Upregulation of smpd3 via BMP2 stimulation and Runx2

  • Chae, Young-Mi (Department of Biochemistry, School of Dentistry, Kyungpook National University) ;
  • Heo, Sun-Hee (Department of Biochemistry, School of Dentistry, Kyungpook National University) ;
  • Kim, Jae-Young (Department of Biochemistry, School of Dentistry, Kyungpook National University) ;
  • Lee, Jae-Mok (Department of Periodontology, School of Dentistry, Kyungpook National University) ;
  • Ryoo, Hyun-Mo (Department of Cell and Developmental Biology, School of Dentistry, Seoul National University) ;
  • Cho, Je-Yoel (Department of Biochemistry, School of Dentistry, Kyungpook National University)
  • 발행 : 2009.02.28


Deletion of smpd3 induces osteogenesis and dentinogenesis imperfecta in mice. smpd3 is highly elevated in the parietal bones of developing mouse calvaria, but not in sutural mesenchymes. Here, we examine the mechanism of smpd3 regulation, which involves BMP2 stimulation of Runx2. smpd3 mRNA expression increased in response to BMP2 treatment and Runx2 transfection in C2C12 cells. The Runx2-responsive element (RRE) encoded within the -562 to -557 region is important for activation of the smpd3 promoter by Runx2. Electrophoretic mobility shift assays revealed that Runx2 binds strongly to the -355 to -350 RRE and less strongly to the -562 to -557 site. Thus, the smpd3 promoter is activated by BMP2 and is directly regulated by the Runx2 transcription factor. This novel description of smpd3 regulation will aid further studies of bone development and osteogenesis.


BMP2;Bone development;Runx2;Smpd3


  1. Tomiuk, S., Hofmann, K., Nix, M., Zumbansen, M. and Stoffel, W. (1998) Cloned mammalian neutral sphingomyelinase: functions in sphingolipid signaling? Proc. Natl. Acad. Sci. U.S.A. 95, 3638-3643
  2. Choi, J.Y., Rosen, V., Stein, J.L., Wijnen van, A.J., Stein, G.S., Lian, J.B. and Ryoo, H.M. (1999) Transient upregulation of CBFA1 in response to bone morphogenetic protein- 2 and transforming growth factor beta1 in C2C12 myogenic cells coincides with suppression of the myogenic phenotype but is not sufficient for osteoblast differentiation. J. Cell Biochem. 73, 114-125<114::AID-JCB13>3.0.CO;2-M
  3. Standal, T., Abildgaard, N., Fagerli, U.M., Stordal, B., Hjertner, O., Borset, M. and Sundan, A. (2007) HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood 109, 3024-3030
  4. Clarke, C.J., Truong,T.G. and Hannun, Y.A. (2007) Role for neutral sphingomyelinase-2 in tumor necrosis factor alpha- stimulated expression of vascular cell adhesion molecule- 1 (VCAM) and intercellular adhesion molecule-1 (ICAM) in lung epithelial cells: p38 MAPK is an upstream regulator of nSMase2. J. Biol. Chem. 282, 1384-1396
  5. Bellido, T., Ali, A.A, Plotkin,. L.I., Fu, Q., Gubrij, I., Roberson, P.K., Weinstein, R.S., O'Brien, C.A., Manolagas, S.C. and Jilka, R.L. (2003) Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. J. Biol. Chem. 278, 50259-50272
  6. Karakashian, A.A., Giltiay, N.V., Smith, G.M. and Nikolova-Karakashian, M.N. (2004) Expression of neutral sphingomyelinase-2 (NSMase-2) in primary rat hepatocytes modulates IL-beta-induced JNK activation. Faseb J. 18, 968-970
  7. Kozawa, O., Hatakeyama, D., Tokuda, H., Oiso, Y., Matsuno, H. and Uematsu, T. (2002) Sphingomyelinase amplifies BMP-4-induced osteocalcin synthesis in osteoblasts: role of ceramide. Cell Signal 14, 999-1004
  8. Kim, W.J., Okimoto,R.A., Purton, L.E., Goodwin, M., Haserlat, S.M., Dayyani, F., Sweetser, D.A., McClatchey, A.I., Bernard, O.A., Look, A.T., Bell, D.W., Scadden, D.T. and Haber D.A. (2008) Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias. Blood 111, 4716-4722
  9. Stoffel, W., Jenke, B., Holz, B., Binczek, E., Gunter, R.H., Knifka, J., Koebke, J. and Niehoff, A. (2007) Neutral sphingomyelinase (SMPD3) deficiency causes a novel form of chondrodysplasia and dwarfism that is rescued by Col2A1-driven smpd3 transgene expression. Am. J. Pathol. 171, 153-161
  10. Park, S.H. (2005) Fine tuning and cross-talking of TGF-beta signal by inhibitory Smads. J. Biochem. Mol. Biol. 38, 9-16
  11. Cho, J.Y., Lee, W.B., Kim, H.J., Woo, K.M., Baek, J.H., Choi, J.Y., Hur, C.G. and Ryoo, H.M. (2006) Bone-related gene profiles in developing calvaria. Gene 372, 71-81
  12. Stoffel, W., Jenke, B., Block, B., Zumbansen, M. and Koebke, J. (2005) Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and development. Proc. Natl. Acad. Sci. U.S.A. 102, 4554-4559
  13. Kim, Y.J., Kim, B.G., Lee, S.J., Lee, H.K., Lee, S.H., Ryoo, H.M. and Cho, J.Y. (2007) The suppressive effect of myeloid Elf-1-like factor (MEF) in osteogenic differentiation. J. Cell Physiol. 211, 253-260
  14. Krut, O., Wiegmann, K., Kashkar, H., Yazdanpanah, B. and Kronke, M. (2006) Novel tumor necrosis factor-responsive mammalian neutral sphingomyelinase-3 is a C-tail-anchored protein. J. Biol. Chem. 281, 13784-13793
  15. Chuang, M.J., Sun, K.H., Tang, S.J., Deng, M.W., Wu,Y.H., Sung, J.S., Cha, T.L. and Sun, G.H. (2008) Tumorderived tumor necrosis factor-alpha promotes progression and epithelial-mesenchymal transition in renal cell carcinoma cells. Cancer Sci. 99, 905-913
  16. Miura, Y., Gotoh, E., Nara, F., Nishijima, M. and Hanada, K. (2004) Hydrolysis of sphingosylphosphocholine by neutral sphingomyelinases. FEBS Lett. 557, 288-292
  17. Hofmann, K., Tomiuk, S., Wolff, G. and Stoffel, W. (2000) Cloning and characterization of the mammalian brain-specific, Mg2+-dependent neutral sphingomyelinase. Proc. Natl. Acad. Sci. U.S.A. 97, 5895-5900
  18. Ihm, H.J., Yang, S.J., Huh, J.W., Choi, S.Y. and Cho, S.W. (2008) Soluble expression and purification of synthetic human bone morphogenetic protein-2 in Escherichia coli. BMB reports 41, 404-407
  19. Bidder, M., Latifi, T. and Towler, D.A. (1998) Reciprocal temporospatial patterns of Msx2 and Osteocalcin gene expression during murine odontogenesis. J. Bone Miner Res.13, 609-619
  20. Tani, M. and Hannun, Y.A. (2007) Analysis of membrane topology of neutral sphingomyelinase 2. FEBS Lett. 581, 1323-1328
  21. Aubin, I., Adams, C.P., Opsahl, S., Septier, D., Bishop, C.E., Auge, N., Salvayre, R., Negre-Salvayre, A., Goldberg, M., Guenet, J.L. and Poirier, C. (2005) A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse. Nat. Genet. 37, 803-805
  22. Kanatani, N., Fujita, T., Fukuyama, R., Liu, W.,Yoshida, C.A., Moriishi, T., Yamana, K., Miyazaki, T., Toyosawa, S. and Komori, T. (2006) Cbf beta regulates Runx2 function isoform-dependently in postnatal bone development. Dev. Biol. 296, 48-61
  23. Goldberg, M., Opsahl, S., Aubin, I., Septier, D., Chaussain-Miller, C., Boskey, A. and Guenet, J.L. (2008) Sphingomyelin degradation is a key factor in dentin and bone mineralization: lessons from the fro/fro mouse. The chemistry and histochemistry of dentin lipids. J. Dent. Res. 87, 9-13

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