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)
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
28.9. References
J. Fang and B.K. Hall, Chondrogenic cell differentiation from membrane bone periostea, Ana. Embryol. 196(5), 349–362(1997).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
S. Stricker, R. Fundele, A. Vortkamp and S. Mundlos, Role of Runx genes in chondrocyte differentiation, Dev. Biol. 245(1), 95–108(2002).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
H.M. Kronenberg, Twist genes regulate Runx2 and bone formation, Dev. Cell 6(3), 317–318(2004).
I. Kazhdan, D. Rickard and P.S. Leboy, HLH transcription factor activity in osteogenic cells, J. Cell Biochem. 65(1), 1–10(1997).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
J. Huelsken and W. Birchmeier, New aspects of Wnt signaling pathways in higher vertebrates, Curr. Opin. Genet. Dev. 11(5), 547–553(2001).
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).
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).
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).
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).
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).
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).
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).
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).
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).
D.M. Ornitz, FGF signaling in the developing endochondral skeleton, Cytokine Growth Factor Rev. 16(2), 205–213(2005).
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).
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).
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).
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)
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights 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)