DOI QR코드

DOI QR Code

GATA4 negatively regulates osteoblast differentiation by downregulation of Runx2

  • Song, Insun (Department of Biochemistry, Ajou University School of Medicine, The Graduate School, Ajou University) ;
  • Kim, Kabsun (Department of Pharmacology, Chonnam National University Medical School) ;
  • Kim, Jung Ha (Department of Pharmacology, Chonnam National University Medical School) ;
  • Lee, Young-Kyoung (Department of Biochemistry, Ajou University School of Medicine, The Graduate School, Ajou University) ;
  • Jung, Hyun-Jung (Department of Biochemistry, Ajou University School of Medicine, The Graduate School, Ajou University) ;
  • Byun, Hae-Ok (Department of Biochemistry, Ajou University School of Medicine, The Graduate School, Ajou University) ;
  • Yoon, Gyesoon (Department of Biochemistry, Ajou University School of Medicine, The Graduate School, Ajou University) ;
  • Kim, Nacksung (Department of Pharmacology, Chonnam National University Medical School)
  • 투고 : 2013.10.14
  • 심사 : 2013.12.16
  • 발행 : 2014.08.31

초록

Osteoblasts are specialized mesenchymal cells that are responsible for bone formation. In this study, we examine the role of GATA4 in osteoblast differentiation. GATA4 was abundantly expressed in preosteoblast cells and gradually down-regulated during osteoblast differentiation. Overexpression of GATA4 in osteoblastic cells inhibited alkaline phosphatase activity and nodule formation in osteogenic conditioned cell culture system. In addition, overexpression of GATA4 attenuated expression of osteogenic marker genes, including Runx2, alkaline phosphatase, bone sialoprotein, and osteocalcin, all of which are important for osteoblast differentiation and function. Overexpression of GATA4 attenuated Runx2 promoter activity, whereas silencing of GATA4 increased Runx2 induction. We found that GATA4 interacted with Dlx5 and subsequently decreased Dlx5 binding activity to Runx2 promoter region. Our data suggest that GATA4 acts as a negative regulator in osteoblast differentiation by downregulation of Runx2.

키워드

참고문헌

  1. Komori, T., Yagi, H., Nomura, S., Yamaguchi, A., Sasaki, K., Deguchi, K., Shimizu, Y., Bronson, R. T., Gao, Y. H., Inada, M., Sato, M., Okamoto, R., Kitamura, Y., Yoshiki, S. and Kishimoto, T. (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755-764. https://doi.org/10.1016/S0092-8674(00)80258-5
  2. Otto, F., Thornell, A. P., Crompton, T., Denzel, A., Gilmour, K. C., Rosewell, I. R., Stamp, G. W., Beddington, R. S., Mundlos, S., Olsen, B. R., Selby, P. B. and Owen, M. J. (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765-771. https://doi.org/10.1016/S0092-8674(00)80259-7
  3. Lee, B., Thirunavukkarasu, K., Zhou, L., Pastore, L., Baldini, A., Hecht, J., Geoffroy, V., Ducy, P. and Karsenty, G. (1997) Missense mutations abolishing DNA binding of the osteoblast- specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat. Genet. 16, 307-310. https://doi.org/10.1038/ng0797-307
  4. Hong, J. H., Hwang, E. S., McManus, M. T., Amsterdam, A., Tian, Y., Kalmukova, R., Mueller, E., Benjamin, T., Spiegelman, B. M., Sharp, P. A., Hopkins, N. and Yaffe, M. B. (2005) TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309, 1074-1078. https://doi.org/10.1126/science.1110955
  5. Zhou, G., Zheng, Q., Engin, F., Munivez, E., Chen, Y., Sebald, E., Krakow, D. and Lee, B. (2006) Dominance of SOX9 function over RUNX2 during skeletogenesis. Proc. Natl. Acad. Sci. U. S. A. 103, 19004-19009. https://doi.org/10.1073/pnas.0605170103
  6. Marie, P. J. (2008) Transcription factors controlling osteoblastogenesis. Arch. Biochem. Biophys. 473, 98-105. https://doi.org/10.1016/j.abb.2008.02.030
  7. Samee, N., de Vernejoul, M. C. and Levi, G. (2007) Role of DLX regulatory proteins in osteogenesis and chondrogenesis. Crit. Rev. Eukaryot. Gene Expr. 17, 173-186. https://doi.org/10.1615/CritRevEukarGeneExpr.v17.i3.10
  8. Zhao, G. Q., Zhao, S., Zhou, X., Eberspaecher, H., Solursh, M. and de Crombrugghe, B. (1994) rDlx, a novel distal- less-like homeoprotein is expressed in developing cartilages and discrete neuronal tissues. Dev. Biol. 164, 37-51. https://doi.org/10.1006/dbio.1994.1178
  9. Holleville, N., Mateos, S., Bontoux, M., Bollerot, K. and Monsoro-Burq, A. H. (2007) Dlx5 drives Runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme. Dev. Biol. 304, 860-874. https://doi.org/10.1016/j.ydbio.2007.01.003
  10. Lee, M. H., Kim, Y. J., Yoon, W. J., Kim, J. I., Kim, B. G., Hwang, Y. S., Wozney, J. M., Chi, X. Z., Bae, S. C., Choi, K. Y., Cho, J. Y., Choi, J. Y. and Ryoo, H. M. (2005) Dlx5 specifically regulates Runx2 type II expression by binding to homeodomain-response elements in the Runx2 distal promoter. J. Biol. Chem. 280, 35579-35587. https://doi.org/10.1074/jbc.M502267200
  11. Lee, M. H., Kim, Y. J., Kim, H. J., Park, H. D., Kang, A. R., Kyung, H. M., Sung, J. H., Wozney, J. M., Kim, H. J. and Ryoo, H. M. (2003) BMP-2-induced Runx2 expression is mediated by Dlx5, and TGF-beta 1 opposes the BMP-2-induced osteoblast differentiation by suppression of Dlx5 expression. J. Biol. Chem. 278, 34387-34394. https://doi.org/10.1074/jbc.M211386200
  12. Miyama, K., Yamada, G., Yamamoto, T. S., Takagi, C., Miyado, K., Sakai, M., Ueno, N. and Shibuya, H. (1999) A BMP-inducible gene, dlx5, regulates osteoblast differentiation and mesoderm induction. Dev. Biol. 208, 123-133. https://doi.org/10.1006/dbio.1998.9197
  13. Tadic, T., Dodig, M., Erceg, I., Marijanovic, I., Mina, M., Kalajzic, Z., Velonis, D., Kronenberg, M. S., Kosher, R. A., Ferrari, D. and Lichtler, A. C. (2002) Overexpression of Dlx5 in chicken calvarial cells accelerates osteoblastic differentiation. J. Bone Miner. Res. 17, 1008-1014. https://doi.org/10.1359/jbmr.2002.17.6.1008
  14. Molkentin, J. D. (2000) The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J. Biol. Chem. 275, 38949-38952. https://doi.org/10.1074/jbc.R000029200
  15. Viger, R. S., Guittot, S. M., Anttonen, M., Wilson, D. B. and Heikinheimo, M. (2008) Role of the GATA family of transcription factors in endocrine development, function, and disease. Mol. Endocrinol. 22, 781-798. https://doi.org/10.1210/me.2007-0513
  16. Pikkarainen, S., Tokola, H., Kerkela, R. and Ruskoaho, H. (2004) GATA transcription factors in the developing and adult heart. Cardiovasc. Res. 63, 196-207. https://doi.org/10.1016/j.cardiores.2004.03.025
  17. Molkentin, J. D., Lu, J. R., Antos, C. L., Markham, B., Richardson, J., Robbins, J., Grant, S. R. and Olson, E. N. (1998) A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215-228. https://doi.org/10.1016/S0092-8674(00)81573-1
  18. Song, I., Kim, B. S., Kim, C. S. and Im, G. I. (2011) Effects of BMP-2 and vitamin D3 on the osteogenic differentiation of adipose stem cells. Biochem. Biophys. Res. Commun. 408, 126-131. https://doi.org/10.1016/j.bbrc.2011.03.135
  19. Miranda-Carboni, G. A., Guemes, M., Bailey, S., Anaya, E., Corselli, M., Peault, B. and Krum, S. A. (2011) GATA4 regulates estrogen receptor-alpha-mediated osteoblast transcription. Mol. Endocrinol. 25, 1126-1136. https://doi.org/10.1210/me.2010-0463
  20. Bisping, E., Ikeda, S., Kong, S. W., Tarnavski, O., Bodyak, N., McMullen, J. R., Rajagopal, S., Son, J. K., Ma, Q., Springer, Z., Kang, P. M., Izumo, S. and Pu, W. T. (2006) Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure. Proc. Natl. Acad. Sci. U. S. A. 103, 14471-14476. https://doi.org/10.1073/pnas.0602543103
  21. Katz, A. M. (1995) The cardiomyopathy of overload: an unnatural growth response. Eur. Heart J. 16(Suppl O), 110-114.

피인용 문헌

  1. GATA4 regulates osteoblastic differentiation and bone remodeling via p38-mediated signaling vol.48, pp.3, 2017, https://doi.org/10.1007/s10735-017-9719-2
  2. DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age vol.16, pp.4, 2017, https://doi.org/10.1111/acel.12597
  3. DNA Damage Follows Repair Factor Depletion and Portends Genome Variation in Cancer Cells after Pore Migration vol.27, pp.2, 2017, https://doi.org/10.1016/j.cub.2016.11.049
  4. Role of GATA binding protein 4 (GATA4) in the regulation of tooth development via GNAI3 vol.7, pp.1, 2017, https://doi.org/10.1038/s41598-017-01689-1
  5. GATA4 negatively regulates bone sialoprotein expression in osteoblasts vol.49, pp.6, 2016, https://doi.org/10.5483/BMBRep.2016.49.6.032
  6. STRA6 as a possible candidate gene for pathogenesis of osteoporosis from RNA-seq analysis of human mesenchymal stem cells vol.16, pp.4, 2017, https://doi.org/10.3892/mmr.2017.7072