Cell and Tissue Research

, 339:189 | Cite as

Regulation of bone development and extracellular matrix protein genes by RUNX2

Review

Abstract

RUNX2 is a multifunctional transcription factor that controls skeletal development by regulating the differentiation of chondrocytes and osteoblasts and the expression of many extracellular matrix protein genes during chondrocyte and osteoblast differentiation. This transcription factor plays a major role at the late stage of chondrocyte differentiation: it is required for chondrocyte maturation and regulates Col10a1 expression in hypertrophic chondrocytes and the expression of Spp1, Ibsp, and Mmp13 in terminal hypertrophic chondrocytes. It is essential for the commitment of pluripotent mesenchymal cells to the osteoblast lineage. During osteoblast differentiation, RUNX2 upregulates the expression of bone matrix protein genes including Col1a1, Spp1, Ibsp, Bglap, and Fn1 in vitro and activates many promoters including those of Col1a1, Col1a2, Spp1, Bglap, and Mmp13. However, overexpression of Runx2 inhibits osteoblast maturation and reduces Col1a1 and Bglap expression. The inhibition of RUNX2 in mature osteoblasts does not reduce the expression of Col1a1 and Bglap in mice. Thus, RUNX2 directs pluripotent mesenchymal cells to the osteoblast lineage, triggers the expression of major bone matrix protein genes, and keeps the osteoblasts in an immature stage, but does not play a major role in the maintenance of the expression of Col1a1 or Bglap in mature osteoblasts. During bone development, RUNX2 induces osteoblast differentiation and increases the number of immature osteoblasts, which form immature bone, whereas Runx2 expression has to be downregulated for differentiation into mature osteoblasts, which form mature bone. During dentinogenesis, Runx2 expression is downregulated, and RUNX2 inhibits the terminal differentiation of odontoblasts.

Keywords

RUNX2 COL1A1 SPP1 BGLAP IBSP Extracellular matrix Skeletal development 

References

  1. Aguiar MC, Arana-Chavez VE (2007) Ultrastructural and immunocytochemical analysis of osteopontin in reactionary and reparative dentine formed after extrusion of upper rat incisors. J Anat 210:418–427CrossRefPubMedGoogle Scholar
  2. Aubin JE, Triffitt JT (2002) Mesenchymal stem cells and osteoblast differentiation. In: Bilezikian JP, Raisz LG, Rodan GA (eds) Principles of bone biology. Academic Press, New York, pp 59–81Google Scholar
  3. 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 66:1–8CrossRefPubMedGoogle Scholar
  4. Banerjee C, Javed A, Choi JY, Green J, Rosen V, Wijnen AJ van, Stein JL, Lian JB, Stein GS (2001) Differential regulation of the two principal Runx2/Cbfa1 N-terminal isoforms in response to bone morphogenetic protein-2 during development of the osteoblast phenotype. Endocrinology 142:4026–4039CrossRefPubMedGoogle Scholar
  5. Begue-Kirn C, Krebsbach PH, Bartlett JD, Butler WT (1998) Dentin sialoprotein, dentin phosphoprotein, enamelysin and ameloblastin: tooth-specific molecules that are distinctively expressed during murine dental differentiation. Eur J Oral Sci 106:963–970CrossRefPubMedGoogle Scholar
  6. Bronckers AL, Engelse MA, Cavender A, Gaikwad J, D’Souza RN (2001) Cell-specific patterns of Cbfa1 mRNA and protein expression in postnatal murine dental tissues. Mech Dev 101:255–258CrossRefPubMedGoogle Scholar
  7. Chen S, Rani S, Wu Y, Unterbrink A, Gu TT, Gluhak-Heinrich J, Chuang H-H, MacDougall M (2005) Differential regulation of dentin sialophosphoprotein expression by Runx2 during odontoblasts cytodifferentiation. J Biol Chem 280:29717–29727CrossRefPubMedGoogle Scholar
  8. Choi KY, Lee SW, Park MH, Bae YC, Shin HI, Nam S, Kim YJ, Kim HJ, Ryoo HM (2002) Spatio-temporal expression patterns of Runx2 isoforms in early skeletogenesis. Exp Mol Med 34:426–433PubMedGoogle Scholar
  9. Drissi MH, Li X, Sheu TJ, Zuscik MJ, Schwarz EM, Puzas JE, Rosier RN, O’Keefe RJ (2003) Runx2/Cbfa1 stimulation by retinoic acid is potentiated by BMP2 signaling through interaction with Smad1 on the collagen X promoter in chondrocytes. J Cell Biochem 90:1287–1298CrossRefPubMedGoogle Scholar
  10. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–754CrossRefPubMedGoogle Scholar
  11. Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V, Amling M, Karsenty G (1999) A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev 13:1025–1036CrossRefPubMedGoogle Scholar
  12. D’Souza RN, Cavender A, Sunavala G, Alvarez J, Oshima T, Kulkarni AB, MacDougall M (1997) Gene expression patterns of murine dentin matrix protein 1 (Dmp1) and dentin sialophosphoprotein (DSPP) suggest distinct developmental functions in vivo. J Bone Miner Res 12:2040–2049CrossRefPubMedGoogle Scholar
  13. Enomoto H, Enomoto-Iwamoto M, Iwamoto M, Nomura S, Himeno M, Kitamura Y, Kishimoto T, Komori T (2000) Cbfa1 is a positive regulatory factor in chondrocyte maturation. J Biol Chem 275:8695–8702CrossRefPubMedGoogle Scholar
  14. Fosang AJ, Last K, Knäuper V, Murphy G, Neame PJ (1996) Degradation of cartilage aggrecan by collagenase-3 (MMP-13). FEBS Lett 380:17–20CrossRefPubMedGoogle Scholar
  15. 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. Mol Cell Biol 22:6222–6233CrossRefPubMedGoogle Scholar
  16. Harada H, Tagashira S, Fujiwara M, Ogawa S, Katsumata T, Yamaguchi A, Komori T, Nakatsuka M (1999) Cbfa1 isoforms exert functional differences in osteoblast differentiation. J Biol Chem 274:6972–6978CrossRefPubMedGoogle Scholar
  17. 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. J Biol Chem 276:20029–20038CrossRefPubMedGoogle Scholar
  18. Higashikawa A, Saito T, Ikeda T, Kamekura S, Kawamura N, Kan A, Oshima Y, Ohba S, Ogata N, Takeshita K, Nakamura K, Chung UI, Kawaguchi H (2009) Identification of the core element responsive to runt-related transcription factor 2 in the promoter of human type X collagen gene. Arthritis Rheum 60:166–178CrossRefPubMedGoogle Scholar
  19. Inada M, Yasui T, Nomura S, Miyake S, Deguchi K, Himeno M, Sato M, Yamagiwa H, Kimura T, Yasui N, Ochi T, Endo N, Kitamura Y, Kishimoto T, Komori T (1999) Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev Dyn 214:279–290CrossRefPubMedGoogle Scholar
  20. Inada M, Wang Y, Byrne MH, Rahman MU, Miyaura C, López-Otín C, Krane SM (2004) Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc Natl Acad Sci USA 101:17192–17197CrossRefPubMedGoogle Scholar
  21. Javed A, Barnes GL, Jasanya BO, Stein JL, Gerstenfeld L, Lian JB, Stein GS (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 21:2891–2905CrossRefPubMedGoogle Scholar
  22. Jiménez MJ, Balbín M, López JM, Alvarez J, Komori T, López-Otín C (1999) Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation. Mol Cell Biol 19:4431–4442PubMedGoogle Scholar
  23. Kamekura S, Kawasaki Y, Hoshi K, Shimoaka T, Chikuda H, Maruyama Z, Komori T, Sato S, Takeda S, Karsenty G, Nakamura K, Chung UI, Kawaguchi H (2006) Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum 54:2462–2470CrossRefPubMedGoogle Scholar
  24. Kanatani N, Fujita T, Fukuyama R, Liu W, Yoshida CA, Moriishi T, Yamana K, Miyazaki T, Toyosawa S, Komori T (2006) Cbfβ regulates Runx2 function isoform-dependently in postnatal bone development. Dev Biol 296:48–61CrossRefPubMedGoogle Scholar
  25. Kern B, Shen J, Starbuck M, Karsenty G (2001) Cbfa1 contributes to the osteoblast-specific expression of type I collagen genes. J Biol Chem 276:7101–7107CrossRefPubMedGoogle Scholar
  26. Kim IS, Otto F, Zabel B, Mundlos S (1999) Regulation of chondrocyte differentiation by Cbfa1. Mech Dev 80:159–170CrossRefPubMedGoogle Scholar
  27. Knäuper V, López-Otin C, Smith B, Knight G, Murphy G (1996) Biochemical characterization of human collagenase-3. J Biol Chem 271:1544–1550CrossRefPubMedGoogle Scholar
  28. Komori T (2005) Regulation of skeletal development by the Runx family of transcription factors. J Cell Biochem 95:445–453CrossRefPubMedGoogle Scholar
  29. Komori T (2006) Regulation of osteoblast differentiation by transcription factors. J Cell Biochem 99:1233–1239CrossRefPubMedGoogle Scholar
  30. Komori T, Kishimoto T (1998) Cbfa1 in bone development. Curr Opin Genet Dev 8:494–499CrossRefPubMedGoogle Scholar
  31. 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 89:755–764CrossRefPubMedGoogle Scholar
  32. Kundu M, Javed A, Jeon JP, Horner A, Shum L, Eckhaus M, Muenke M, Lian JB, Yang Y, Nuckolls GH, Stein GS, Liu PP (2002) Cbfβ interacts with Runx2 and has a critical role in bone development. Nat Genet 32:547–552CrossRefGoogle Scholar
  33. Lamour V, Detry C, Sanchez C, Henrotin Y, Castronovo V, Bellahcène A (2007) Runx2- and histone deacetylase 3-mediated repression is relieved in differentiating human osteoblast cells to allow high bone sialoprotein expression. J Biol Chem 282:36240–36249CrossRefPubMedGoogle Scholar
  34. Lee KS, Kim HJ, Li QL, Chi XZ, Ueta C, Komori T, Wozney JM, Kim EG, Choi JY, Ryoo HM, Bae SC (2000) Runx2 is a common target of transforming growth factor β1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Mol Cell Biol 20:8783–8792CrossRefPubMedGoogle Scholar
  35. 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. J Cell Biol 155:157–166CrossRefPubMedGoogle Scholar
  36. Marks SC Jr, Odgren PR (2002) Structure and development of the skeleton. In: Bilezikian JP, Raisz LG, Rodan GA (eds) Principles of bone biology. Academic Press, pp 3–15Google Scholar
  37. Maruyama Z, Yoshida CA, Furuichi T, Amizuka N, Ito M, Fukuyama R, Miyazaki T, Kitaura H, Nakamura K, Fujita T, Kanatani N, Moriishi T, Yamana K, Liu W, Kawaguchi H, Nakamura K, Komori T (2007) Runx2 determines bone maturity and turnover rate in postnatal bone development and is involved in bone loss in estrogen deficiency. Dev Dyn 236:1876–1890CrossRefPubMedGoogle Scholar
  38. Miller J, Horner A, Stacy T, Lowrey C, Lian JB, Stein G, Nuckolls GH, Speck NA (2002) The core-binding factor β subunit is required for bone formation and hematopoietic maturation. Nat Genet 32:645–649CrossRefPubMedGoogle Scholar
  39. Miyazaki T, Kanatani N, Rokutanda S, Yoshida C, Toyosawa S, Nakamura R, Takada S, Komori T (2008) Inhibition of terminal differentiation of odontoblasts and their transdifferentiation into osteoblasts in Runx2 transgenic mice. Arch Histol Cytol 71:131–146CrossRefPubMedGoogle Scholar
  40. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, 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 89:765–771CrossRefPubMedGoogle Scholar
  41. Pacifici M (1995) Tenascin-C and the development of articular cartilage. Matrix Biol 14:689–698CrossRefPubMedGoogle Scholar
  42. Porte D, Tuckermann J, Becker M, Baumann B, Teurich S, Higgins T, Owen MJ, Schorpp-Kistner M, Angel P (1999) Both AP-1 and Cbfa1-like factors are required for the induction of interstitial collagenase by parathyroid hormone. Oncogene 18:667–678CrossRefPubMedGoogle Scholar
  43. Sato M, Morii E, Komori T, Kawahata H, Sugimoto M, Terai K, Shimizu H, Yasui T, Ogihara H, Yasui N, Ochi T, Kitamura Y, Ito Y, Nomura S (1998) Transcriptional regulation of osteopontin gene in vivo by PEBP2aA/CBFA1 and ETS1 in the skeletal tissues. Oncogene 17:1517–1525CrossRefPubMedGoogle Scholar
  44. Selvamurugan N, Pulumati MR, Tyson DR, Partridge NC (2000) Parathyroid hormone regulation of the rat collagenase-3 promoter by protein kinase A-dependent transactivation of core binding factor α1. J Biol Chem 275:5037–5042CrossRefPubMedGoogle Scholar
  45. Simeone A, Daga A, Calabi F (1995) Expression of runt in the mouse embryo. Dev Dyn 203:61–70PubMedGoogle Scholar
  46. Stricker S, Fundele R, Vortkamp A, Mundlos S (2002) Role of Runx genes in chondrocyte differentiation. Dev Biol 245:95–108CrossRefPubMedGoogle Scholar
  47. Terling C, Rass A, Mitsiadis TA, Fried K, Lendahl U, Wroblewski J (1995) Expression of the intermediate filament nestin during rodent tooth development. Int J Dev Biol 39:947–956PubMedGoogle Scholar
  48. 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. J Bone Miner Res 16:2017–2026CrossRefPubMedGoogle Scholar
  49. Ueta C, Iwamoto M, Kanatani N, Yoshida C, Liu Y, Enomoto-Iwamoto M, Ohmori T, Enomoto H, Nakata K, Takada K, Kurisu K, Komori T (2001) Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J Cell Biol 153:87–100CrossRefPubMedGoogle Scholar
  50. Wang X, Manner PA, Horner A, Shum L, Tuan RS, Nuckolls GH (2004) Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage. Osteoarthritis Cartilage 12:963–973CrossRefPubMedGoogle Scholar
  51. Xiao Z, Awad HA, Liu S, Mahlios J, Zhang S, Guilak F, Mayo MS, Quarles LD (2005) Selective Runx2-II deficiency leads to low-turnover osteopenia in adult mice. Dev Biol 283:345–356CrossRefPubMedGoogle Scholar
  52. Yamashiro T, Aberg T, Levanon D, Groner Y, Thesleff I (2002) Expression of Runx1, -2 and -3 during tooth, palate and craniofacial bone development. Mech Dev 119S:S107–S110CrossRefGoogle Scholar
  53. Yoshida CA, 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. Nat Genet 32:633–638CrossRefPubMedGoogle Scholar
  54. Yoshida CA, 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 Dev 18:952–963CrossRefPubMedGoogle Scholar
  55. Young MF, Ibaraki K, Kerr JM, Heegaard AM (1993) Molecular and cellular biology of the major noncollagenous proteins in bone. In: Noda M (ed) Cellular and molecular biology of bone. Academic Press, London, pp 191–234Google Scholar
  56. Zheng Q, Zhou G, Morello R, Chen Y, Garcia-Rojas X, Lee B (2003) Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J Cell Biol 162:833–842CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

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

Personalised recommendations