J. Cell Biol., Volume 142, Number 1, July 13, 1998 295-305

Differential Roles for Bone Morphogenetic Protein (BMP) Receptor Type IB and IA in Differentiation and Specification of Mesenchymal Precursor Cells to Osteoblast and Adipocyte Lineages

D. Chen,^* X. Ji,^* M.A. Harris,^* J.Q. Feng,^* G. Karsenty, A.J. Celeste,^§ V. Rosen,^§ G.R. Mundy,^* and S.E. Harris^*

^* Department of Medicine, Division of Endocrinology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284;  Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030; and ^§ Genetics Institute, Cambridge, Massachusetts 02140

Cumulative evidence indicates that osteoblasts and adipocytes share a common mesenchymal precursor and that bone morphogenetic proteins (BMPs) can induce both osteoblast and adipocyte differentiation of this precursor. In the present study, we investigated the roles of BMP receptors in differentiation along these separate lineages using a well-characterized clonal cell line, 2T3, derived from the mouse calvariae. BMP-2 induced 2T3 cells to differentiate into mature osteoblasts or adipocytes depending upon culture conditions. To test the specific roles of the type IA and IB BMP receptor components, truncated and constitutively active type IA and IB BMP receptor cDNAs were stably expressed in these cells. Overexpression of truncated type IB BMP receptor (trBMPR-IB) in 2T3 cells completely blocked BMP-2-induced osteoblast differentiation and mineralized bone matrix formation. Expression of trBMPR-IB also blocked mRNA expression of the osteoblast specific transcription factor, Osf2/ Cbfa1, and the osteoblast differentiation-related genes, alkaline phosphatase (ALP) and osteocalcin (OC). BMP-2-induced ALP activity could be rescued by transfection of wild-type (wt) BMPR-IB into 2T3 clones containing trBMPR-IB. Expression of a constitutively active BMPR-IB (caBMPR-IB) induced formation of mineralized bone matrix by 2T3 cells without addition of BMP-2. In contrast, overexpression of trBMPR-IA blocked adipocyte differentiation and expression of caBMPR-IA induced adipocyte formation in 2T3 cells. Expression of the adipocyte differentiation-related genes, adipsin and PPAR, correlated with the distinct phenotypic changes found after overexpression of the appropriate mutant receptors. These results demonstrate that type IB and IA BMP receptors transmit different signals to bone-derived mesenchymal progenitors and play critical roles in both the specification and differentiation of osteoblasts and adipocytes.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Jeong, B.-C., Lee, Y.-S., Park, Y.-Y., Bae, I.-H., Kim, D.-K., Koo, S.-H., Choi, H.-R., Kim, S.-H., Franceschi, R. T., Koh, J.-T., Choi, H.-S. (2009). The Orphan Nuclear Receptor Estrogen Receptor-related Receptor {gamma} Negatively Regulates BMP2-induced Osteoblast Differentiation and Bone Formation. J. Biol. Chem. 284: 14211-14218 [Abstract] [Full Text]  
• Li, X., Huang, M., Zheng, H., Wang, Y., Ren, F., Shang, Y., Zhai, Y., Irwin, D. M., Shi, Y., Chen, D., Chang, Z. (2008). CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation. JCB 181: 959-972 [Abstract] [Full Text]  
• Lavery, K., Swain, P., Falb, D., Alaoui-Ismaili, M. H. (2008). BMP-2/4 and BMP-6/7 Differentially Utilize Cell Surface Receptors to Induce Osteoblastic Differentiation of Human Bone Marrow-derived Mesenchymal Stem Cells. J. Biol. Chem. 283: 20948-20958 [Abstract] [Full Text]  
• Wise, G.E., King, G.J. (2008). Mechanisms of Tooth Eruption and Orthodontic Tooth Movement. JDR 87: 414-434 [Abstract] [Full Text]  
• Hadfield, K. D., Rock, C. F., Inkson, C. A., Dallas, S. L., Sudre, L., Wallis, G. A., Boot-Handford, R. P., Canfield, A. E. (2008). HtrA1 Inhibits Mineral Deposition by Osteoblasts: REQUIREMENT FOR THE PROTEASE AND PDZ DOMAINS. J. Biol. Chem. 283: 5928-5938 [Abstract] [Full Text]  
• Kotzsch, A., Nickel, J., Seher, A., Heinecke, K., van Geersdaele, L., Herrmann, T., Sebald, W., Mueller, T. D. (2008). Structure Analysis of Bone Morphogenetic Protein-2 Type I Receptor Complexes Reveals a Mechanism of Receptor Inactivation in Juvenile Polyposis Syndrome. J. Biol. Chem. 283: 5876-5887 [Abstract] [Full Text]  
• Zhou, H., Mak, W., Zheng, Y., Dunstan, C. R., Seibel, M. J. (2008). Osteoblasts Directly Control Lineage Commitment of Mesenchymal Progenitor Cells through Wnt Signaling. J. Biol. Chem. 283: 1936-1945 [Abstract] [Full Text]  
• Tan, X., Weng, T., Zhang, J., Wang, J., Li, W., Wan, H., Lan, Y., Cheng, X., Hou, N., Liu, H., Ding, J., Lin, F., Yang, R., Gao, X., Chen, D., Yang, X. (2007). Smad4 is required for maintaining normal murine postnatal bone homeostasis. J. Cell Sci. 120: 2162-2170 [Abstract] [Full Text]  
• Lee, K. B, Khivansara, V., Santos, M. M, Lamba, P., Yuen, T., Sealfon, S. C, Bernard, D. J (2007). Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone {beta} subunit transcription. J Mol Endocrinol 38: 315-330 [Abstract] [Full Text]  
• Bowers, R. R., Kim, J. W., Otto, T. C., Lane, M. D. (2006). Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: Role of the BMP-4 gene. Proc. Natl. Acad. Sci. USA 103: 13022-13027 [Abstract] [Full Text]  
• Wan, D. C., Shi, Y.-Y., Nacamuli, R. P., Quarto, N., Lyons, K. M., Longaker, M. T. (2006). Osteogenic differentiation of mouse adipose-derived adult stromal cells requires retinoic acid and bone morphogenetic protein receptor type IB signaling. Proc. Natl. Acad. Sci. USA 103: 12335-12340 [Abstract] [Full Text]  
• Zhao, M., Qiao, M., Harris, S. E., Chen, D., Oyajobi, B. O., Mundy, G. R. (2006). The zinc finger transcription factor gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling.. Mol. Cell. Biol. 26: 6197-6208 [Abstract] [Full Text]  
• Qin, L., Wine-Lee, L., Ahn, K. J., Crenshaw, E. B. III (2006). Genetic Analyses Demonstrate That Bone Morphogenetic Protein Signaling Is Required for Embryonic Cerebellar Development. J. Neurosci. 26: 1896-1905 [Abstract] [Full Text]  
• Shen, R., Chen, M., Wang, Y.-J., Kaneki, H., Xing, L., O'Keefe, R. J., Chen, D. (2006). Smad6 Interacts with Runx2 and Mediates Smad Ubiquitin Regulatory Factor 1-induced Runx2 Degradation. J. Biol. Chem. 281: 3569-3576 [Abstract] [Full Text]  
• Babitt, J. L., Zhang, Y., Samad, T. A., Xia, Y., Tang, J., Campagna, J. A., Schneyer, A. L., Woolf, C. J., Lin, H. Y. (2005). Repulsive Guidance Molecule (RGMa), a DRAGON Homologue, Is a Bone Morphogenetic Protein Co-receptor. J. Biol. Chem. 280: 29820-29827 [Abstract] [Full Text]  
• Botolin, S., Faugere, M.-C., Malluche, H., Orth, M., Meyer, R., McCabe, L. R. (2005). Increased Bone Adiposity and Peroxisomal Proliferator-Activated Receptor-{gamma}2 Expression in Type I Diabetic Mice. Endocrinology 146: 3622-3631 [Abstract] [Full Text]  
• Yang, W., Lu, Y., Kalajzic, I., Guo, D., Harris, M. A., Gluhak-Heinrich, J., Kotha, S., Bonewald, L. F., Feng, J. Q., Rowe, D. W., Turner, C. H., Robling, A. G., Harris, S. E. (2005). Dentin Matrix Protein 1 Gene Cis-regulation: USE IN OSTEOCYTES TO CHARACTERIZE LOCAL RESPONSES TO MECHANICAL LOADING IN VITRO AND IN VIVO. J. Biol. Chem. 280: 20680-20690 [Abstract] [Full Text]  
• Brederlau, A., Faigle, R., Elmi, M., Zarebski, A., Sjoberg, S., Fujii, M., Miyazono, K., Funa, K. (2004). The Bone Morphogenetic Protein Type Ib Receptor Is a Major Mediator of Glial Differentiation and Cell Survival in Adult Hippocampal Progenitor Cell Culture. Mol. Biol. Cell 15: 3863-3875 [Abstract] [Full Text]  
• Nifuji, A., Kellermann, O., Noda, M. (2004). Noggin Inhibits Chondrogenic But Not Osteogenic Differentiation in Mesodermal Stem Cell Line C1 and Skeletal Cells. Endocrinology 145: 3434-3442 [Abstract] [Full Text]  
• Mishina, Y., Starbuck, M. W., Gentile, M. A., Fukuda, T., Kasparcova, V., Seedor, J. G., Hanks, M. C., Amling, M., Pinero, G. J., Harada, S.-i., Behringer, R. R. (2004). Bone Morphogenetic Protein Type IA Receptor Signaling Regulates Postnatal Osteoblast Function and Bone Remodeling. J. Biol. Chem. 279: 27560-27566 [Abstract] [Full Text]  
• Dvorak, M. M., Siddiqua, A., Ward, D. T., Carter, D. H., Dallas, S. L., Nemeth, E. F., Riccardi, D. (2004). Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones. Proc. Natl. Acad. Sci. USA 101: 5140-5145 [Abstract] [Full Text]  
• Pereira, R. C., Delany, A. M., Canalis, E. (2004). CCAAT/Enhancer Binding Protein Homologous Protein (DDIT3) Induces Osteoblastic Cell Differentiation. Endocrinology 145: 1952-1960 [Abstract] [Full Text]  
• Zhao, M., Qiao, M., Harris, S. E., Oyajobi, B. O., Mundy, G. R., Chen, D. (2004). Smurf1 Inhibits Osteoblast Differentiation and Bone Formation in Vitro and in Vivo. J. Biol. Chem. 279: 12854-12859 [Abstract] [Full Text]  
• Enomoto, H., Furuichi, T., Zanma, A., Yamana, K., Yoshida, C., Sumitani, S., Yamamoto, H., Enomoto-Iwamoto, M., Iwamoto, M., Komori, T. (2004). Runx2 deficiency in chondrocytes causes adipogenic changes in vitro. J. Cell Sci. 117: 417-425 [Abstract] [Full Text]  
• Hay, E., Lemonnier, J., Fromigue, O., Guenou, H., Marie, P. J. (2004). Bone Morphogenetic Protein Receptor IB Signaling Mediates Apoptosis Independently of Differentiation in Osteoblastic Cells. J. Biol. Chem. 279: 1650-1658 [Abstract] [Full Text]  
• Fux, C., Mitta, B., Kramer, B. P., Fussenegger, M. (2004). Dual-regulated expression of C/EBP-{alpha} and BMP-2 enables differential differentiation of C2C12 cells into adipocytes and osteoblasts. Nucleic Acids Res 32: e1-e1 [Abstract] [Full Text]  
• Sciaudone, M., Gazzerro, E., Priest, L., Delany, A. M., Canalis, E. (2003). Notch 1 Impairs Osteoblastic Cell Differentiation. Endocrinology 144: 5631-5639 [Abstract] [Full Text]  
• Chan, G. K., Miao, D., Deckelbaum, R., Bolivar, I., Karaplis, A., Goltzman, D. (2003). Parathyroid Hormone-Related Peptide Interacts with Bone Morphogenetic Protein 2 to Increase Osteoblastogenesis and Decrease Adipogenesis in Pluripotent C3H10T1/2 Mesenchymal Cells. Endocrinology 144: 5511-5520 [Abstract] [Full Text]  
• Zhao, M., Qiao, M., Oyajobi, B. O., Mundy, G. R., Chen, D. (2003). E3 Ubiquitin Ligase Smurf1 Mediates Core-binding Factor {alpha}1/Runx2 Degradation and Plays A Specific Role in Osteoblast Differentiation. J. Biol. Chem. 278: 27939-27944 [Abstract] [Full Text]  
• Canalis, E., Economides, A. N., Gazzerro, E. (2003). Bone Morphogenetic Proteins, Their Antagonists, and the Skeleton. Endocr. Rev. 24: 218-235 [Abstract] [Full Text]  
• Zhao, M., Berry, J.E., Somerman, M.J. (2003). Bone Morphogenetic Protein-2 Inhibits Differentiation and Mineralization of Cementoblasts in vitro. JDR 82: 23-27 [Abstract] [Full Text]  
• Skillington, J., Choy, L., Derynck, R. (2002). Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes. JCB 159: 135-146 [Abstract] [Full Text]  
• Gevers, E. F., Loveridge, N., Robinson, I. C. A. F. (2002). Bone Marrow Adipocytes: A Neglected Target Tissue for Growth Hormone. Endocrinology 143: 4065-4073 [Abstract] [Full Text]  
• Ghosh-Choudhury, N., Abboud, S. L., Nishimura, R., Celeste, A., Mahimainathan, L., Choudhury, G. G. (2002). Requirement of BMP-2-induced Phosphatidylinositol 3-Kinase and Akt Serine/Threonine Kinase in Osteoblast Differentiation and Smad-dependent BMP-2 Gene Transcription. J. Biol. Chem. 277: 33361-33368 [Abstract] [Full Text]  
• Zhao, M., Harris, S. E., Horn, D., Geng, Z., Nishimura, R., Mundy, G. R., Di Chen, (2002). Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation. JCB 157: 1049-1060 [Abstract] [Full Text]  
• Okazaki, R., Inoue, D., Shibata, M., Saika, M., Kido, S., Ooka, H., Tomiyama, H., Sakamoto, Y., Matsumoto, T. (2002). Estrogen Promotes Early Osteoblast Differentiation and Inhibits Adipocyte Differentiation in Mouse Bone Marrow Stromal Cell Lines that Express Estrogen Receptor (ER) {alpha} or {beta}. Endocrinology 143: 2349-2356 [Abstract] [Full Text]  
• Chen, S., Guttridge, D. C., Tang, E., Shi, S., Guan, K.-l., Wang, C.-Y. (2001). Suppression of Tumor Necrosis Factor-mediated Apoptosis by Nuclear Factor kappa B-independent Bone Morphogenetic Protein/Smad Signaling. J. Biol. Chem. 276: 39259-39263 [Abstract] [Full Text]  
• Javed, A., Barnes, G. L., Jasanya, B. O., Stein, J. L., Gerstenfeld, L., Lian, J. B., Stein, G. S. (2001). runt Homology Domain Transcription Factors (Runx, Cbfa, and AML) Mediate Repression of the Bone Sialoprotein Promoter: Evidence for Promoter Context-Dependent Activity of Cbfa Proteins. Mol. Cell. Biol. 21: 2891-2905 [Abstract] [Full Text]  
• Wilson, T., Wu, X.-Y., Juengel, J. L., Ross, I. K., Lumsden, J. M., Lord, E. A., Dodds, K. G., Walling, G. A., McEwan, J. C., O'Connell, A. R., McNatty, K. P., Montgomery, G. W. (2001). Highly Prolific Booroola Sheep Have a Mutation in the Intracellular Kinase Domain of Bone Morphogenetic Protein IB Receptor (ALK-6) That Is Expressed in Both Oocytes and Granulosa Cells. Biol. Reprod. 64: 1225-1235 [Abstract] [Full Text]  
• Mundy, G. R. (2000). Secondary Osteoporosis: The Potential Relevance of Leptin and Low Body Weight. ANN INTERN MED 133: 828-830 [Full Text]  
• Yamaguchi, A., Komori, T., Suda, T. (2000). Regulation of Osteoblast Differentiation Mediated by Bone Morphogenetic Proteins, Hedgehogs, and Cbfa1. Endocr. Rev. 21: 393-411 [Abstract] [Full Text]  
• Manolagas, S. C. (2000). Birth and Death of Bone Cells: Basic Regulatory Mechanisms and Implications for the Pathogenesis and Treatment of Osteoporosis. Endocr. Rev. 21: 115-137 [Abstract] [Full Text]  
• Jaiswal, R. K., Jaiswal, N., Bruder, S. P., Mbalaviele, G., Marshak, D. R., Pittenger, M. F. (2000). Adult Human Mesenchymal Stem Cell Differentiation to the Osteogenic or Adipogenic Lineage Is Regulated by Mitogen-activated Protein Kinase. J. Biol. Chem. 275: 9645-9652 [Abstract] [Full Text]  
• Gilboa, L., Nohe, A., Geissendörfer, T., Sebald, W., Henis, Y. I., Knaus, P. (2000). Bone Morphogenetic Protein Receptor Complexes on the Surface of Live Cells: A New Oligomerization Mode for Serine/Threonine Kinase Receptors. Mol. Biol. Cell 11: 1023-1035 [Abstract] [Full Text]  
• Yang, X., Ji, X., Shi, X., Cao, X. (2000). Smad1 Domains Interacting with Hoxc-8 Induce Osteoblast Differentiation. J. Biol. Chem. 275: 1065-1072 [Abstract] [Full Text]  
• Shou, J, Murray, R., Rim, P., Calof, A. (2000). Opposing effects of bone morphogenetic proteins on neuron production and survival in the olfactory receptor neuron lineage. Development 127: 5403-5413 [Abstract]  
• Yi, S., Daluiski, A, Pederson, R, Rosen, V, Lyons, K. (2000). The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. Development 127: 621-630 [Abstract]  
• PIEK, E., HELDIN, C.-H., TEN DIJKE, P. (1999). Specificity, diversity, and regulation in TGF-{beta} superfamily signaling. FASEB J. 13: 2105-2124 [Abstract] [Full Text]  
• Fujii, M., Takeda, K., Imamura, T., Aoki, H., Sampath, T. K., Enomoto, S., Kawabata, M., Kato, M., Ichijo, H., Miyazono, K. (1999). Roles of Bone Morphogenetic Protein Type I Receptors and Smad Proteins in Osteoblast and Chondroblast Differentiation. Mol. Biol. Cell 10: 3801-3813 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents