H. Maehr, M. Uskokovic, and N. Suh Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase C{alpha} Cancer Res., December 15, 2007; 67(24): 11840 - 11847. [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]
|
|
|
|
 |
|
 G. Lagna, P. H. Nguyen, W. Ni, and A. Hata BMP-dependent activation of caspase-9 and caspase-8 mediates apoptosis in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L1059 - L1067. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Aghaloo, C. M. Cowan, Y.-F. Chou, X. Zhang, H. Lee, S. Miao, N. Hong, S. Kuroda, B. Wu, K. Ting, et al. Nell-1-Induced Bone Regeneration in Calvarial Defects Am. J. Pathol., September 1, 2006; 169(3): 903 - 915. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Pache, C. Schafer, S. Wiesemann, E. Springer, M. Liebau, H. C. Reinhardt, C. August, H. Pavenstadt, and M. J. Bek Upregulation of Id-1 via BMP-2 receptors induces reactive oxygen species in podocytes Am J Physiol Renal Physiol, September 1, 2006; 291(3): F654 - F662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Deregowski, E. Gazzerro, L. Priest, S. Rydziel, and E. Canalis Notch 1 Overexpression Inhibits Osteoblastogenesis by Suppressing Wnt/beta-Catenin but Not Bone Morphogenetic Protein Signaling J. Biol. Chem., March 10, 2006; 281(10): 6203 - 6210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Csiszar, M. Ahmad, K. E. Smith, N. Labinskyy, Q. Gao, G. Kaley, J. G. Edwards, M. S. Wolin, and Z. Ungvari Bone Morphogenetic Protein-2 Induces Proinflammatory Endothelial Phenotype Am. J. Pathol., February 1, 2006; 168(2): 629 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Langenfeld, Y. Kong, and J. Langenfeld Bone Morphogenetic Protein-2-Induced Transformation Involves the Activation of Mammalian Target of Rapamycin Mol. Cancer Res., December 1, 2005; 3(12): 679 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Langenfeld, J. Bojnowski, J. Perone, and J. Langenfeld Expression of Bone Morphogenetic Proteins in Human Lung Carcinomas Ann. Thorac. Surg., September 1, 2005; 80(3): 1028 - 1032. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Gazzerro, V. Deregowski, S. Vaira, and E. Canalis Overexpression of Twisted Gastrulation Inhibits Bone Morphogenetic Protein Action and Prevents Osteoblast Cell Differentiation in Vitro Endocrinology, September 1, 2005; 146(9): 3875 - 3882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Jadlowiec, D. Dongell, J. Smith, C. Conover, and P. Campbell Pregnancy-Associated Plasma Protein-A Is Involved in Matrix Mineralization of Human Adult Mesenchymal Stem Cells and Angiogenesis in the Chick Chorioallontoic Membrane Endocrinology, September 1, 2005; 146(9): 3765 - 3772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Yang, L. Long, M. Southwood, N. Rudarakanchana, P. D. Upton, T. K. Jeffery, C. Atkinson, H. Chen, R. C. Trembath, and N. W. Morrell Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension Circ. Res., May 27, 2005; 96(10): 1053 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nudi, J.-F. Ouimette, and J. Drouin Bone Morphogenic Protein (Smad)-Mediated Repression of Proopiomelanocortin Transcription by Interference with Pitx/Tpit Activity Mol. Endocrinol., May 1, 2005; 19(5): 1329 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, S. Yin, N. Reddy, C. Spencer, and S. Sheng Bax Mediates the Apoptosis-Sensitizing Effect of Maspin Cancer Res., March 1, 2004; 64(5): 1703 - 1711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Shimasaki, R. K. Moore, F. Otsuka, and G. F. Erickson The Bone Morphogenetic Protein System In Mammalian Reproduction Endocr. Rev., February 1, 2004; 25(1): 72 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Hay, J. Lemonnier, O. Fromigue, H. Guenou, and P. J. Marie Bone Morphogenetic Protein Receptor IB Signaling Mediates Apoptosis Independently of Differentiation in Osteoblastic Cells J. Biol. Chem., January 16, 2004; 279(3): 1650 - 1658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lemonnier, C. Ghayor, J. Guicheux, and J. Caverzasio Protein Kinase C-independent Activation of Protein Kinase D Is Involved in BMP-2-induced Activation of Stress Mitogen-activated Protein Kinases JNK and p38 and Osteoblastic Cell Differentiation J. Biol. Chem., January 2, 2004; 279(1): 259 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mogi and A. Togari Activation of Caspases Is Required for Osteoblastic Differentiation J. Biol. Chem., November 28, 2003; 278(48): 47477 - 47482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hassel, S. Schmitt, A. Hartung, M. Roth, A. Nohe, N. Petersen, M. Ehrlich, Y. I. Henis, W. Sebald, and P. Knaus Initiation of Smad-Dependent and Smad-Independent Signaling via Distinct BMP-Receptor Complexes J. Bone Joint Surg. Am., August 1, 2003; 85(90003): 44 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Canalis, A. N. Economides, and E. Gazzerro Bone Morphogenetic Proteins, Their Antagonists, and the Skeleton Endocr. Rev., April 1, 2003; 24(2): 218 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Hata, R. Nishimura, F. Ikeda, K. Yamashita, T. Matsubara, T. Nokubi, and T. Yoneda Differential Roles of Smad1 and p38 Kinase in Regulation of Peroxisome Proliferator-activating Receptor gamma during Bone Morphogenetic Protein 2-induced Adipogenesis Mol. Biol. Cell, February 1, 2003; 14(2): 545 - 555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Li, P. E. Massa, A. Hanidu, G. W. Peet, P. Aro, A. Savitt, S. Mische, J. Li, and K. B. Marcu IKKalpha , IKKbeta , and NEMO/IKKgamma Are Each Required for the NF-kappa B-mediated Inflammatory Response Program J. Biol. Chem., November 15, 2002; 277(47): 45129 - 45140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Street, M. Bao, L. deGuzman, S. Bunting, F. V. Peale Jr., N. Ferrara, H. Steinmetz, J. Hoeffel, J. L. Cleland, A. Daugherty, et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover PNAS, July 23, 2002; 99(15): 9656 - 9661. [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]
|
|
|
|
 |
|
 M. Yousfi, F. Lasmoles, V. El Ghouzzi, and P. J. Marie Twist haploinsufficiency in Saethre-Chotzen syndrome induces calvarial osteoblast apoptosis due to increased TNF{alpha} expression and caspase-2 activation Hum. Mol. Genet., February 1, 2002; 11(4): 359 - 369. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |