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Cbfa1 Is a Master Gene for Osteoblast Differentiation

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Mechanical Loading of Bones and Joints
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Summary

A transcription factor, Cbfa1, which belongs to the runt-domain gene family, is expressed restrictively in fetal development. Cbfa1 expression was first detected at embryonic day 9.5, which is four days earlier than the beginning of ossification, and was preferentially detected in the osteoblast lineage during osteogenesis. Cbfa1 deficient mice lacked both intramembranous and endochondral ossification completely. The skeletons of the mutant mice are composed of cartilage and fibrous tissues in calvaria. Cbfa1 mutant mice expressed alkaline phosphatase and osteonectin, which are the markers for osteoprogenitors, but not osteopontin and osteocalcin, which are the markers for immature osteoblasts and mature osteoblasts respectively. Therefore, the differentiation of osteoblast was blocked in the mutant mice. Further, Cbfa1 expression in nonosteoblastic cells induced osteoblastic markers in vitro. These data demonstrate that Cbfa1 is an essential transcription factor for osteoblast differentiation. The maturational disturbance of osteoclast and chondrocyte was also observed in the mutant mice, indicating the direct or indirect role of Cbfa1 in the differentiation of osteoclast and chondrocyte. Heterozygously mutated mice in the Cbfa1 locus showed the similar phenotype with cleidocranial dysplasia, which is an autosomal inherited disease. The mutations of CBFA1 locus were identified in cleidocranial dysplasia patients.

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References

  1. Suda T, Udagawa N, Takahashi N (1996) Cells of bone: osteoclast generation. In: Bilezikian JP, Raisz LG, Rodan GA (eds) Principles of bone biology. Academic, London, pp 87–102

    Google Scholar 

  2. Aubin JE, Turksen K, Heersche JNM (1993) Osteoblastic lineage. In: Noda M (ed) Cellular and molecular biology of bone. Academic, London, pp 1–45

    Google Scholar 

  3. Weintraub H (1993) The MyoD family and myogenesis: redundancy, networks, and thresholds. Cell 75:1241–1244

    Article  PubMed  CAS  Google Scholar 

  4. Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPARy2, a lipid-activated transcription factor. Cell 79:1147–1156

    Article  PubMed  CAS  Google Scholar 

  5. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, 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 89:755–764

    Article  PubMed  CAS  Google Scholar 

  6. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GWH, Beddington RSP, Mundlos S, Olsen BR, Selby PB, Owen MJ (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–771

    Article  PubMed  CAS  Google Scholar 

  7. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–754

    Article  PubMed  CAS  Google Scholar 

  8. Ogawa E, Maruyama M, Kagoshima H, Inuzuka M, Lu J, Satake M, Shigesada K, Ito Y (1993) PEBP2/PEA2 represents a new family of transcription factor homologous to the products of the Drosophila runt and the human AML1 gene. Proc Natl Acad Sei USA 90:6859–6863

    Article  CAS  Google Scholar 

  9. Bae SC, Yamaguchi-Iwai Y, Ogawa E, Maruyama M, Inuzuka M, Kagoshima H, Shigesada K, Satake M, Ito Y (1993) Isolation of PEBP2ocB cDNA representing the mouse homolog of human acute myeloid leukemia gene, AML1. Oncogene 8:809–814

    PubMed  CAS  Google Scholar 

  10. Bae SC, Takahashi E, Zhang YW, Ogawa E, Shigesada K, Namba Y, Satake M, Ito Y (1995) Cloning, mapping and expression of PEBP2aC, a third gene encoding the mammalian Runt domain. Gene 159:245–248

    Article  PubMed  CAS  Google Scholar 

  11. Kania MA, Bonner AS, Duffy JB, Gergen JP (1990) The Drosophila segmentation gene runt encodes a novel nuclear regulatory protein that is also expressed in the developing nervous system. Genes Dev 4:1701–1713

    Article  PubMed  CAS  Google Scholar 

  12. Ogawa E, Inuzaka M, Maruyama M, Satake M, Naito-Fujimoto M, Ito Y, Shigesada K (1993) Molecular cloning and characterization of PEBP2ß, the heterodimeric partner of a novel Dorosophila runt-related DNA binding protein PEBP2α. Virology 194:314–331

    Article  PubMed  CAS  Google Scholar 

  13. Wang S, Wang Q, Crute BE, Melnikova IN, Keller SR, Speck NA (1993) Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor. Mol Cell Biol 13:3324–3339

    PubMed  CAS  Google Scholar 

  14. Kamachi Y, Ogawa E, Asano M, Ishida S, Murakami Y, Satake M, Ito Y, Shigesada K (1990) Purification of a mouse nuclear factor that binds to both the A and B cores of the Polyomavirus enhancer. J Virol 64:4808–4819

    PubMed  CAS  Google Scholar 

  15. Wang S, Speck NA (1992) Purification of core-binding factor, a protein that binds the conserved core site in murine leukemia virus enhancers. Mol Cell Biol 12:89–102

    PubMed  CAS  Google Scholar 

  16. Geoffroy V, Ducy P, Karsenty G (1995) A PEBP2α/AML-1-related factor increases osteocalcin promoter activity through its binding to an osteoblast-specific cis-acting element. J Biol Chem 270:30973–30979

    Article  PubMed  CAS  Google Scholar 

  17. Merriman HL, van Wijnen AJ, Hiebert S, Bidwell JP, Fey E, Lian J, Stein J, Stein GS (1995) The tissue-specific nuclear matrix protein, NMP-2, is a member of the AML/CBF/PEBP2/Runt domain transcription factor family: interaction with the osteocalcin gene promoter. Biochemistry 34:13125–13132

    Article  PubMed  CAS  Google Scholar 

  18. Banerjee C, Hiebert SW, Stein JL, Lian JB, Stein GS (1996) An AML-1 consensus sequence binds an osteoblast-specific complex and transcriptionally activates the osteocalcin gene. Proc Natl Acad Sei USA 93:4968–4973

    Article  CAS  Google Scholar 

  19. Sasaki K, Yagi H, Bronson RT, Tominaga K, Matsunashi T, Deguchi K, Tani Y, Kishimoto T, Komori T (1996) Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor ß. Proc Natl Acad Sci USA 93:12359–12363

    Article  PubMed  CAS  Google Scholar 

  20. Wang Q, Stacy T, Miller JD, Lewis AF, Gu TL, Huang X, Bushweller JH, Bories JC, Alt FW, Ryan G, Liu PP, Wynshaw-Boris A, Binder M, Marin-Padilla M, Sharp AH, Speck NA (1996) The CBFß subunit is essential for CBFα2 (AML1) function in vivo. Cell 87:697–708

    Article  PubMed  CAS  Google Scholar 

  21. Satake M, Nomura S, Yamaguchi-Iwai Y, Takahama Y, Hashimoto Y, Niki M, Kitamura Y, Ito Y (1995) Expression of the runt domain-encoding PEBP2α genes in T cells during thymic development. Mol Cell Biol 15:1662–1670

    PubMed  CAS  Google Scholar 

  22. Ahn MY, Bae SC, Maruyama M, Ito Y (1996) Comparison of the human genomic structure of the Runt domain-encoding PEBP2/CBFα gene family. Gene 168:279–280

    Article  PubMed  CAS  Google Scholar 

  23. Stewart M, Terry A, Hu M, O’hara M, Blyth K, Baxter E, Cameron E, Onions DE, Neil JC (1997) Proviral insertions induce the expression of bone-specific isoforms of PEBP2αA (CBFA1): evidence for a new myc collaborating oncogene. Proc Natl Acad Sci USA 94:8646–8651

    Article  PubMed  CAS  Google Scholar 

  24. Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Henn W, Knoll JH M, Owen MJ, Mertelsmann R, Zabel BU, Olsen BR (1997) Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89:773–779

    Article  PubMed  CAS  Google Scholar 

  25. Banerjee C, McCabe LR, Choi J, Hiebert SW, Stein JL, Stein GS, Lian JB (1997) Runt homology domain proteins in osteoblast differentiation: AML3/CBFA1 is a major component of a bone-specific complex. J Cell Biochem 66:1–8

    Article  PubMed  CAS  Google Scholar 

  26. Jarvis JL, Keats TE (1974) Cleidocranial dysostosis, a review of 40 new cases. Am J Radiol 121:5–16

    CAS  Google Scholar 

  27. Mundlos S, Mulliken JB, Abramson DL, Warman ML, Knoll JH M, Olsen BR (1995) Genetic mapping of cleidocranial dysplasia and evidence of a microdeletion in one family. Hum Mol Genet 4:71–75

    PubMed  CAS  Google Scholar 

  28. Mundlos S, Huang LF, Selby P, Olsen BR (1996) Cleidocranial dysplasia in mice. Ann NY Acad Sci 785:301–302

    Article  PubMed  CAS  Google Scholar 

  29. Levanon D, Negreanu V, Bernstein Y, Bar-Am I, Avivi L, Groner, Y (1994) AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression, and chromosomal localization. Genomics 23:425–432

    Article  PubMed  CAS  Google Scholar 

  30. Lee B, Thirunavukkarasu K, Zhou L, Pastore L, Baldini A, Hecht J, Geoffroy V, Ducy P, Karsenty G (1997) Missense mutations abolishing DNA binding of the osteoblast-specifk transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nature Genet 16:307–310

    Article  PubMed  CAS  Google Scholar 

  31. Zhang Y, Bae S, Takahashi E, Ito Y (1997) The cDNA cloning of the transcripts of human PEBP2αA/CBFA1 mapped to 6p12.3–p21.1, the locus for cleidocranial dysplasia. Oncogene 15:367–371

    Article  PubMed  CAS  Google Scholar 

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© 1999 Springer-Verlag Tokyo

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Komori, T. (1999). Cbfa1 Is a Master Gene for Osteoblast Differentiation. In: Takahashi, H.E. (eds) Mechanical Loading of Bones and Joints. Springer, Tokyo. https://doi.org/10.1007/978-4-431-65892-4_29

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  • DOI: https://doi.org/10.1007/978-4-431-65892-4_29

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-65894-8

  • Online ISBN: 978-4-431-65892-4

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