Molecular Mechanism of Osteochondroprogenitor Fate Determination During Bone Formation

  • Lijin Zou
  • Xuenong Zou
  • Haisheng Li
  • Tina Mygind
  • Yuanlin Zeng
  • Nonghua Lü
  • Cody Bünger
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 585)

28.1 Abstract

Osteoblasts and chondrocytes, which derive from a common mesenchymal precursor (osteochondroprogenitor), are involved in bone formation and remodeling in vivo. Determination of osteochondroprogenitor fate is under the control of complex hormonal and local factors converging onto a series of temporospatial dependent transcription regulators. Sox9, together with L-Sox5 and Sox6, of the Sox family is required for chondrogenic differentiation commitment, while Runx2/Cbfa1, a member of runt family and Osterix/Osx, a novel zinc finger-containing transcription factor play a pivotal role in osteoblast differentiation decision and hypertrophic chondrocyte maturation. Recent in vitro and in vivo evidence suggests β-catenin, a transcriptional activator in the canonical Wnt pathway, can act as a determinant factor for controlling chondrocyte and osteoblast differentiation. Here we focus on several intensively studied transcription factors and Wnt/β-catenin signal molecules to illustrate the regulatory mechanism in directing commitment between osteoblast and chondrocyte, which will eventually allow us to properly manipulate the mesenchymal progenitor cell differentiation on bone and regeneration of cartilage tissue engineering.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

28.9. References

  1. 1.
    J. Fang and B.K. Hall, Chondrogenic cell differentiation from membrane bone periostea, Ana. Embryol. 196(5), 349–362(1997).CrossRefGoogle Scholar
  2. 2.
    C.D. Toma, J.L. Schaffer, M.C. Meazzini, D. Zurakowski, H.D. Nah and L.C. Gerstenfeld, Developmental restriction of embryonic calvarial cell populations as characterized by their in vitro potential for chondrogenic differentiation, J. Bone Miner. Res. 12(12), 2024–2039(1997).CrossRefGoogle Scholar
  3. 3.
    T. Aberg, R. Rice, D. Rice, I. Thesleff and J. Waltimo-Siren, Chondrogenic potential of mouse calvarial mesenchyme, J. Histochem. Cytochem. 3(5), 653–663(2005).CrossRefGoogle Scholar
  4. 4.
    H. Akiyama, M.C. Chaboisser, J.F. Martin, A. Schedl and B. de Crombrugghe, The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6, Genes Dev. 16(21), 2813–2828(2002).CrossRefGoogle Scholar
  5. 5.
    Q. Zhao, H. Eberspaecher, V. Lefebvre and B. de Crombrugghe, Parallel expression of Sox9 and Col2a1 in cells undergoing chondrogenesis, Dev. Dyn. 209(4), 377–386(1997).CrossRefGoogle Scholar
  6. 6.
    V. Lefebvre, W. Huang, V.R. Harley, P.N. Goodfellow and B. de Crombrugghe, SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro α1(II) collagen gene, Mol. Cell Biol. 17(4), 2336–2346(1997).Google Scholar
  7. 7.
    L.C. Bridgewater, V. Lefebvre and B. de Crombrugghe, Chondrocyte-specific enhancer elements in the Col11a2 gene resemble the Col2a1 tissue-specific enhancer, J. Biol. Chem. 273(24), 14998–15006(1998).CrossRefGoogle Scholar
  8. 8.
    I. Sekiya, K. Tsuji, P. Koopman, H. Watanabe, Y. Yamada, K. Shinomiya, A. Nifuji and M. Noda, SOX9 enhances aggrecan gene promoter/enhancer activity and is up-regulated by retinoic acid in a cartilagederived cell line, TC6, J. Biol. Chem. 275(15), 10738–10744(2000).CrossRefGoogle Scholar
  9. 9.
    P. Smits, P. Li, J. Mandel, Z. Zhang, J.M. Deng, R.R. Behringer, B. de Croumbrugghe and V. Lefebvre, The transcription factors L-Sox5 and Sox6 are essential for cartilage formation, Dev. Cell 1(2), 277–290(2001).CrossRefGoogle Scholar
  10. 10.
    V. Lefebvre, P. Li and B. de Crombrugghe, A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene, EMBO J. 17(19), 5718–5733(1998).CrossRefGoogle Scholar
  11. 11.
    J. Chimal-Monroy, J. Rodriguez-Leon, J.A. Montero, Y. Gañan, D. Macias, R. Merino R and J.M. Hurle, Analysis of the molecular cascade responsible for mesodermal limb chondrogenesis: sox genes and BMP signaling, Dev. Biol. 257(2), 292–301(2003).CrossRefGoogle Scholar
  12. 12.
    H. Tsuchiya, H. Kitoh, F. Sugiura and N. Ishiguro, Chondrogenesis enhanced by overexpression of sox9 gene in mouse bone marrow-derived mesenchymal stem cells, Biochem. Biophys. Res. Commun. 301(2), 338–343(2003).CrossRefGoogle Scholar
  13. 13.
    B.F. Eames, P.T. Sharpe and J.A. Helms, Hierarchy revealed in the specification of three skeletal fates by Sox9 and Runx2, Dev. Biol. 274(1), 188–200(2004).CrossRefGoogle Scholar
  14. 14.
    H. Akiyama, M.C. Chaboissier, J.F. Martin, A. Schedl and B. de Crombrugghe, The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6, Genes. Dev. 16(21), 2813–2828(2002).CrossRefGoogle Scholar
  15. 15.
    Y. Mori-Akiyama, H. Akiyama, D.H. Rowitch and B. de Crombrugghe, Sox9 is required for determination of the chondrogenic cell lineage in the cranial neural crest, Proc. Natl. Acad. Sci. U.S.A. 100(16), 9360–9365(2003).CrossRefGoogle Scholar
  16. 16.
    T. Komori, H. Yagi, S. Nomura, A. Yamaguchi, K. Sasaki, K. Deguchi, Y. Shimizu, R.T. Bronson, Y.H. Gao, M. Inada, M. Sato, R. Okamoto, Y. Kitamura, S. Yoshiki and T. Kishimoto, Targeted Disruption of Cbfa1 Results in a Complete Lack of Bone Formation owing to Maturational Arrest of Osteoblasts, Cell 89(5), 755–764(1997).CrossRefGoogle Scholar
  17. 17.
    P. Ducy, M. Starbuck, M. Priemel, J. Shen, G. Pinero, V. Geoffroy, M. Amling and G. Karsenty, A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development, Genes Dev. 13(8),1025–36(1999).Google Scholar
  18. 18.
    H. Kobayashi, Y. Gao, C. Ueta, A. Yamaguchi and T. Komori, Multilineage differentiation of Cbfa1-deficient calvarial cells in vitro, Biochem. Biophys. Res. Commun. 273(2), 630–636(2000).CrossRefGoogle Scholar
  19. 19.
    W. Liu, S. Toyosawa, T. Furuichi, N. Kanatani, C. Yoshida, Y. Liu, M. Himeno, S. Narai, A. Yamaguchi and T. Komori, Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures, J. Cell Biol. 155(1), 157–166(2001).CrossRefGoogle Scholar
  20. 20.
    S. Stricker, R. Fundele, A. Vortkamp and S. Mundlos, Role of Runx genes in chondrocyte differentiation, Dev. Biol. 245(1), 95–108(2002).CrossRefGoogle Scholar
  21. 21.
    J.L. Frendo, G Xiao, S. Fuchs, R.T. Franceschi, G. Karsenty and P. Ducy, Functional hierarchy between two OSE2 elements in the control of osteocalcin gene expression in vivo, J. Biol. Chem. 273(46), 30509–30516(1998).CrossRefGoogle Scholar
  22. 22.
    B. Kern, J. Shen, M. Starbuck, G. Karsenty, Cbfa1 contributes to the osteoblast-specific expression of type I collagen genes, J. Biol. Chem. 276(10), 7101–7107(2001).CrossRefGoogle Scholar
  23. 23.
    M.A. Milona, J.E. Gough, A.J. Edgar, Expression of alternatively spliced isoforms of human Sp7 in osteoblast-like cells, BMC Genomics 4(1),43–53(2003).CrossRefGoogle Scholar
  24. 24.
    K.Y. Choi, S.W. Lee, M.H. Park, Y.C. Bae, H.I. Shin, S. Nam, Y.J. Kim, H.J. Kim and H.M. Ryoo, Spatio-temporal expression patterns of Runx2 isoforms in early skeletogenesis, Exp. Mol. Med. 34(6), 426–433(2002).Google Scholar
  25. 25.
    M.H. Park, H.I. Shin, J.Y. Choi, S.H. Nam, Y.J. Kim, H.J. Kim and H.M. Ryoo, Differential expression patterns of Runx2 isoforms in cranial suture morphogenesis, J. Bone. Miner. Res. 16(5), 885–892(2001).CrossRefGoogle Scholar
  26. 26.
    C. Ueta, M. Iwamoto, N. Kanatani, C. Yoshida, Y. Liu, M. Enomoto-Iwamoto, T. Ohmori, H. Enomoto, K. Nakata, K. Takada, K. Kurisu and T. Komori, Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes, J. Cell. Biol. 153(1), 87–100(2001).CrossRefGoogle Scholar
  27. 27.
    Z. Xiao, H.A. Awad, S. Liu, J. Mahlios, S. Zhang, F. Guilak, M.S. Mayo and L.D. Quarles, Selective Runx2-II deficiency leads to low-turnover osteopenia in adult mice, Dev. Biol. 283(2), 345–356(2005).CrossRefGoogle Scholar
  28. 28.
    C.A. Yoshida, H. Yamamoto, T. Fujita, T. Furuichi, K. Ito, K. Inoue, K. Yamana, A. Zanma, K. Takada, Y. Ito and T. Komori, Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog, Genes Dev. 18(8), 952–963(2004).CrossRefGoogle Scholar
  29. 29.
    N. Smith, Y. Dong, J.B. Lian, J. Pratap, P.D. Kingsley, A.J. van Wijnen, J.L. Stein, E.M. Schwarz, R.J. O’Keefe, G.S. Stein and M.H. Drissi, Overlapping expression of Runx1 (Cbfa2) and Runx2(Cbfa1) transcription factors supports cooperative induction of skeletal development, J. Cell Physiol. 203(1), 133–143(2005).CrossRefGoogle Scholar
  30. 30.
    M. Yousfi, F. Lasmoles and P.J. Marie, TWIST inactivation reduces CBFA1/RUNX2 expression and DNA binding to the osteocalcin promoter in osteoblasts, Biochem. Biophys. Res. Commun. 297(3), 641–644(2002).CrossRefGoogle Scholar
  31. 31.
    P. Bialek, B. Kern, X. Yang, M. Schrock, D. Sosic, N. Hong, H. Wu, K. Yu, D.M. Ornitz, E.N. Olson, M.J. Justice and G. Karsenty, A twist code determines the onset of osteoblast differentiation, Dev. Cell 6(3), 423–435(2004).CrossRefGoogle Scholar
  32. 32.
    H.M. Kronenberg, Twist genes regulate Runx2 and bone formation, Dev. Cell 6(3), 317–318(2004).CrossRefGoogle Scholar
  33. 33.
    I. Kazhdan, D. Rickard and P.S. Leboy, HLH transcription factor activity in osteogenic cells, J. Cell Biochem. 65(1), 1–10(1997).CrossRefGoogle Scholar
  34. 34.
    Y. Maeda, K. Tsuji, A. Nifuji and M. Noda, Inhibitory helix-loop-helix transcription factors Id1/Id3 promote bone formation in vivo, J. Cell Biochem. 93(2), 337–344(2004).CrossRefGoogle Scholar
  35. 35.
    K. Nakashima, X. Zhou, G. Kunkel, Z. Zhang, J.M. Deng, R.R. Behringer and B de Crombrugghe, The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation, Cell 108(1), 17–29(2002).CrossRefGoogle Scholar
  36. 36.
    G. Tai, I. Christodoulou, A.E. Bishop and J.M. Polak, Use of green fluorescent fusion protein to track activation of the transcription factor osterix during early osteoblast differentiation, Biochem. Biophys. Res. Commun. 333(4), 1116–1122(2005).CrossRefGoogle Scholar
  37. 37.
    M.H. Lee, T.G. Kwon, H.S. Park, J.M. Wozney and H.M. Ryoo, BMP-2-induced Osterix expression is mediated by Dlx5 but is independent of Runx2, Biochem. Biophys. Res. Commun. 309(3), 689–694(2003).CrossRefGoogle Scholar
  38. 38.
    A.B. Celil and P.G. Campbell, BMP-2 and IGF-I mediate Osx expression in human mesenchymal stem cells via the MAPK and PKD signaling pathways, J. Biol. Chem. 280(36), 31353–31359(2005).CrossRefGoogle Scholar
  39. 39.
    G. Tai, J.M. Polak, A.E. Bishop, I. Christodoulou and L.D. Buttery, Differentiation of osteoblasts from murine embryonic stem cells by overexpression of the transcriptional factor osterix, Tissue Eng. 10(9–10), 1456–1466(2004).Google Scholar
  40. 40.
    Y. Gao, A. Jheon, H. Nourkeyhani, H. Kobayashi and B. Ganss, Molecular cloning, structure, expression, and chromosomal localization of the human Osterix (SP7) gene, Gene 341(1), 101–110(2004).CrossRefGoogle Scholar
  41. 41.
    X. Guo, T.F. Day, X. Jiang, L. Garrett-Beal, L. Topol and Y. Yang, Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation, Genes. Dev. 18(19), 2404–2417(2004).CrossRefGoogle Scholar
  42. 42.
    C. Hartmann and C.J. Tabin, Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton, Cell 104(3), 341–351(2001).CrossRefGoogle Scholar
  43. 43.
    J.A. Rudnicki, A.M. Brown, Inhibition of chondrogenesis by Wnt gene expression in vivo and in vitro, Dev. Biol. 185(1), 104–118(1997).CrossRefGoogle Scholar
  44. 44.
    N.S. Stott, T.X. Jiang and C.M. Chuong, Successive formative stages of precartilaginous mesenchymal condensations in vitro: modulation of cell adhesion by Wnt-7A and BMP-2, J. Cell Physiol. 180(3), 314–324(1999).CrossRefGoogle Scholar
  45. 45.
    G. Rawadi, B. Vayssiere, F. Dunn, R. Baron and S. Roman-Roman, BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop, J. Bone Miner. Res. 18(10), 1842–1853(2003).CrossRefGoogle Scholar
  46. 46.
    C.N. Bennett, K.A. Longo, W.S. Wright, L.J. Suva, T.F. Lane, K.D. Hankenson and O.A. MacDougald, Regulation of osteoblastogenesis and bone mass by Wnt10b, Proc. Natl. Acad. Sci. U.S.A. 102(9), 3324–3329(2005).CrossRefGoogle Scholar
  47. 47.
    T.F. Day, X. Guo, L. Garrett-Beal and Y. Yang, Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis, Dev. Cell 8(5), 739–750(2005).CrossRefGoogle Scholar
  48. 48.
    J. Huelsken and W. Birchmeier, New aspects of Wnt signaling pathways in higher vertebrates, Curr. Opin. Genet. Dev. 11(5), 547–553(2001).CrossRefGoogle Scholar
  49. 49.
    M. Logan, J.F. Martin, A. Nagy, C. Lobe, E.N. Olson and C.J. Tabin, Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer, Genesis 33(2), 77–80(2002).CrossRefGoogle Scholar
  50. 50.
    T.P. Hill, D. Spater, M.M. Taketo, W. Birchmeier and C. Hartmann, Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes, Dev. Cell 8(5), 727–738(2005).CrossRefGoogle Scholar
  51. 51.
    H. Hu, M.J. Hilton, X. Tu, K. Yu, D.M. Ornitz and F. Long, Sequential roles of Hedgehog and Wnt signaling in osteoblast development, Development 132(1), 49–60(2005).CrossRefGoogle Scholar
  52. 52.
    J.H. Eggers, M. Stock, M. Fliegauf, B. Vonderstrass and F. Otto, Genomic characterization of the RUNX2 gene of Fugu rubripes, Gene 291(1–2), 159–167(2002).CrossRefGoogle Scholar
  53. 53.
    M. Stock, H. Schafer, M. Fliegauf, F. Otto, Identification of novel genes of the bone-specific transcription factor Runx2, J. Bone Miner. Res. 19(6), 959–972(2004).CrossRefGoogle Scholar
  54. 54.
    C.J. Lengner, M.Q. Hassan, R.W. Serra, C. Lepper, A.J. van Wijnen, J.L. Stein, J.B. Lian and G.S. Stein, Nkx3.2-mediated repression of Runx2 promotes chondrogenic differentiation, J. Biol. Chem. 280(16), 15872–15879(2005).CrossRefGoogle Scholar
  55. 55.
    G. Mbalaviele, S. Sheikh, J.P. Stains, V.S. Salazar, S.L. Cheng, D. Chen and R. Civitelli, Beta-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation, J. Cell Biochem. 94(2), 403–418(2005).CrossRefGoogle Scholar
  56. 56.
    H. Akiyama, J.P. Lyons, Y. Mori-Akiyama, X. Yang, R. Zhang, Z. Zhang, J.M. Deng, M.M. Taketo, T. Nakamura, R.R. Behringer, P.D. McCrea and B. de Crombrugghe, Interactions between Sox9 and betacatenin control chondrocyte differentiation, Genes Dev. 18(9), 1072–1087(2004).CrossRefGoogle Scholar
  57. 57.
    A.B. Celil, J.O. Hollinger and P.G. Campbell, Osx transcriptional regulation is mediated by additional pathways to BMP2/Smad signaling, J. Cell Biochem. 95(3), 518–528(2005).CrossRefGoogle Scholar
  58. 58.
    D.M. Ornitz, FGF signaling in the developing endochondral skeleton, Cytokine Growth Factor Rev. 16(2), 205–213(2005).CrossRefGoogle Scholar
  59. 59.
    M. Qiao, P. Shapiro, R. Kumar and A. Passaniti, Insulin-like growth factor-1 regulates endogenous RUNX2 activity in endothelial cells through a phosphatidylinositol 3-kinase/ERK-dependent and Aktindependent signaling pathway, J. Biol. Chem. 279(41), 42709–42718(2004).CrossRefGoogle Scholar
  60. 60.
    M. Sato, G.Q. Zeng and C.H. Turner, Biosynthetic human parathyroid hormone (1-34) effects on bone quality in aged ovariectomized rats, Endocrinology 138(10), 4330–4337(1997).CrossRefGoogle Scholar
  61. 61.
    C.P. Jerome, C.S. Johnson, H.T. Vafai, K.C. Kaplan, J. Bailey, B. Capwell, F. Fraser, L. Hansen, H. Ramsay, M. Shadoan, J.S. Thomsen and L. Mosekilde, Effect of treatment for 6 months with human parathyroid hormone (1–34) peptide in ovariectomized cynomolgus monkeys (Macaca fascicularis), Bone 25(3), 301–309(1999).CrossRefGoogle Scholar
  62. 62.
    N.H. Kulkarni, D.L. Halladay, R.R. Miles, L.M. Gilbert, C.A. Frolik, R.J. Galvin, T.J. Martin, M.T. Gillespie and J.E. Onyia, Effects of parathyroid hormone on Wnt signaling pathway in bone, J. Cell Biochem. 95(6), 1178–1190(2005)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Lijin Zou
    • 1
    • 2
  • Xuenong Zou
    • 1
    • 3
  • Haisheng Li
    • 1
  • Tina Mygind
    • 1
  • Yuanlin Zeng
    • 2
  • Nonghua Lü
    • 2
  • Cody Bünger
    • 1
  1. 1.Orthopaedic Research LaboratoryAarhus University HospitalAarhus CDenmark
  2. 2.The First Affiliated Hospital of Nanchang UniversityNanchang, JiangxiChina
  3. 3.Department of Orthopaedicsthe 5th Affiliated Hospital of Sun Yat-sen UniversityZhuhai, GuangdongChina

Personalised recommendations