Roles of Runx2 in Skeletal Development

  • Toshihisa KomoriEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 962)


Runx2 is the most upstream transcription factor essential for osteoblast differentiation. It regulates the expression of Sp7, the protein of which is a crucial transcription factor for osteoblast differentiation, as well as that of bone matrix genes including Spp1, Ibsp, and Bglap2. Runx2 is also required for chondrocyte maturation, and Runx3 has a redundant function with Runx2 in chondrocyte maturation. Runx2 regulates the expression of Col10a1, Spp1, Ibsp, and Mmp13 in chondrocytes. It also inhibits chondrocytes from acquiring the phenotypes of permanent cartilage chondrocytes. It regulates chondrocyte proliferation through the regulation of Ihh expression. Runx2 enhances osteoclastogenesis by regulating Rankl. Cbfb, which is a co-transcription factor for Runx family proteins, plays an important role in skeletal development by stabilizing Runx family proteins. In Cbfb isoforms, Cbfb1 is more potent than Cbfb2 in Runx2-dependent transcriptional regulation; however, the expression level of Cbfb2 is three-fold higher than that of Cbfb1, demonstrating the requirement of Cbfb2 in skeletal development. The expression of Runx2 in osteoblasts is regulated by a 343-bp enhancer located upstream of the P1 promoter. This enhancer is activated by an enhanceosome composed of Dlx5/6, Mef2, Tcf7, Ctnnb1, Sox5/6, Smad1, and Sp7. Thus, Runx2 is a multifunctional transcription factor that is essential for skeletal development, and Cbfb regulates skeletal development by modulating the stability and transcriptional activity of Runx family proteins.


Runx2 Osteoblast Chondrocyte Cbfb Enhancer 



This work was supported by the grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology to TK (Grant number: 26221310).


  1. Adhami, M. D., Rashid, H., Chen, H., Clarke, J. C., Yang, Y., & Javed, A. (2015). Loss of Runx2 in committed osteoblasts impairs postnatal skeletogenesis. Journal of Bone and Mineral Research, 30(1), 71–82. doi: 10.1002/jbmr.2321.
  2. Aubin, J., & Triffitt, J. (2002). Mesenchymal stem cells and osteoblast differentiation. In J. P. Bilezikian, L. G. Raisz, & G. A. Rodan (Eds.), Principles of bone biology. New York: Academic Press.Google Scholar
  3. Banerjee, C., McCabe, L. R., Choi, J. Y., Hiebert, S. W., Stein, J. L., Stein, G. S., & Lian, J. B. (1997). Runt homology domain proteins in osteoblast differentiation: AML3/CBFA1 is a major component of a bone-specific complex. Journal of Cellular Biochemistry, 66(1), 1–8.CrossRefPubMedGoogle Scholar
  4. Bauer, O., Sharir, A., Kimura, A., Hantisteanu, S., Takeda, S., & Groner, Y. (2015). Loss of osteoblast Runx3 produces severe congenital osteopenia. Molecular and Cellular Biology, 35(7), 1097–1109. doi: 10.1128/mcb.01106-14.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Chen, W., Ma, J., Zhu, G., Jules, J., Wu, M., McConnell, M., et al. (2014). Cbfβ deletion in mice recapitulates cleidocranial dysplasia and reveals multiple functions of Cbfβ required for skeletal development. Proceedings of the National Academy of Sciences of the United States of America, 111(23), 8482–8487. doi: 10.1073/pnas.1310617111.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L., & Karsenty, G. (1997). Osf2/Cbfa1: A transcriptional activator of osteoblast differentiation. Cell, 89(5), 747–754.CrossRefPubMedGoogle Scholar
  7. Enomoto, H., Enomoto-Iwamoto, M., Iwamoto, M., Nomura, S., Himeno, M., Kitamura, Y., et al. (2000). Cbfa1 is a positive regulatory factor in chondrocyte maturation. The Journal of Biological Chemistry, 275(12), 8695–8702.CrossRefPubMedGoogle Scholar
  8. Enomoto, H., Shiojiri, S., Hoshi, K., Furuichi, T., Fukuyama, R., Yoshida, C. A., Kanatani, N., Nakamura, R., Mizuno, A., Zanma, A., Yano, K., Yasuda, H., Higashio, K., Takada, K., Komori, T. (2003). Induction of osteoclast differentiation by Runx2 through receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin regulation and partial rescue of osteoclastogenesis in Runx2−/− mice by RANKL transgene. The Journal of Biological Chemistry, 278(26), 23971–23977. doi:10.1074/jbc.M302457200 M302457200 [pii].Google Scholar
  9. Fei, T., Mengrui, W., Lianfu, D., Guochun, Z., Junqing, M., Bo, G., et al. (2014). Core binding factor beta (Cbfβ) controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog (Ihh) expression and inhibiting parathyroid hormone-related protein receptor (PPR) expression in postnatal cartilage and bone formation. Journal of Bone and Mineral Research, 29(7), 1564–1574. doi: 10.1002/jbmr.2275.CrossRefGoogle Scholar
  10. Fujiwara, M., Tagashira, S., Harada, H., Ogawa, S., Katsumata, T., Nakatsuka, M., Komori, T., Takada, H. (1999). Isolation and characterization of the distal promoter region of mouse Cbfa1. Biochimica et Biophysica Acta, 1446(3), 265–272. doi:S0167–4781(99)00113-X [pii].Google Scholar
  11. Gaur, T., Lengner, C. J., Hovhannisyan, H., Bhat, R. A., Bodine, P. V., Komm, B. S., et al. (2005). Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. The Journal of Biological Chemistry, 280(39), 33132–33140. doi: 10.1074/jbc.M500608200.CrossRefPubMedGoogle Scholar
  12. Geoffroy, V., Kneissel, M., Fournier, B., Boyde, A., & Matthias, P. (2002). High bone resorption in adult aging transgenic mice overexpressing Cbfa1/Runx2 in cells of the osteoblastic lineage. Molecular and Cellular Biology, 22(17), 6222–6233.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Harada, H., Tagashira, S., Fujiwara, M., Ogawa, S., Katsumata, T., Yamaguchi, A., et al. (1999). Cbfa1 isoforms exert functional differences in osteoblast differentiation. The Journal of Biological Chemistry, 274(11), 6972–6978.CrossRefPubMedGoogle Scholar
  14. Hassan, M. Q., Tare, R., Lee, S. H., Mandeville, M., Weiner, B., Montecino, M., et al. (2007). HOXA10 controls osteoblastogenesis by directly activating bone regulatory and phenotypic genes. Molecular and Cellular Biology, 27(9), 3337–3352. doi: 10.1128/mcb.01544-06.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Hess, J., Porte, D., Munz, C., & Angel, P. (2001). AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2/AP-1 composite element. The Journal of Biological Chemistry, 276(23), 20029–20038. doi: 10.1074/jbc.M010601200.CrossRefPubMedGoogle Scholar
  16. Himeno, M., Enomoto, H., Liu, W., Ishizeki, K., Nomura, S., Kitamura, Y., & Komori, T. (2002). Impaired vascular invasion of Cbfa1-deficient cartilage engrafted in the spleen. Journal of Bone and Mineral Research, 17(7), 1297–1305. doi: 10.1359/jbmr.2002.17.7.1297.CrossRefPubMedGoogle Scholar
  17. Huang, L. F., Fukai, N., Selby, P. B., Olsen, B. R., & Mundlos, S. (1997). Mouse clavicular development: Analysis of wild-type and cleidocranial dysplasia mutant mice. Developmental Dynamics, 210(1), 33–40. doi: 10.1002/(sici)1097-0177(199709)210:1<33::aid-aja4>;2-2.CrossRefPubMedGoogle Scholar
  18. Inada, M., Yasui, T., Nomura, S., Miyake, S., Deguchi, K., Himeno, M., et al. (1999). Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Developmental Dynamics, 214(4), 279–290. doi: 10.1002/(sici)1097-0177(199904)214:4<279::aid-aja1>;2-w.CrossRefPubMedGoogle Scholar
  19. 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. Molecular and Cell Biology, 21(8), 2891–2905 (0270-7306 (Print)).CrossRefGoogle Scholar
  20. Jiang, Q., Qin, X., Kawane, T., Komori, H., Matsuo, Y., Taniuchi, I., et al. (2016). Cbfb2 isoform dominates more potent Cbfb1 and is required for skeletal development. Journal of Bone and Mineral Research. doi: 10.1002/jbmr.2814.Google Scholar
  21. Jimenez, M. J., Balbin, M., Lopez, J. M., Alvarez, J., Komori, T., & Lopez-Otin, C. (1999). Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation. Molecular and Cellular Biology, 19(6), 4431–4442.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kamekura, S., Kawasaki, Y., Hoshi, K., Shimoaka, T., Chikuda, H., Maruyama, Z., et al. (2006). Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis and Rheumatism, 54(8), 2462–2470. doi: 10.1002/art.22041.CrossRefPubMedGoogle Scholar
  23. Kanatani, N., Fujita, T., Fukuyama, R., Liu, W., Yoshida, C. A., Moriishi, T., Yamana, K., Miyazaki, T., Toyosawa, S., Komori, T. (2006). Cbfβ regulates Runx2 function isoform-dependently in postnatal bone development. Developmental Biology, 296(1), 48–61. doi:S0012–1606(06)00242–9 [pii]10.1016/j.ydbio.2006.03.039.Google Scholar
  24. Kawane, T., Komori, H., Liu, W., Moriishi, T., Miyazaki, T., Mori, M., et al. (2014). Dlx5 and Mef2 regulate a novel Runx2 enhancer for osteoblast-specific expression. Journal of Bone and Mineral Research, 29(9), 1960–1969. doi: 10.1002/jbmr.2240.CrossRefPubMedGoogle Scholar
  25. Kern, B., Shen, J., Starbuck, M., & Karsenty, G. (2001). Cbfa1 contributes to the osteoblast-specific expression of type I collagen genes. The Journal of Biological Chemistry, 276(10), 7101–7107. doi: 10.1074/jbc.M006215200.CrossRefPubMedGoogle Scholar
  26. Kimura, A., Inose, H., Yano, F., Fujita, K., Ikeda, T., Sato, S., et al. (2010). Runx1 and Runx2 cooperate during sternal morphogenesis. Development, 137(7), 1159–1167. doi: 10.1242/dev.045005.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Komori, T. (2000). A fundamental transcription factor for bone and cartilage. Biochemical and Biophysical Research Communications, 276(3), 813–816. doi:10.1006/bbrc.2000.3460S0006-291X(00)93460–0 [pii].Google Scholar
  28. Komori, T. (2005). Regulation of skeletal development by the Runx family of transcription factors. Journal of Cellular Biochemistry, 95(3), 445–453. doi: 10.1002/jcb.20420.CrossRefPubMedGoogle Scholar
  29. Komori, T. (2006). Regulation of osteoblast differentiation by transcription factors. Journal of Cellular Biochemistry, 99(5), 1233–1239. doi: 10.1002/jcb.20958.CrossRefPubMedGoogle Scholar
  30. 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., Kishimoto, T. (1997). Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell, 89(5), 755–764. doi:S0092–8674(00)80258–5 [pii].Google Scholar
  31. Kundu, M., Javed, A., Jeon, J. P., Horner, A., Shum, L., Eckhaus, M., et al. (2002). Cbfβ interacts with Runx2 and has a critical role in bone development. Nature Genetics, 32(4), 639–644. doi: 10.1038/ng1050.CrossRefPubMedGoogle Scholar
  32. Lamour, V., Detry, C., Sanchez, C., Henrotin, Y., Castronovo, V., & Bellahcene, A. (2007). Runx2- and histone deacetylase 3-mediated repression is relieved in differentiating human osteoblast cells to allow high bone sialoprotein expression. The Journal of Biological Chemistry, 282(50), 36240–36249. doi: 10.1074/jbc.M705833200.CrossRefPubMedGoogle Scholar
  33. Lee, K. S., Kim, H. J., Li, Q. L., Chi, X. Z., Ueta, C., Komori, T., et al. (2000). Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Molecular and Cellular Biology, 20(23), 8783–8792.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Lee, M. H., Kim, Y. J., Yoon, W. J., Kim, J. I., Kim, B. G., Hwang, Y. S., et al. (2005). Dlx5 specifically regulates Runx2 type II expression by binding to homeodomain-response elements in the Runx2 distal promoter. The Journal of Biological Chemistry, 280(42), 35579–35587. doi: 10.1074/jbc.M502267200.CrossRefPubMedGoogle Scholar
  35. Lee, S. H., Che, X., Jeong, J. H., Choi, J. Y., Lee, Y. J., Lee, Y. H., et al. (2012). Runx2 protein stabilizes hypoxia-inducible factor-1alpha through competition with von Hippel-Lindau protein (pVHL) and stimulates angiogenesis in growth plate hypertrophic chondrocytes. The Journal of Biological Chemistry, 287(18), 14760–14771. doi: 10.1074/jbc.M112.340232.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Lengner, C. J., Drissi, H., Choi, J. Y., van Wijnen, A. J., Stein, J. L., Stein, G. S., & Lian, J. B. (2002). Activation of the bone-related Runx2/Cbfa1 promoter in mesenchymal condensations and developing chondrocytes of the axial skeleton. Mechanisms of Development, 114(1–2), 167–170.CrossRefPubMedGoogle Scholar
  37. Li, F., Lu, Y., Ding, M., Napierala, D., Abbassi, S., Chen, Y., et al. (2011). Runx2 contributes to murine Col10a1 gene regulation through direct interaction with its cis-enhancer. Journal of Bone and Mineral Research, 26(12), 2899–2910. doi: 10.1002/jbmr.504.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Liakhovitskaia, A., Lana-Elola, E., Stamateris, E., Rice, D. P., van’t Hof, R. J., & Medvinsky, A. (2010). The essential requirement for Runx1 in the development of the sternum. Developmental Biology, 340(2), 539–546. doi: 10.1016/j.ydbio.2010.02.005.CrossRefPubMedGoogle Scholar
  39. Lim, K. E., Park, N. R., Che, X., Han, M. S., Jeong, J. H., Kim, S. Y., et al. (2015). Core binding factor β of osteoblasts maintains cortical bone mass via stabilization of Runx2 in mice. Journal of Bone and Mineral Research, 30(4), 715–722. doi: 10.1002/jbmr.2397.CrossRefPubMedGoogle Scholar
  40. Liu, W., Toyosawa, S., Furuichi, T., Kanatani, N., Yoshida, C., Liu, Y., Himeno, M., Narai, S., Yamaguchi, A., Komori, T. (2001). Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures. The Journal of Cell Biology, 155(1), 157–166. doi:10.1083/jcb.200105052155/1/157 [pii].Google Scholar
  41. Marks Jr., S., & Odgren, P. (2002). Structure and development of the skeleton. In J. P. Bilezikian, L. G. Raisz, & G. A. Rodan (Eds.), Principles of bone biology. New York: Academic Press.Google Scholar
  42. Maruyama, Z., Yoshida, C. A., Furuichi, T., Amizuka, N., Ito, M., Fukuyama, R., et al. (2007). Runx2 determines bone maturity and turnover rate in postnatal bone development and is involved in bone loss in estrogen deficiency. Developmental Dynamics, 236(7), 1876–1890. doi: 10.1002/dvdy.21187.CrossRefPubMedGoogle Scholar
  43. Mikasa, M., Rokutanda, S., Komori, H., Ito, K., Tsang, Y. S., Date, Y., et al. (2011). Regulation of Tcf7 by Runx2 in chondrocyte maturation and proliferation. Journal of Bone and Mineral Metabolism, 29(3), 291–299. doi: 10.1007/s00774-010-0222-z.CrossRefPubMedGoogle Scholar
  44. Miller, J., Horner, A., Stacy, T., Lowrey, C., Lian, J. B., Stein, G., et al. (2002). The core-binding factor β subunit is required for bone formation and hematopoietic maturation. Nature Genetics, 32(4), 645–649. doi: 10.1038/ng1049.CrossRefPubMedGoogle Scholar
  45. Mundlos, S., Otto, F., Mundlos, C., Mulliken, J. B., Aylsworth, A. S., Albright, S., et al. (1997). Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell, 89(5), 773–779.CrossRefPubMedGoogle Scholar
  46. Ogawa, E., Inuzuka, M., Maruyama, M., Satake, M., Naito-Fujimoto, M., Ito, Y., & Shigesada, K. (1993). Molecular cloning and characterization of PEBP2 β, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2α. Virology, 194(1), 314–331. doi: 10.1006/viro.1993.1262.CrossRefPubMedGoogle Scholar
  47. Okuda, T., van Deursen, J., Hiebert, S. W., Grosveld, G., & Downing, J. R. (1996). AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell, 84(2), 321–330.CrossRefPubMedGoogle Scholar
  48. Otto, F., Thornell, A. P., Crompton, T., Denzel, A., Gilmour, K. C., Rosewell, I. R., et al. (1997). Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell, 89(5), 765–771.CrossRefPubMedGoogle Scholar
  49. Park, M. H., Shin, H. I., Choi, J. Y., Nam, S. H., Kim, Y. J., Kim, H. J., & Ryoo, H. M. (2001). Differential expression patterns of Runx2 isoforms in cranial suture morphogenesis. Journal of Bone and Mineral Research, 16(5), 885–892. doi: 10.1359/jbmr.2001.16.5.885.CrossRefPubMedGoogle Scholar
  50. Porte, D., Tuckermann, J., Becker, M., Baumann, B., Teurich, S., Higgins, T., et al. (1999). Both AP-1 and Cbfa1-like factors are required for the induction of interstitial collagenase by parathyroid hormone. Oncogene, 18(3), 667–678. doi: 10.1038/sj.onc.1202333.CrossRefPubMedGoogle Scholar
  51. Pullig, O., Weseloh, G., Gauer, S., & Swoboda, B. (2000). Osteopontin is expressed by adult human osteoarthritic chondrocytes: protein and mRNA analysis of normal and osteoarthritic cartilage. Matrix Biology, 19(3), 245–255.CrossRefPubMedGoogle Scholar
  52. Qin, X., Jiang, Q., Matsuo, Y., Kawane, T., Komori, H., Moriishi, T., et al. (2015). Cbfb regulates bone development by stabilizing Runx family proteins. Journal of Bone and Mineral Research, 30(4), 706–714. doi: 10.1002/jbmr.2379.CrossRefPubMedGoogle Scholar
  53. Sasaki, K., Yagi, H., Bronson, R. T., Tominaga, K., Matsunashi, T., Deguchi, K., et al. (1996). Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor β. Proceedings of the National Academy of Sciences of the United States of America, 93(22), 12359–12363.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Sato, M., Morii, E., Komori, T., Kawahata, H., Sugimoto, M., Terai, K., et al. (1998). Transcriptional regulation of osteopontin gene in vivo by PEBP2αA/CBFA1 and ETS1 in the skeletal tissues. Oncogene, 17(12), 1517–1525. doi: 10.1038/sj.onc.1202064.CrossRefPubMedGoogle Scholar
  55. Selvamurugan, N., Pulumati, M. R., Tyson, D. R., & Partridge, N. C. (2000). Parathyroid hormone regulation of the rat collagenase-3 promoter by protein kinase A-dependent transactivation of core binding factor α1. The Journal of Biological Chemistry, 275(7), 5037–5042.CrossRefPubMedGoogle Scholar
  56. Shlopov, B. V., Lie, W. R., Mainardi, C. L., Cole, A. A., Chubinskaya, S., & Hasty, K. A. (1997). Osteoarthritic lesions: Involvement of three different collagenases. Arthritis and Rheumatism, 40(11), 2065–2074. doi: 10.1002/1529-0131(199711)40:11&lt;2065::AID-ART20&gt;3.0.CO;2-0.CrossRefPubMedGoogle Scholar
  57. Tachibana, M., Tenno, M., Tezuka, C., Sugiyama, M., Yoshida, H., & Taniuchi, I. (2011). Runx1/Cbfβ2 complexes are required for lymphoid tissue inducer cell differentiation at two developmental stages. Journal of Immunology, 186(3), 1450–1457. doi: 10.4049/jimmunol.1000162.CrossRefGoogle Scholar
  58. Takarada, T., Hinoi, E., Nakazato, R., Ochi, H., Xu, C., Tsuchikane, A., et al. (2013). An analysis of skeletal development in osteoblast-specific and chondrocyte-specific runt-related transcription factor-2 (Runx2) knockout mice. Journal of Bone and Mineral Research, 28(10), 2064–2069. doi: 10.1002/jbmr.1945.CrossRefPubMedGoogle Scholar
  59. Takeda, S., Bonnamy, J. P., Owen, M. J., Ducy, P., & Karsenty, G. (2001). Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes & Development, 15(4), 467–481. doi: 10.1101/gad.845101.CrossRefGoogle Scholar
  60. Toyosawa, S., Shintani, S., Fujiwara, T., Ooshima, T., Sato, A., Ijuhin, N., & Komori, T. (2001). Dentin matrix protein 1 is predominantly expressed in chicken and rat osteocytes but not in osteoblasts. Journal of Bone and Mineral Research, 16(11), 2017–2026. doi: 10.1359/jbmr.2001.16.11.2017.CrossRefPubMedGoogle Scholar
  61. Ueta, C., Iwamoto, M., Kanatani, N., Yoshida, C., Liu, Y., Enomoto-Iwamoto, M., et al. (2001). Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. The Journal of Cell Biology, 153(1), 87–100.CrossRefPubMedPubMedCentralGoogle Scholar
  62. von der Mark, K., Kirsch, T., Nerlich, A., Kuss, A., Weseloh, G., Gluckert, K., & Stoss, H. (1992). Type X collagen synthesis in human osteoarthritic cartilage. Indication of chondrocyte hypertrophy. Arthritis and Rheumatism, 35(7), 806–811.CrossRefPubMedGoogle Scholar
  63. Wang, Q., Stacy, T., Binder, M., Marin-Padilla, M., Sharpe, A. H., & Speck, N. A. (1996a). Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proceedings of the National Academy of Sciences of the United States of America, 93(8), 3444–3449.CrossRefPubMedPubMedCentralGoogle Scholar
  64. Wang, Q., Stacy, T., Miller, J. D., Lewis, A. F., Gu, T. L., Huang, X., et al. (1996b). The CBFβ subunit is essential for CBFα2 (AML1) function in vivo. Cell, 87(4), 697–708.CrossRefPubMedGoogle Scholar
  65. Wu, M., Li, C., Zhu, G., Wang, Y., Jules, J., Lu, Y., et al. (2014a). Deletion of core-binding factor β (Cbfβ) in mesenchymal progenitor cells provides new insights into Cbfβ/Runxs complex function in cartilage and bone development. Bone, 65, 49–59. doi: 10.1016/j.bone.2014.04.031.CrossRefPubMedPubMedCentralGoogle Scholar
  66. Wu, M., Li, Y. P., Zhu, G., Lu, Y., Wang, Y., Jules, J., et al. (2014b). Chondrocyte-specific knockout of Cbfβ reveals the indispensable function of Cbfβ in chondrocyte maturation, growth plate development and trabecular bone formation in mice. International Journal of Biological Sciences, 10(8), 861–872. doi: 10.7150/ijbs.8521.CrossRefPubMedPubMedCentralGoogle Scholar
  67. Yoshida, C. A., Furuichi, T., Fujita, T., Fukuyama, R., Kanatani, N., Kobayashi, S., Satake, M., Takada, K., Komori, T. (2002). Core-binding factor β interacts with Runx2 and is required for skeletal development. Nature Genetics, 32(4), 633–638. doi: 10.1038/ng1015ng1015 [pii].
  68. Yoshida, C. A., Yamamoto, H., Fujita, T., Furuichi, T., Ito, K., Inoue, K., Yamana, K., Zanma, A., Takada, K., Ito, Y., Komori, T. (2004). Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Developement, 18(8), 952–963. doi:10.1101/gad.1174704 18/8/952 [pii].Google Scholar
  69. Yoshida, C. A., Komori, H., Maruyama, Z., Miyazaki, T., Kawasaki, K., Furuichi, T., et al. (2012). SP7 inhibits osteoblast differentiation at a late stage in mice. PloS One, 7(3), e32364. doi: 10.1371/journal.pone.0032364.CrossRefPubMedPubMedCentralGoogle Scholar
  70. Zambotti, A., Makhluf, H., Shen, J., & Ducy, P. (2002). Characterization of an osteoblast-specific enhancer element in the CBFA1 gene. The Journal of Biological Chemistry, 277(44), 41497–41506. doi: 10.1074/jbc.M204271200.CrossRefPubMedGoogle Scholar
  71. Zelzer, E., Glotzer, D. J., Hartmann, C., Thomas, D., Fukai, N., Soker, S., & Olsen, B. R. (2001). Tissue specific regulation of VEGF expression during bone development requires Cbfa1/Runx2. Mechanisms of Development, 106(1–2), 97–106.CrossRefPubMedGoogle Scholar
  72. Zhang, Y., Hassan, M. Q., Xie, R. L., Hawse, J. R., Spelsberg, T. C., Montecino, M., et al. (2009). Co-stimulation of the bone-related Runx2 P1 promoter in mesenchymal cells by SP1 and ETS transcription factors at polymorphic purine-rich DNA sequences (Y-repeats). The Journal of Biological Chemistry, 284(5), 3125–3135. doi: 10.1074/jbc.M807466200.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Department of Cell Biology, Unit of Basic Medical SciencesNagasaki University Graduate School of Biomedical SciencesNagasakiJapan

Personalised recommendations