Skip to main content
SpringerLink
Log in

Molecular Mechanism of Osteochondroprogenitor Fate Determination During Bone Formation

  • Conference paper
Tissue Engineering

Part of the book series: Advances in Experimental Medicine and Biology ((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.

Correspondence and reprint requests: zxnong@hotmail.com (X. Zou)

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

28.9. References

  1. J. Fang and B.K. Hall, Chondrogenic cell differentiation from membrane bone periostea, Ana. Embryol. 196(5), 349–362(1997).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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. 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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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. 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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  20. S. Stricker, R. Fundele, A. Vortkamp and S. Mundlos, Role of Runx genes in chondrocyte differentiation, Dev. Biol. 245(1), 95–108(2002).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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. 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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  32. H.M. Kronenberg, Twist genes regulate Runx2 and bone formation, Dev. Cell 6(3), 317–318(2004).

    Article  Google Scholar 

  33. I. Kazhdan, D. Rickard and P.S. Leboy, HLH transcription factor activity in osteogenic cells, J. Cell Biochem. 65(1), 1–10(1997).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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. 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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  48. J. Huelsken and W. Birchmeier, New aspects of Wnt signaling pathways in higher vertebrates, Curr. Opin. Genet. Dev. 11(5), 547–553(2001).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  58. D.M. Ornitz, FGF signaling in the developing endochondral skeleton, Cytokine Growth Factor Rev. 16(2), 205–213(2005).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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)

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Orthopaedic Research Laboratory, Aarhus University Hospital, 8000, Aarhus C, Denmark

    Lijin Zou, Xuenong Zou, Haisheng Li, Tina Mygind & Cody Bünger

  2. The First Affiliated Hospital of Nanchang University, 330006, Nanchang, Jiangxi, China

    Lijin Zou, Yuanlin Zeng & Nonghua Lü

  3. Department of Orthopaedics, the 5th Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China

    Xuenong Zou

Authors
  1. Lijin Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuenong Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Haisheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tina Mygind
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuanlin Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nonghua Lü
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cody Bünger
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Maryland, College Park, MD, 20742, USA

    John P. Fisher

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer Science+Business Media, LLC

About this paper

Cite this paper

Zou, L. et al. (2006). Molecular Mechanism of Osteochondroprogenitor Fate Determination During Bone Formation. In: Fisher, J.P. (eds) Tissue Engineering. Advances in Experimental Medicine and Biology, vol 585. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-34133-0_28

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-34133-0_28

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-32664-1

  • Online ISBN: 978-0-387-34133-0

  • eBook Packages: EngineeringEngineering (R0)

Publish with us

Policies and ethics

Search

Navigation