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The Molecular Genetics of Bone Formation

Implications for Therapeutic Interventions in Bone Disorders

  • Genomics in Human Disease
  • Published:
American Journal of Pharmacogenomics

Abstract

Skeletal biology is a complex process involving the developmental commitment and differentiation of chondrocytes and osteoblasts which produce and mineralize cartilage and bone matrix during growth and postnatal life. Several genes are involved in controlling osteogenesis by acting on target cells in a very complex manner. Manipulation of genes in mice and studies of genetic mutations affecting the skeleton in humans have enabled the assessment of the role of transcription factors, bone matrix proteins and regulatory factors involved in the control of chondrocyte and osteoblast differentiation, and have considerably improved our understanding of the bone formation process. Clinical studies and gene polymorphism analyses suggest that the variable expression of particular genes may be linked to clinical osteoporosis. A major challenge in the future will be to develop molecularly targeted approaches to stimulating bone formation and increasing bone mass. The use of mouse strain models and transgenic animals with variable bone density may be useful to identify genetic determinants of bone mass which may serve as a basis for drug discovery and development. On the other hand, the availability of gene microarrays and other emerging genomic techniques are promising tools to identify genes that are distinctly expressed in health and disease. These technologies may also serve to test the mechanisms of action of drugs aimed at increasing bone formation. Genetic studies of the molecular signaling pathways involved in normal and pathological osteogenesis may also help to identify genes that could be targeted for therapeutic intervention. Candidate approaches include selective gene transfection in target cells and the use of drugs acting on gene promoters to selectively enhance gene expression in osteoblasts. The development of these strategies is expected not only to bring new insight into the molecular mechanisms that govern bone formation in normal and pathological situations but, in the long term, may also result in the identification of novel molecular targets for therapeutic interventions for bone formation disorders.

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References

  1. Karsenty G. Genetics of skeletogenesis. Dev Genet 1998; 22: 301–13

    Article  PubMed  CAS  Google Scholar 

  2. Olsen BR, Reginato AM, Wang W. Bone Development. Annu Rev Cell Dev Biol 2000; 16: 191–220

    Article  PubMed  CAS  Google Scholar 

  3. Kingsley DM. What do BMPs do in mammals? Clues from the mouse short-ear mutation. Trends Genet. 1994; 10(1): 16–21

    Article  PubMed  CAS  Google Scholar 

  4. Erlebacher A, Filvaroff EH, Gitelman SE, Derynck R. Toward a molecular understanding of skeletal development. Cell 1995; 80(3): 371–8

    Article  PubMed  CAS  Google Scholar 

  5. Hogan BL. Bone morphogenetic proteins in development. Curr Opin Genet Dev 1996; 6(4): 432–8

    Article  PubMed  CAS  Google Scholar 

  6. Johnson RL, Tabin CJ. Molecular models for vertebrate limb development. Cell 1997; 90(6): 979–80

    Article  PubMed  CAS  Google Scholar 

  7. Ala-Kokko L, Baldwin CT, Moskowitz RW, et al. Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia. Proc Natl Acad Sci U S A 1990; 87(17): 6565–8

    Article  PubMed  CAS  Google Scholar 

  8. Olsen BR. Mutations in collagen genes resulting in metaphyseal and epiphyseal dysplasias. Bone 1995; 17(2 S): 45S–9S

    Article  PubMed  CAS  Google Scholar 

  9. Vikkula M, Mariman EC, Lui VC, et al. Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell 1995; 80(3): 431–7

    Article  PubMed  CAS  Google Scholar 

  10. Warman ML, Abbott M, Apte SS, et al. A type X collagen mutation causes Schmid metaphyseal chondrodysplasia. Nat Genet 1993; 5(1): 79–82

    Article  PubMed  CAS  Google Scholar 

  11. Gress CJ, Jacenko O. Growth plate compressions and altered hematopoiesis in collagen X null mice. J Cell Biol 2000; 149(4): 983–93

    Article  PubMed  CAS  Google Scholar 

  12. Kuivaniemi H, Tromp G, Prockop DJ. Mutations in collagen genes: causes of rare and some common diseases in humans. FASEB J 1991; 5(7): 2052–60

    PubMed  CAS  Google Scholar 

  13. Byers PH, Steiner RD. Osteogenesis imperfecta. Annu Rev Med 1992; 43: 269–82

    Article  PubMed  CAS  Google Scholar 

  14. Marie PJ, dePollak C, Chanson P, et al. Increased osteoblastic cell proliferation associated with activating Gsα mutation in monostotic and polyostotic fibrous dysplasia. Am J Pathol 1997; 150(3): 1059–69

    PubMed  CAS  Google Scholar 

  15. Riminucci M, Fisher LW, Shenker A, et al. Fibrous dysplasia of bone in the McCune-Albright syndrome: abnormalities in bone formation. Am J Pathol 1997; 151(6): 1587–600

    PubMed  CAS  Google Scholar 

  16. Mansukhani A, Bellosta P, Sahni M, et al. Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. J Cell Biol 2000; 149(6): 1297–1308

    Article  PubMed  CAS  Google Scholar 

  17. Lemonnier J, Hay E, Delannoy P, et al. Increased osteoblast apoptosis in apert craniosynostosis: role of protein kinase c and interleukin-1. Am J Pathol 2001; 158(5): 1833–42

    Article  PubMed  CAS  Google Scholar 

  18. Rousseau F, Bonaventure J, Legeai-Mallet L, et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 1994; 371(6494): 252–4

    Article  PubMed  CAS  Google Scholar 

  19. Webster MK, Donoghue DJ. Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J 1996; 15(3): 520–7

    PubMed  CAS  Google Scholar 

  20. Naski MC, Wang Q, Xu J, et al. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet 1996; 13(2): 233–7

    Article  PubMed  CAS  Google Scholar 

  21. Chen L, Adar R, Yang X, et al. Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. J Clin Invest 1999; 104(11): 1517–25

    Article  PubMed  CAS  Google Scholar 

  22. Karaplis AC. Gene targeting. In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. New York: Acad Press, 1996: 1189–201

    Google Scholar 

  23. Ducy P, Desbois C, Boyce B, et al. Increased bone formation in osteocalcin-deficient mice. Nature 1996; 382: 448–52

    Article  PubMed  CAS  Google Scholar 

  24. Luo G, Ducy P, McKee MD, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997; 386(6620): 78–81

    Article  PubMed  CAS  Google Scholar 

  25. Xu T, Bianco P, Fisher LW, et al. Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice. Nat Genet 1998; 20(1): 78–82

    Article  PubMed  CAS  Google Scholar 

  26. Delany AM, Amling M, Priemel M, et al. Osteopenia and decreased bone formation in osteonectin-deficient mice. J Clin Invest 2000; 105(7): 915–23

    Article  PubMed  CAS  Google Scholar 

  27. Yoshitake H, Rittling SR, Denhardt DT, et al. Osteopontin-deficient mice are resistant to ovariectomy-induced bone resorption. Proc Natl Acad Sci U S A 1999; 96(14): 8156–60

    Article  PubMed  CAS  Google Scholar 

  28. Satokata I, Ma L, Ohshima H, et al. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat Genet 2000; 24(4): 391–5

    Article  PubMed  CAS  Google Scholar 

  29. Wilkie AO, Tang Z, Elanko N, et al. Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. Nat Genet 2000; 24(4): 387–90

    Article  PubMed  CAS  Google Scholar 

  30. Grigoriadis AE, Wang ZQ, Wagner EF. Fos and bone cell development: lessons from a nuclear oncogene. Trends Genet 1995; 11(11): 436–41

    Article  PubMed  CAS  Google Scholar 

  31. Matsuo K, Jochum W, Owens JM, et al. Function of Fos proteins in bone cell differentiation. Bone 1999; 25(1): 141

    Article  PubMed  CAS  Google Scholar 

  32. Sabatakos G, Sims NA, Chen J, et al. Overexpression of DeltaFosB transcription factor (s) increases bone formation and inhibits adipogenesis. Nat Med 2000; 6(9): 985–90

    Article  PubMed  CAS  Google Scholar 

  33. Jochum W, David JP, Elliott C, et al. Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1. Nat Med 2000 Sep; 6(9): 980–4

    Article  PubMed  CAS  Google Scholar 

  34. Fedde KN, Blair L, Silverstein J, et al. Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia. J Bone Miner Res 1999; 14(12): 2015–26

    Article  PubMed  CAS  Google Scholar 

  35. Aguirre J, Buttery L, O’Shaughnessy M, et al. Endothelial nitric oxide synthase gene-deficient mice demonstrate marked retardation in postnatal bone formation reduced bone volume, and defects in osteoblast maturation and activity. Am J Pathol 2001; 158(1): 247–57

    Article  PubMed  CAS  Google Scholar 

  36. Holmbeck K, Bianco P, Caterina J, et al. MT1 -MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 1999; 99(1): 81–92

    Article  PubMed  CAS  Google Scholar 

  37. Zimmerman D, Jin F, Leboy P, et al. Impaired bone formation in transgenic mice resulting from altered integrin function in osteoblasts. Dev Biol 2000; 220(1): 2–15

    Article  PubMed  CAS  Google Scholar 

  38. Lecanda F, Warlow PM, Sheikh S, et al. Connexin 43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction. J Cell Biol 2000; 4(13): 931–43

    Article  Google Scholar 

  39. Li B, Boast S, de los Santos K, et al. Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation. Nat Genet 2000; 24(3): 304–8

    Article  PubMed  CAS  Google Scholar 

  40. Marzia M, Sims NA, Voit S, et al. Decreased c-Src expression enhances osteoblast differentiation and bone formation. J Cell Biol 2000; 151(2): 311–20

    Article  PubMed  CAS  Google Scholar 

  41. Ng LJ, Wheatley S, Muscat GE, et al. SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse. Dev Biol 1997; 183(1): 108–21

    Article  PubMed  CAS  Google Scholar 

  42. Bell DM, Leung KK, Wheatley SC, et al. SOX9 directly regulates the type-II collagen gene. Nat Genet 1997; 16(2): 174–8

    Article  PubMed  CAS  Google Scholar 

  43. Huang W, Chung Ui, Kronenberg HM, 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. Proc Natl Acad Sci U S A 2001; 98(1): 160–5

    Article  PubMed  CAS  Google Scholar 

  44. Wagner T, Wirth J, Meyer J, et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 1994; 79(6): 1111–20

    Article  PubMed  CAS  Google Scholar 

  45. Bi W, Deng JM, Zhang Z, et al. Sox9 is required for cartilage formation. Nat Genet 1999; 22(1): 85–9

    Article  PubMed  CAS  Google Scholar 

  46. de Crombrugghe B, Lefebvre V, Behringer RR, et al. Transcriptional mechanisms of chondrocyte differentiation. Matrix Biol 2000; 19(5): 389–94

    Article  PubMed  Google Scholar 

  47. Karaplis AC, Luz A, Glowacki J, et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 1994; 8(3): 277–89

    Article  PubMed  CAS  Google Scholar 

  48. Lanske B, Amling M, Neff L, et al. Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development. J Clin Invest 1999; 104(4): 399–407

    Article  PubMed  CAS  Google Scholar 

  49. Schipani E, Kruse K, Juppner H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 1995; 268(5207): 98–100

    Article  PubMed  CAS  Google Scholar 

  50. Jobert AS, Zhang P, Couvineau A, et al. Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J Clin Invest 1998; 102(1): 34–40

    Article  PubMed  CAS  Google Scholar 

  51. Vortkamp A, Lee K, Lanske B, et al. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 1996; 273(5275): 613–22

    Article  PubMed  CAS  Google Scholar 

  52. Chung UI, Schipani E, McMahon AP, et al. Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. J Clin Invest 2001; 107(3): 295–304

    Article  PubMed  CAS  Google Scholar 

  53. Inada M, Yasui T, Nomura S, et al. Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev Dyn 1999; 214(4): 279–90

    Article  PubMed  CAS  Google Scholar 

  54. Kim IS, Otto F, Zabel B, et al. Regulation of chondrocyte differentiation by Cbfa1. Mech Dev 1999; 80(2): 159–70

    Article  PubMed  CAS  Google Scholar 

  55. Colvin JS, Bohne BA, Harding GW, et al. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 1996; 12(4): 390–7

    Article  PubMed  CAS  Google Scholar 

  56. Coffin JD, Florkiewicz RZ, Neumann J, et al. Abnormal bone growth and selective translational regulation in basic fibroblast growth factor (FGF-2) transgenic mice. Mol Biol Cell 1995; 6(12): 1861–73

    PubMed  CAS  Google Scholar 

  57. Aubin JE, Liu F. The osteoblast lineage. In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. New York: Acad Press, 1996: 51–68

    Google Scholar 

  58. Marie PJ. Osteoblasts and bone formation. In: Zaidi M, editor. Advances in organ biology: molecular and cellular biology of bone. Stamford, CT: JAI Press, 1998 Vol. 5B: 401–427

    Google Scholar 

  59. Triffitt JT. The stem cell of the osteoblast. In: Bilezikian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. New York: Acad Press, 1996: 39–50

    Google Scholar 

  60. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenshymal stem cells. Science 1999; 284: 143–7

    Article  PubMed  CAS  Google Scholar 

  61. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000; 21(2): 115–37

    Article  PubMed  CAS  Google Scholar 

  62. Ducy P, Zhang R, Geoffroy V, et al. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 1997; 89: 747–54

    Article  PubMed  CAS  Google Scholar 

  63. Ducy P, Karsenty G. Genetic control of cell differentiation in the skeleton. Curr Opin Cell Biol 1998; 10: 614–9

    Article  PubMed  CAS  Google Scholar 

  64. Drissi H, Luc Q, Shakoori R, et al. Transcriptional autoregulation of the bone related CBFA1/RUNX2 gene. J Cell Physiol 2000; 184(3): 341–50

    Article  PubMed  CAS  Google Scholar 

  65. Komori T, Yagi H, Nomura S, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997; 89(5): 755–64

    Article  PubMed  CAS  Google Scholar 

  66. Otto F, Thornell AP, Crompton T, et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 1997; 89(5): 765–71

    Article  PubMed  CAS  Google Scholar 

  67. Mundlos S, Otto F, Mundlos C, et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 1997; 89(5): 773–9

    Article  PubMed  CAS  Google Scholar 

  68. Lee B, Thirunavukkarasu K, Zhou L, et al. Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat Genet 1997; 16(3): 307–10

    Article  PubMed  CAS  Google Scholar 

  69. Ducy P, Starbuck M, Priemel M, et al. A Cbfa1 -dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev 1999; 13: 1025–36

    Article  PubMed  CAS  Google Scholar 

  70. Gao YH, Shinki T, Yuasa T, et al. Potential role of cbfa1, an essential transcriptional factor for osteoblast differentiation, in osteoclastogenesis: regulation of mRNA expression of osteoclast differentiation factor (ODF). Biochem Biophys Res Commun 1998; 252(3): 697–702

    Article  PubMed  CAS  Google Scholar 

  71. Thirunavukkarasu K, Halladay DL, Miles RR, et al. The osteoblast-specific transcription factor Cbfa1 contributes to the expression of osteoprotegerin, apotent inhibitor of osteoclast differentiation and function. J Biol Chem 2000; 275(33): 25163–72

    Article  PubMed  CAS  Google Scholar 

  72. Kitazawa R, Kitazawa S, Maeda S. Promoter structure of mouse RANKL/TRANCE/OPGL/ODF gene. Biochim Biophys Acta 1999; 1445(1): 134–41

    Article  PubMed  CAS  Google Scholar 

  73. Priemel MH, Amling M, Shen J, et al. Increased bone formation in Cbfa1 over-expressing mice [abstract]. J Bone Miner Res 1999; 14: S1 1155A

    Google Scholar 

  74. Geoffroy V. in vivo over expression of Cbfa1 in osteoblasts induces severe osteopenia in adult bone [abstract]. Proceedings of EMBO Workshop; 2001 Mar 31-Apr 4; Sestri Levante, Italy

  75. Wozney JM, Rosen V. Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair. Clin Orthop 1998; (346): 26–37

    Google Scholar 

  76. Thomas JT, Kilpatrick MW, Lin K, et al. Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat Genet 1997; 17(1): 58–64

    Article  PubMed  CAS  Google Scholar 

  77. Katagiri T, Boorla S, Frendo JL, et al. Skeletal abnormalities in doubly heterozygous Bmp4 and Bmp7 mice. Dev Genet 1998; 22(4): 340–8

    Article  PubMed  CAS  Google Scholar 

  78. Storm EE, Huynh TV, Copeland NG, et al. Limb alterations in brachypodism mice due to mutations in a new member of the TGF beta-superfamily. Nature 1994; 368(6472): 639–43

    Article  PubMed  CAS  Google Scholar 

  79. Gori F, Thomas T, Hicok KC, et al. Differentiation of human marrow stromal precursor cells: bone morphogenetic protein-2 increases OSF2/CBFA1, enhances osteoblast commitment, and inhibits late adipocyte maturation. J Bone Miner Res 1999; 14(9): 1522–35

    Article  PubMed  CAS  Google Scholar 

  80. Hay E, Lemonnier J, Modrowski D, et al. N- and E-cadherin mediate early human calvaria osteoblast differentiation promoted by bone morphogenetic protein-2. J Cell Physiol 2000; 183(1): 117–28

    Article  PubMed  CAS  Google Scholar 

  81. Erlebacher A, Derynck R. Increased expression of TGF-beta 2 in osteoblasts results in an osteoporosis-like phenotype. J Cell Biol 1996; 132(1–2): 195–210

    Article  PubMed  CAS  Google Scholar 

  82. Calvi LM, Sims NA, Hunzelman JL, et al. Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J Clin Invest 2001; 107(3): 277–86

    Article  PubMed  CAS  Google Scholar 

  83. Strewler GJ. Local and systemic control of the osteoblast. J Clin Invest 2001; 107(3): 271–

    Article  PubMed  CAS  Google Scholar 

  84. Zhao G, Monier-Faugere MC, Langub MC, et al. Targeted overexpression of insulin-like growth factor I to osteoblasts to transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology 2000; 141(7): 2674–82

    Article  PubMed  CAS  Google Scholar 

  85. Ogata N, Chikazu D, Kubota N, et al. Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover. J Clin Invest 2000; 105(7): 935–43

    Article  PubMed  CAS  Google Scholar 

  86. Montero A, Okada Y, Tomita M, et al. Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. J Clin Invest 2000; 105(8): 1085–93

    Article  PubMed  CAS  Google Scholar 

  87. Jerome CP, Burr DB, Van Bibber T, et al. Brommage R.Treatment with human parathyroid hormone (1–34) for 18 months increases cancellous bone volume and improves trabecular architecture in ovariectomized cynomolgus monkeys (Macaca fascicularis). Bone 2001; 28(2): 150–9

    Article  PubMed  CAS  Google Scholar 

  88. Rittmaster RS, Bolognese M, Ettinger MP, et al. Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab 2000; 85: 2129–34

    Article  PubMed  CAS  Google Scholar 

  89. Cosman F, Nieves J, Woelfert L, et al. Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res 2001; 16(5): 925–31

    Article  PubMed  CAS  Google Scholar 

  90. Eisman JA. Pharmacogenetics of the vitamin D receptor and osteoporosis. Drug Metab Dispos 2001; 29 (4 Pt 2): 505–12

    PubMed  CAS  Google Scholar 

  91. Yoshizawa T, Handa Y, Uematsu Y, et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 1997; 16(4): 391–6

    Article  PubMed  CAS  Google Scholar 

  92. Kato S, Takeyama K, Kitanaka S, et al. in vivo function of VDR in gene expression-VDR knock-out mice. J Steroid Biochem Mol Biol 1999; 69(1–6): 247–51

    Article  PubMed  CAS  Google Scholar 

  93. Spelsberg TC, Subramaniam M, Riggs BL, et al.The actions and interactions of sex steroids and growth factors/cytokines on the skeleton. Mol Endocrinol 1999; 6: 819–28

    Article  Google Scholar 

  94. Vidal O, Lindberg MK, Hollberg K, et al. Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. Proc Natl Acad Sci USA 2000; 97(10): 5474–9

    Article  PubMed  CAS  Google Scholar 

  95. Windahl SH, Vidal O, Andersson G, et al. Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta (-/-) mice. J Clin Invest 1999; 104(7): 895–901

    Article  PubMed  CAS  Google Scholar 

  96. Canalis E. Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab 1996; 81(10): 3441–7

    Article  PubMed  CAS  Google Scholar 

  97. Clement-Lacroix P, Ormandy C, Lepescheux L, et al. Osteoblasts are a new target for prolactin: analysis of bone formation in prolactin receptor knockout mice. Endocrinology 1999; 140(1): 96–105

    Article  PubMed  CAS  Google Scholar 

  98. Sims NA, Clement-Lacroix P, Da Ponte F, et al. Bone homeostasis in growth hormone receptor-null mice is restored by IGF-I but independent of Stat5. J Clin Invest 2000; 106(9): 1095–1103

    Article  PubMed  CAS  Google Scholar 

  99. Ducy P, Amling M, Takeda S, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000; 100(2): 197–207

    Article  PubMed  CAS  Google Scholar 

  100. Karsenty G. Leptin controls bone formation through a hypothalamic relay. Recent Prog Horm Res 2001; 56: 401–15

    Article  PubMed  CAS  Google Scholar 

  101. Marie PJ. Human osteoblastic cells: relationship with bone formation. Calcif Tissue Int 1995; 56 S: 13–6

    Google Scholar 

  102. Jilka RL, Weinstein RS, Bellido T, et al. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 1999; 104(4): 439–46

    Article  PubMed  CAS  Google Scholar 

  103. Weinstein RS, Jilka RL, Parfitt AM, et al. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 1998; 102(2): 274–82

    Article  PubMed  CAS  Google Scholar 

  104. Jilka RL, Weinstein RS, Bellido T, et al. Osteoblast programmed cell death (apoptosis): modulation by growth factors and cytokines. J Bone Miner Res 1998; 13(5): 793–802

    Article  PubMed  CAS  Google Scholar 

  105. Jabs, EW, Muller U, Li X, et al. A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell 1993; 75(3): 443–50

    Article  PubMed  CAS  Google Scholar 

  106. Liu YH, Tang Z, Kundu RK, 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. Dev Biol 1999; 205(2): 260–74

    Article  PubMed  CAS  Google Scholar 

  107. Acampora D, Merla GR, Paleari L, et al. Craniofacial, vestibular and bone defects in mice lacking the distal-less-related gene Dlx5. Development 1999; 126: 3795–3809

    PubMed  CAS  Google Scholar 

  108. Newberry EP, Boudreaux JM, Towler DA. Stimulus-selective inhibition of rat osteocalcin promoter induction and protein-DNA interactions by the homeodomain repressor Msx2. J Biol Chem 1997; 272(47): 29607–13

    Article  PubMed  CAS  Google Scholar 

  109. Ryoo HM, Hoffmann HM, Beumer T, et al. Stage-specific expression of Dlx-5 during osteoblast differentiation: involvement in regulation of osteocalcin gene expression. Mol Endocrinol 1997; 11(11): 1681–94

    Article  PubMed  CAS  Google Scholar 

  110. el Ghouzzi V, Le Merrer M, Perrin-Schmitt F, et al. Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat Genet 1997; 15(1): 42–6

    Article  PubMed  Google Scholar 

  111. Yousfi M, Lasmoles F, Lomri A, et al. Increased bone formation and decreased osteocalcin expression induced by reduced Twist dosage in Saethre-Chotzen syndrome. J Clin Invest 2001; 107(9): 1153–61

    Article  PubMed  CAS  Google Scholar 

  112. Webster MK, Donoghue DJ. FGFR activation in skeletal disorders: too much of a good thing. Trends Genet 1997; 13(5): 178–82

    Article  PubMed  CAS  Google Scholar 

  113. Wilkie AO. Craniosynostosis: genes and mechanisms. Hum Mol Genet 1997; 6: 1647–56

    Article  PubMed  CAS  Google Scholar 

  114. Jabs EW. Toward understanding the pathogenesis of craniosynostosis through clinical and molecular correlates. Clin Genet 1998; 53(2): 79–86

    Article  PubMed  CAS  Google Scholar 

  115. Fragale A, Tartaglia M, Bernardini S, et al. Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders. Am J Pathol 1999; 154(5): 1465–77

    Article  PubMed  CAS  Google Scholar 

  116. Lomri A, Lemonnier J, Hott M, et al. Increased calvaria cell differentiation and bone matrix formation induced by fibroblast growth factor receptor-2 mutations in Apert syndrome. J Clin Invest 1998; 101: 1310–7

    PubMed  CAS  Google Scholar 

  117. Lemonnier J, Hott M, Delannoy P, et al. Down regulation of fibroblast growth factor receptor-2 in Apert syndromic craniosynostosis. Exp Cell Res 2000; 256(1): 158–67

    Article  PubMed  CAS  Google Scholar 

  118. Zhou YX, Xu X, Chen L, Li C, et al. A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures. Hum Mol Genet 2000; 9(13): 2001–8

    Article  PubMed  CAS  Google Scholar 

  119. Debiais F, Hott M, Graulet AM, et al. The effects of fibroblast growth factor-2 on human neonatal calvaria osteoblastic cells are differentiation stage specific. J Bone Miner Res 1998; 13(4): 645–54

    Article  PubMed  CAS  Google Scholar 

  120. St-Jacques B, Hammerschmidt M, McMahon AP. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 1999; 13(16): 2072–86

    Article  PubMed  CAS  Google Scholar 

  121. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309–19

    Article  PubMed  CAS  Google Scholar 

  122. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165–76

    Article  PubMed  CAS  Google Scholar 

  123. Suda T, Kobayashi K, Jimi E, et al. The molecular basis of osteoclast differentiation and activation. Novartis Found Symp 2001; 232: 235–47

    Article  PubMed  CAS  Google Scholar 

  124. Bucay N, Sarosi I, Dunstan CR, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12(9): 1260–8

    Article  PubMed  CAS  Google Scholar 

  125. Kim N, Odgren PR, Kim DK, et al. Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. Proc Natl Acad Sci U S A 2000; 97(20): 10905–10

    Article  PubMed  CAS  Google Scholar 

  126. Rodan GA, Martin TJ. Therapeutic approaches to bone diseases. Science 2000; 289(5484): 1508–14

    Article  PubMed  CAS  Google Scholar 

  127. Niu T, Xu X. Candidate genes for osteoporosis: therapeutic implications. Am J Pharmacogenomics 2001; 1: 11–19

    Article  PubMed  CAS  Google Scholar 

  128. Ralston SH. The genetics of osteoporosis. Q J Med 1997; 90: 247–51

    Article  CAS  Google Scholar 

  129. Eisman JA. Genetics of osteoporosis. Endocr Rev 1999; 20(6): 788–804

    Article  PubMed  CAS  Google Scholar 

  130. Brown MA, Haughton MA, Grant SF, et al. Genetic control of bone density and turnover: role of the collagen 1alpha1, estrogen receptor, and vitamin D receptor genes. J Bone Miner Res 2001; 16(4): 758–64

    Article  PubMed  CAS  Google Scholar 

  131. Langdahl BL, Knudsen JY, Jensen HK, et al. A sequence variation: 713-8delC in the transforming growth factor-beta 1 gene has higher prevalence in osteoporotic women than in normal women and is associated with very low bone mass in osteoporotic women and increased bone turnover in both osteoporotic and normal women. Bone 1997; 20(3): 289–94

    Article  PubMed  CAS  Google Scholar 

  132. Ferrari S, Rizzoli R, Chevalley T, et al. Vitamin-D-receptor-gene polymorphisms and change in lumbar-spine bone mineral density. Lancet 1995 Feb 18; 345(8947): 423–4

    Article  PubMed  CAS  Google Scholar 

  133. Mann V, Hobson EE, Li B, et al. A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest 2001; 107(7): 899–907

    Article  PubMed  CAS  Google Scholar 

  134. Niu, T and Xu, X. Candidate genes for osteoporosis: Therapeutic implications. Am J. Pharmacogenomics 2001; 1(1): 11–19

    Article  PubMed  CAS  Google Scholar 

  135. Duncan EL, Brown MA, Sinsheimer J, et al. Suggestive linkage of the parathyroid receptor type 1 to osteoporosis. J Bone Miner Res 1999; 14(12): 1993–9

    Article  PubMed  CAS  Google Scholar 

  136. Dimai HP, Linkhart TA, Linkhart SG, et al. Alkaline phosphatase levels and osteoprogenitor cell numbers suggest bone formation may contribute to peak bone density differences between two inbred strains of mice. Bone 1998; 22(3): 211–6

    Article  PubMed  CAS  Google Scholar 

  137. Sheng MH, Baylink DJ, Beamer WG, et al. Histomorphometric studies show that bone formation and bone mineral apposition rates are greater in C3H/HeJ (high-density) than C57BL/6J (low-density) mice during growth. Bone 1999; 25(4): 421–9

    Article  PubMed  CAS  Google Scholar 

  138. Jilka RL, Weinstein RS, Takahashi K, et al. Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence. J Clin Invest 1996; 97(7): 1732–40

    Article  PubMed  CAS  Google Scholar 

  139. Fuchs B, Zhang K, Bolander ME, et al. Identification of differentially expressed genes by mutually subtracted RNA fingerprinting. Anal Biochem 2000; 286(1): 91–8

    Article  PubMed  CAS  Google Scholar 

  140. Jiang H, Kang DC, Alexandre D, et al. RaSH, a rapid subtraction hybridization approach for identifying and cloning differentially expressed genes. PNAS 2000; 97(23): 12684–9

    Article  PubMed  CAS  Google Scholar 

  141. Waye MM, Li VK. Isolation of cDNA clones from an osteosarcoma-ROS17/2.8 library by differential hybridization. J Cell Biochem 1994; 54(3): 273–80

    Article  PubMed  CAS  Google Scholar 

  142. Peterson D, Tkalcevic GT, Mansolf AL, et al. Identification of osteoblast/osteocyte factor 45 (OF45), a bone specific cDNA endcoding an RGD-containing protein that is highly expressed in osteoblasts and osteocytes. J Biol Chem., 2000; 275,46: 36172–80

    Article  Google Scholar 

  143. Ryoo HM, van Wijnen AJ, Stein JL, et al. Detection of a proliferation specific gene during development of the osteoblast phenotype by mRNA differential display. J Cell Biochem 1997; 64(1): 106–16

    Article  PubMed  CAS  Google Scholar 

  144. Dieudonne SC, Kerr JM, Xu TS, et al. Differential display of human stromal cells reveals unique mRNA expression patterns in response to dexamethasone. J Cell Biochem 2000; 76: 231–43

    Article  CAS  Google Scholar 

  145. Schutze N, Bachthaler M, Lechner A, et al. Identification by differential display PCR of the selenoprotein thioredoxin reductase as a 1 alpha,25 (OH)2-vitamin D3-responsive gene in human osteoblasts—regulation by selenite. Biofactors 1998; 7(4): 299–310

    Article  PubMed  CAS  Google Scholar 

  146. Chen J, Zhong Q, Wang I, et al. Microarray analysis of Tbx2-directed gene expression: a possible role in osteogenesis. Mol Cell Endocrinol 2001; 177: 43–54

    Article  PubMed  CAS  Google Scholar 

  147. Lomri A, Lemonnier J, Delannoy P, et al. Identification of genes induced by the Ser252Trp FGFR-2 Apert mutation in osteoblasts using atlas human expression arrays: evidence for increased expression of PKCα, IL-1α_and RhoA GTPase. J Bone Miner Res 2001; 16(4): 705–12

    Article  PubMed  CAS  Google Scholar 

  148. Beck Jr GR, Zerler B, Moran E. Gene array analysis of osteoblast differentiation. Cell Growth Differ 2001 Feb; 12(2): 61–83

    PubMed  CAS  Google Scholar 

  149. Garcia T, Roman-Roman S, Jackson A, et al. Identification of new genes during osteoblast differentiation by genome-wide expression analysis of mouse calvaria primary osteoblasts in vitro. J Bone Miner Res 2000; 15(S1): S274

    Google Scholar 

  150. Hou Z, Nguyen Q, Frenkel B, et al. Osteoblast-specific gene expression after transplantation of marrow cells: implications for skeletal gene therapy. Proc Natl Acad Sci U S A 1999; 96(13): 7294–9

    Article  PubMed  CAS  Google Scholar 

  151. Horwitz EM, Prockop DJ, Fitzpatrick LA, et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999; 5(3): 309–13

    Article  PubMed  CAS  Google Scholar 

  152. Fang J, Zhu YY, Smiley E, et al. Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci U S A 1996; 93(12): 5753–8

    Article  PubMed  CAS  Google Scholar 

  153. Hackett NR, Crystal RG. Adenovirus for gene therapy. In: Smyth Templeton N, Lasic DD, editors. Gene therapy, therapeutic mechanisms and strategies. New York: Marcel Dekker, 2000: 17–40

    Google Scholar 

  154. Cannon PM, Anderson WF. Retroviral vactors for gene therapy. In: Smyth Templeton N, Lasic DD, editors. Gene therapy, therapeutic mechanisms and strategies. New York: Marcel Dekker, 2000: 1–16

    Google Scholar 

  155. Lasic DD, Smyth Templeton N. Bioorganic colloids: macromolecules, DNA, self-assembled particles and their complexes. In: Smyth Templeton N, Lasic DD, editors. Gene therapy, therapeutic mechanisms and strategies. New York: Marcel Dekker, 2000: 241–66

    Google Scholar 

  156. Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science 1999; 286(5446): 1946–9

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The author thanks Dr. H. Drissi (Worcester, Massachusetts, USA) for critical reading of the manuscript.

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  1. Laboratory on Osteoblast Biology and Pathology, Paris, France

    Pierre J. Marie (Director of Research, Head of the Laboratory)

  2. CNRS, France

    Pierre J. Marie (Director of Research, Head of the Laboratory)

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Marie, P.J. The Molecular Genetics of Bone Formation. Am J Pharmacogenomics 1, 175–187 (2001). https://doi.org/10.2165/00129785-200101030-00003

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