Sequential roles of Hedgehog and Wnt signaling in osteoblast development

Signals that govern development of the osteoblast lineage are not well understood. Indian hedgehog (Ihh), a member of the hedgehog (Hh) family of proteins, is essential for osteogenesis in the endochondral skeleton during embryogenesis. The canonical pathway of Wnt signaling has been implicated by studies of Lrp5, a co-receptor for Wnt proteins, in postnatal bone mass homeostasis. In the present study we demonstrate that β-catenin, a central player in the canonical Wnt pathway, is indispensable for osteoblast differentiation in the mouse embryo. Moreover, we present evidence that Wnt signaling functions downstream of Ihh in development of the osteoblast lineage. Finally Wnt7b is identified as a potential endogenous ligand regulating osteogenesis. These data support a model that integrates Hh and Wnt signaling in the regulation of osteoblast development.

[1]  M. Riminucci.  [Bone stem cells]. , 2005, Pathologica.

[2]  Jie J. Zheng,et al.  The LRP5 High-Bone-Mass G171V Mutation Disrupts LRP5 Interaction with Mesd , 2004, Molecular and Cellular Biology.

[3]  P. McCrea,et al.  Interactions between Sox9 and β-catenin control chondrocyte differentiation , 2004 .

[4]  Toyoaki Tenzen,et al.  Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. , 2004, Genes & development.

[5]  A. McMahon,et al.  Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton , 2004, Development.

[6]  P. McCrea,et al.  Interactions between Sox9 and beta-catenin control chondrocyte differentiation. , 2004, Genes & development.

[7]  Jie J. Zheng,et al.  The LRP 5 High-Bone-Mass G 171 V Mutation Disrupts LRP 5 Interaction with Mesd , 2004 .

[8]  H. Varmus,et al.  Requirement for a Nuclear Function of β-Catenin in Wnt Signaling , 2003, Molecular and Cellular Biology.

[9]  Roland Baron,et al.  BMP‐2 Controls Alkaline Phosphatase Expression and Osteoblast Mineralization by a Wnt Autocrine Loop , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[10]  E. Olson,et al.  Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth , 2003, Development.

[11]  C. Tabin,et al.  A Somitic Compartment of Tendon Progenitors , 2003, Cell.

[12]  Andrew P McMahon,et al.  Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. , 2003, Genes & development.

[13]  J. Papkoff,et al.  Activated β-catenin induces osteoblast differentiation of C3H10T1/2 cells and participates in BMP2 mediated signal transduction , 2003 .

[14]  Andrew P McMahon,et al.  Developmental roles and clinical significance of hedgehog signaling. , 2003, Current topics in developmental biology.

[15]  H. Varmus,et al.  Requirement for a nuclear function of beta-catenin in Wnt signaling. , 2003, Molecular and cellular biology.

[16]  J. Papkoff,et al.  Activated beta-catenin induces osteoblast differentiation of C3H10T1/2 cells and participates in BMP2 mediated signal transduction. , 2003, Biochemical and biophysical research communications.

[17]  N. Ueno,et al.  Sonic hedgehog is involved in osteoblast differentiation by cooperating with BMP‐2 , 2002, Journal of cellular physiology.

[18]  M. Lu,et al.  Wnt7b regulates mesenchymal proliferation and vascular development in the lung. , 2002, Development.

[19]  L. Hofbauer,et al.  High bone density due to a mutation in LDL-receptor-related protein 5. , 2002, The New England journal of medicine.

[20]  Richard P Lifton,et al.  High bone density due to a mutation in LDL-receptor-related protein 5. , 2002, The New England journal of medicine.

[21]  Andrew P McMahon,et al.  A mitogen gradient of dorsal midline Wnts organizes growth in the CNS. , 2002, Development.

[22]  Ivan Lobov,et al.  Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor , 2002, The Journal of cell biology.

[23]  B. Wang,et al.  Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus , 2002, Nature.

[24]  D. Kalderon,et al.  Proteolysis of the Hedgehog Signaling Effector Cubitus interruptus Requires Phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1 , 2002, Cell.

[25]  J. Deng,et al.  The Novel Zinc Finger-Containing Transcription Factor Osterix Is Required for Osteoblast Differentiation and Bone Formation , 2002, Cell.

[26]  N. Takahashi,et al.  Bone Morphogenetic Protein-2 Converts the Differentiation Pathway of C2C12 Myoblasts into the Osteoblast Lineage , 2002 .

[27]  Mark L. Johnson,et al.  A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. , 2002, American journal of human genetics.

[28]  C. Hartmann,et al.  Cbfa 1-independent decrease in osteoblast proliferation , osteopenia , and persistent embryonic eye vascularization in mice deficient in Lrp 5 , a Wnt coreceptor , 2002 .

[29]  A. McMahon,et al.  Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. , 2001, Development.

[30]  Miikka Vikkula,et al.  LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development , 2001, Cell.

[31]  B. Alman,et al.  Suppressor of Fused Negatively Regulates β-Catenin Signaling* , 2001, The Journal of Biological Chemistry.

[32]  W. Birchmeier,et al.  New aspects of Wnt signaling pathways in higher vertebrates. , 2001, Current opinion in genetics & development.

[33]  M. Cybulsky,et al.  Wnt7b regulates placental development in mice. , 2001, Developmental biology.

[34]  R. Baron,et al.  Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation. , 2001, Journal of cell science.

[35]  Yan Li,et al.  LDL-receptor-related protein 6 is a receptor for Dickkopf proteins , 2001, Nature.

[36]  Tao Sun,et al.  Wnt signals are targets and mediators of Gli function , 2001, Current Biology.

[37]  A. McMahon,et al.  Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. , 2001, Development.

[38]  J Mao,et al.  Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. , 2001, Molecular cell.

[39]  A. McMahon,et al.  Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. , 2001, The Journal of clinical investigation.

[40]  B. Alman,et al.  Suppressor of fused negatively regulates beta-catenin signaling. , 2001, The Journal of biological chemistry.

[41]  William C. Skarnes,et al.  An LDL-receptor-related protein mediates Wnt signalling in mice , 2000, Nature.

[42]  Andrew Tomlinson,et al.  arrow encodes an LDL-receptor-related protein essential for Wingless signalling , 2000, Nature.

[43]  Yoichi Kato,et al.  LDL-receptor-related proteins in Wnt signal transduction , 2000, Nature.

[44]  Carmen Birchmeier,et al.  Requirement for beta-catenin in anterior-posterior axis formation in mice. , 2000 .

[45]  H. Clevers,et al.  Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. , 1999, Science.

[46]  A. McMahon,et al.  Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. , 1999, Genes & development.

[47]  R. Grosschedl,et al.  Regulation of LEF-1/TCF transcription factors by Wnt and other signals. , 1999, Current opinion in cell biology.

[48]  F. McCormick,et al.  Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. , 1999, Nature.

[49]  C. Niehrs,et al.  Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction , 1998, Nature.

[50]  Q. Gu,et al.  Activating Smoothened mutations in sporadic basal-cell carcinoma , 1998, Nature.

[51]  R. Nusse,et al.  Mechanisms of Wnt signaling in development. , 1998, Annual review of cell and developmental biology.

[52]  A. Yamaguchi,et al.  Induction of osteogenic differentiation by hedgehog proteins. , 1997, Biochemical and biophysical research communications.

[53]  S. Mundlos,et al.  Cbfa1, a Candidate Gene for Cleidocranial Dysplasia Syndrome, Is Essential for Osteoblast Differentiation and Bone Development , 1997, Cell.

[54]  Makoto Sato,et al.  Targeted Disruption of Cbfa1 Results in a Complete Lack of Bone Formation owing to Maturational Arrest of Osteoblasts , 1997, Cell.

[55]  G. Karsenty,et al.  Osf2/Cbfa1: A Transcriptional Activator of Osteoblast Differentiation , 1997, Cell.

[56]  H. Ohuchi,et al.  Fibroblasts expressing Sonic hedgehog induce osteoblast differentiation and ectopic bone formation , 1997, FEBS letters.

[57]  R. Mulligan,et al.  A stable human-derived packaging cell line for production of high titer retrovirus/vesicular stomatitis virus G pseudotypes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Clifford J. Tabin,et al.  Regulation of Rate of Cartilage Differentiation by Indian Hedgehog and PTH-Related Protein , 1996, Science.

[59]  H Clevers,et al.  Extensive alternative splicing and dual promoter usage generate Tcf-1 protein isoforms with differential transcription control properties , 1996, Molecular and cellular biology.

[60]  L. Larue,et al.  Lack of beta-catenin affects mouse development at gastrulation. , 1995, Development.

[61]  Hans Clevers,et al.  An HMG-box-containing T-cell factor required for thymocyte differentiation , 1995, Nature.

[62]  R. Mayne,et al.  Collagen types IX and X in the developing chick tibiotarsus: analyses of mRNAs and proteins. , 1991, Development.

[63]  Peter A. Jones,et al.  Multiple new phenotypes induced in 10T 1 2 and 3T3 cells treated with 5-azacytidine , 1979, Cell.