Minireview: transcriptional regulation in development of bone.

Regulation of gene expression by transcription factors is one of the major mechanisms for controlling cellular functions. Recent advances in genetic manipulation of model animals has allowed the study of the roles of various genes and their products in physiological settings and has demonstrated the importance of specific transcription factors in bone development. Three lineages of bone cells, chondrocytes, osteoblasts, and osteoclasts, develop and differentiate according to their distinct developmental programs. These cells go through multiple differentiation stages, which are often regulated by specific transcription factors. In this minireview, we will discuss selected transcription factors that have been demonstrated to critically affect bone cell development. Further study of these molecules will lead to deeper understanding in mechanisms that govern development of bone.

[1]  M. Pondel,et al.  Mitf-PU.1 interactions with the tartrate-resistant acid phosphatase gene promoter during osteoclast differentiation. , 2004, Bone.

[2]  Ulrich Siebenlist,et al.  Requirement for NF-κB in osteoclast and B-cell development , 1997 .

[3]  Michael C. Ostrowski,et al.  Microphthalmia Transcription Factor and PU.1 Synergistically Induce the Leukocyte Receptor Osteoclast-associated Receptor Gene Expression* , 2003, Journal of Biological Chemistry.

[4]  A. McMahon,et al.  Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways. , 2000, Development.

[5]  C. Hartmann,et al.  Dual roles of Wnt signaling during chondrogenesis in the chicken limb. , 2000, Development.

[6]  E. Wagner,et al.  Bone and haematopoietic defects in mice lacking c-fos , 1992, Nature.

[7]  M. Justice,et al.  A twist code determines the onset of osteoblast differentiation. , 2004, Developmental cell.

[8]  R. Baron,et al.  A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice. , 2003, The Journal of clinical investigation.

[9]  S Sakano,et al.  Trans‐activation of the Mouse Cartilage‐Derived Retinoic Acid‐Sensitive Protein Gene by Sox9 , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[10]  P. Ducy.  CBFA1: A molecular switch in osteoblast biology , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[11]  S. Mckercher,et al.  Osteopetrosis in mice lacking haematopoietic transcription factor PU.1 , 1997, Nature.

[12]  C. Rose,et al.  A TWIST in development. , 1997, Trends in genetics : TIG.

[13]  B. Lanske,et al.  PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps. , 2002, Development.

[14]  K. Chihara,et al.  Menin Is Required for Bone Morphogenetic Protein 2- and Transforming Growth Factor β-regulated Osteoblastic Differentiation through Interaction with Smads and Runx2* , 2004, Journal of Biological Chemistry.

[15]  P. Hogan,et al.  Transcription factors of the NFAT family: regulation and function. , 1997, Annual review of immunology.

[16]  M. Šuša,et al.  Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity. , 2004, The Journal of biological chemistry.

[17]  A. Baldwin,et al.  NF-κB mediates inhibition of mesenchymal cell differentiation through a posttranscriptional gene silencing mechanism , 2003 .

[18]  C. Grimsrud,et al.  BMP‐6 Is an Autocrine Stimulator of Chondrocyte Differentiation , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[19]  You‐Gan Wang,et al.  Groucho homologue Grg5 interacts with the transcription factor Runx2-Cbfa1 and modulates its activity during postnatal growth in mice. , 2004, Developmental biology.

[20]  B. Spiegelman,et al.  Pleiotropic effects of a null mutation in the c-fos proto-oncogene , 1992, Cell.

[21]  F. Luyten,et al.  Role of CDMP-1 in Skeletal Morphogenesis: Promotion of Mesenchymal Cell Recruitment and Chondrocyte Differentiation , 1999, The Journal of cell biology.

[22]  R. Maxson,et al.  Premature suture closure and ectopic cranial bone in mice expressing Msx2 transgenes in the developing skull. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  R. Maas,et al.  Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation , 2000, Nature Genetics.

[24]  C. Remé,et al.  Fra-1 replaces c-Fos-dependent functions in mice. , 2000, Genes & development.

[25]  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.

[26]  H. Kronenberg,et al.  The chondrogenic transcription factor Sox9 is a target of signaling by the parathyroid hormone-related peptide in the growth plate of endochondral bones. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Ken-ichi Inoue,et al.  Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. , 2004, Genes & development.

[28]  D. Levy,et al.  FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. , 1999, Genes & development.

[29]  K. Miyazono,et al.  Two major Smad pathways in TGF‐β superfamily signalling , 2002, Genes to cells : devoted to molecular & cellular mechanisms.

[30]  D. Ornitz,et al.  Sequential roles of Hedgehog and Wnt signaling in osteoblast development , 2004, Development.

[31]  P. Marie,et al.  FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. , 2002, Genes & development.

[32]  T. Lufkin,et al.  The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development. , 2002, Genes & development.

[33]  R. Maxson,et al.  Msx2 gene dosage influences the number of proliferative osteogenic cells in growth centers of the developing murine skull: a possible mechanism for MSX2-mediated craniosynostosis in humans. , 1999, Developmental biology.

[34]  T. Takeya,et al.  Large Scale Gene Expression Analysis of Osteoclastogenesisin Vitro and Elucidation of NFAT2 as a Key Regulator* , 2002, The Journal of Biological Chemistry.

[35]  T. Taniguchi,et al.  Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. , 2003, Genes & development.

[36]  B. Hall,et al.  All for one and one for all: condensations and the initiation of skeletal development. , 2000, BioEssays : news and reviews in molecular, cellular and developmental biology.

[37]  V. Lefebvre,et al.  Chondrocyte-specific Enhancer Elements in the Col11a2Gene Resemble the Col2a1 Tissue-specific Enhancer* , 1998, The Journal of Biological Chemistry.

[38]  L. Niswander,et al.  BMPs are required at two steps of limb chondrogenesis: formation of prechondrogenic condensations and their differentiation into chondrocytes. , 2000, Developmental biology.

[39]  S. Nomura,et al.  Maturational disturbance of chondrocytes in Cbfa1‐deficient mice , 1999, Developmental dynamics : an official publication of the American Association of Anatomists.

[40]  V. Lefebvre,et al.  The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. , 2001, Developmental cell.

[41]  S. Nishikawa,et al.  The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene , 1990, Nature.

[42]  E. Wagner,et al.  Reaching a genetic and molecular understanding of skeletal development. , 2002, Developmental cell.

[43]  H. Shibuya,et al.  A BMP-inducible gene, dlx5, regulates osteoblast differentiation and mesoderm induction. , 1999, Developmental biology.

[44]  S. Bae,et al.  Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-β and bone morphogenetic protein , 2002, Oncogene.

[45]  N. Kanatani,et al.  Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures , 2001, The Journal of cell biology.

[46]  L. Topol,et al.  Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation , 2003, Development.

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

[48]  N. Kanatani,et al.  Skeletal Malformations Caused by Overexpression of Cbfa1 or Its Dominant Negative Form in Chondrocytes , 2001, The Journal of cell biology.

[49]  N. Copeland,et al.  Mitf and Tfe3, two members of the Mitf-Tfe family of bHLH-Zip transcription factors, have important but functionally redundant roles in osteoclast development , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[50]  P N Goodfellow,et al.  SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene , 1997, Molecular and cellular biology.

[51]  P. Sassone-Corsi,et al.  ATF4 Is a Substrate of RSK2 and an Essential Regulator of Osteoblast Biology Implication for Coffin-Lowry Syndrome , 2004, Cell.

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

[53]  G. Merlo,et al.  Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5. , 1999, Development.

[54]  G. Karsenty,et al.  A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. , 1999, Genes & development.

[55]  R. Kosher,et al.  Dlx5 is a positive regulator of chondrocyte differentiation during endochondral ossification. , 2002, Developmental biology.

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

[57]  M Noda,et al.  SOX9 Enhances Aggrecan Gene Promoter/Enhancer Activity and Is Up-regulated by Retinoic Acid in a Cartilage-derived Cell Line, TC6* , 2000, The Journal of Biological Chemistry.

[58]  O. Coqueret.  Linking cyclins to transcriptional control. , 2002, Gene.

[59]  J. Baron,et al.  Regulation of growth plate chondrogenesis by bone morphogenetic protein-2. , 2001, Endocrinology.

[60]  V. Lefebvre,et al.  Potent Inhibition of the Master Chondrogenic FactorSox9 Gene by Interleukin-1 and Tumor Necrosis Factor-α* , 2000, The Journal of Biological Chemistry.

[61]  K. Miyazono,et al.  A RUNX2/PEBP2alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[62]  T. Ochi,et al.  Microphthalmia-associated transcription factor interacts with PU.1 and c-Fos: determination of their subcellular localization. , 1999, Biochemical and biophysical research communications.

[63]  S. Yeh,et al.  Generation and characterization of androgen receptor knockout (ARKO) mice: An in vivo model for the study of androgen functions in selective tissues , 2002, Proceedings of the National Academy of Sciences of the United States of America.

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

[65]  Sandrine Bongiovanni,et al.  Transcriptional Program of Mouse Osteoclast Differentiation Governed by the Macrophage Colony-stimulating Factor and the Ligand for the Receptor Activator of NFκB* , 2002, The Journal of Biological Chemistry.

[66]  Hiroshi Takayanagi,et al.  Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. , 2002, Developmental cell.

[67]  Marie-Christine Chaboissier,et al.  The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. , 2002, Genes & development.

[68]  R. Maas,et al.  Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development , 1994, Nature Genetics.

[69]  P N Goodfellow,et al.  Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[70]  P. Sharpe,et al.  Regulation and role of Sox9 in cartilage formation , 1999, Developmental dynamics : an official publication of the American Association of Anatomists.

[71]  Richard R. Behringer,et al.  Sox9 is required for cartilage formation , 1999, Nature Genetics.

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

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

[74]  G. Stein,et al.  Regulation of the Bone-Specific Osteocalcin Gene by p300 Requires Runx2/Cbfa1 and the Vitamin D3 Receptor but Not p300 Intrinsic Histone Acetyltransferase Activity , 2003, Molecular and Cellular Biology.

[75]  Hideki Yoshikawa,et al.  Bone Morphogenetic Protein Signals Are Required for Cartilage Formation and Differently Regulate Joint Development During Skeletogenesis , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[76]  Steven J. M. Jones,et al.  A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. , 1999, Development.

[77]  H. Aburatani,et al.  Nuclear Factor of Activated T-cells (NFAT) Rescues Osteoclastogenesis in Precursors Lacking c-Fos* , 2004, Journal of Biological Chemistry.

[78]  R. Derynck,et al.  TGF‐β‐induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation , 2001, The EMBO journal.

[79]  D. Fisher,et al.  Linking osteopetrosis and pycnodysostosis: Regulation of cathepsin K expression by the microphthalmia transcription factor family , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[80]  Jens Bollerslev,et al.  Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. , 2003, American journal of human genetics.

[81]  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.

[82]  S. Takeda,et al.  Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. , 2001, Genes & development.

[83]  C. Deng,et al.  Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice. , 2001, Human molecular genetics.

[84]  M. Kelz,et al.  Overexpression of ΔFosB transcription factor(s) increases bone formation and inhibits adipogenesis , 2000, Nature Medicine.

[85]  Michael C. Ostrowski,et al.  The Microphthalmia Transcription Factor Regulates Expression of the Tartrate‐Resistant Acid Phosphatase Gene During Terminal Differentiation of Osteoclasts , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[86]  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.

[87]  D. Fisher,et al.  Mitf and Tfe3: members of a b-HLH-ZIP transcription factor family essential for osteoclast development and function. , 2004, Bone.

[88]  W Gaffield,et al.  BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. , 2001, Development.

[89]  L. Topol,et al.  Wnt/β-catenin signaling is sufficient and necessary for synovial joint formation , 2004 .