Advertisement

Transgenic and Gene Knock-Out Animals in Skeletal Research

  • M. Amling
  • M. W. Hentz
  • M. Priemel
  • G. Delling
Conference paper
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 25)

Abstract

Until recently most of our knowledge about the skeleton was derived from descriptive morphology, histomorphometry, endocrinology, and cellular studies of bone turnover (Delling 1987; Delling and Amling 1995; Amling et al. 1994, 1996). Recent approaches have led to the identification of local factors that regulate skeletal morphogenesis. Molecular and biochemical studies of bone cells in vitro and, most importantly, the power of genetics entering the bone field have led us toward the beginning of a molecular understanding of the skeletal system (Erlebacher et al. 1995). Indeed the identification of genes responsible for mouse and human skeletal abnormalities, gene inactivation and targeted gene misexpression in mice have documented the importance of specific signaling molecules and their receptors, as well as growth factors, matrix proteins, and transcription factors in the development and maintenance of bone. The successful convergence of mouse and human genetics in skeletal biology has been demonstrated several times, e.g. chondrodysplasia in parathyroid hormone-related protein (PTHrP) receptor mutant mice (Amizuka et al. 1994; Karaplis et al. 1994; Lanske et al. 1996; Weir et al. 1996; Amling et al. 1997) and patients with Jansens metaphyseal dysplasia (Schipani et al. 1995). Mutations in collagen type XI in cho/cho mice (Li et al. 1995) and patients with Stickler syndrome (Vikkula et al. 1995); identical phenotypes of Cbfa1 +/− heterozygous mice (Otto et al. 1997) and patients with cleidocranial dysplasia (Mundlos et al. 1997), which lack the expression of one allele of the Cbfal gene; as well as mice with targeted ablation of the second zinc finger of the vitamin D receptor DNA-binding domain as a model of vitamin D-dependent rickets type II (Li et al. 1997). The latter examples underscore the invaluable importance of transgenic and knock-out animals in skeletal research.

Keywords

Endochondral Bone Formation Stickler Syndrome Cleidocranial Dysplasia Metaphyseal Dysplasia Skeletal Maintenance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Akagi K, Sandig V, Vooijs M, Van der Valk M, Giovannini M, Strauss M, Berns A (1997) Cre-mediated somatic site-specific recombination in mice. Nucleic Acids Res 25: 1766–1773PubMedCrossRefGoogle Scholar
  2. Alkema MJ, Bronk M, Verhoeven E, Otte A, van’t Veer LJ, Berns A, van Lohuizen M (1997) Identification of Bmi-1-interacting proteins as constituents of a multimeric mammalian polycomb complex. Genes Dev 11: 226–240PubMedCrossRefGoogle Scholar
  3. Allsopp TE, Wyatt S, Paterson HF, Davies AM (1993) The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell 73: 295–307PubMedCrossRefGoogle Scholar
  4. Amizuka N, Warshawsky H, Henderson JE, Goltzman D, Karaplis AC (1994) Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation. J Cell Biol 126: 1611–123PubMedCrossRefGoogle Scholar
  5. Amizuka N, AC Karaplis, Henderson JE, Warshawsky H, Lipman ML, Matsuki Y, Ejiri S, Tanaka M, Izumi N, Ozawa H, Goltzman D (1996a) Haploinsufficiency of parathyroid hormone-related peptide ( PTHrP) results in abnormal postnatal bone development. Dev Biol 175: 166–176PubMedCrossRefGoogle Scholar
  6. Amizuka N, Henderson JE, Hoshi K, Warshawsky H, Ozawa H, Goltzman D, Karaplis AC (1996b) Programmed cell death of chondrocytes and aberrant chondrogenesis in mice homozygous for parathyroid hormone-related peptide gene deletion. Endocrinology 137: 5055–5067PubMedCrossRefGoogle Scholar
  7. Amling M, Delling G (1996) Zellbiologie des Osteoklasten and molekulare Mechanismen der Knochenresorption Pathologe 17: 358–367Google Scholar
  8. Amling M, Grote H, Pösl M, Hahn M, Delling G (1994) Polyostotic heterogeneity of the spine in osteoporosis. Bone Mineral 27: 193–208CrossRefGoogle Scholar
  9. Amling M, Herden S, Pösl M, Hahn M, Ritzel H, Delling G (1996) Heterogeneity of the skeleton. J Bone Miner Res 11: 36 115Google Scholar
  10. Amling M, Neff L, Tanaka S, Inoue D, Kuida K, Weir E C, Philbrick WM, Broadus AE, Baron R (1997) Bc1–2 lies downstream of parathyroid hormone-related peptide in a signaling pathway that regulates chondrocyte maturation during skeletal development. J Cell Biol 136: 205–213PubMedCrossRefGoogle Scholar
  11. Amling M, Neff L, Priemel M, Delling G, Baron R (1998) Progressive osteopetrosis and development of odontomas in aging Src-deficient mice. Bone (in press)Google Scholar
  12. Baker J, Liu JP, Robertson EJ, Efstratiadis A (1993) Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75: 73–82PubMedGoogle Scholar
  13. Baron R, Neff L, Brown W, Courtoy PJ, Louvard D, Farquhar MG (1988) Polarized secretion of lysosomal enzymes: co-distribution of cation-independent mannose-6-phosphate receptors and lysosomal enzymes along the osteoclast exocytic pathway. J Cell Biol 106: 1863–1872PubMedCrossRefGoogle Scholar
  14. Blake TJ, Shapiro M, Morse HC, Langdon WY (1991) The sequence of the human c-cbl proto-oncogene show v-cbl was generated by a large truncation encompassing a proline-rich domain and a leucine zipper-like motif. Oncogene 6: 653–657PubMedGoogle Scholar
  15. Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turca LA, Mao X, Nunez G, Thompson CB (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74: 597–608Google Scholar
  16. Boyce BF, Yoneda T, Lowe C, Soriano P, Mundy GR(1992) Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J Clin Invest 90: 1622–1627Google Scholar
  17. Broadus A, Stewart E AF (1994) Parathyroid hormone-related protein. In Bilezikian JP, Levine MA, Marcus R (eds) The parathyroids. Raven, New York, pp 259–294Google Scholar
  18. Capecchi MR (1989a) The new mouse genetics: altering the genome by gene targeting. Trends Genet 5: 70–76PubMedCrossRefGoogle Scholar
  19. Capecchi MR (1989b) Altering the genome by homologous recombination. Science 244: 1288–1292PubMedCrossRefGoogle Scholar
  20. Coffin JD, Florakiewicz RZ, Neumann J, Mort-Hopkins T, Dorn II GW, Lightfoot P, German R, Howles PN, Kier A, O’Toole BA, Sasse J, Gonzales AM, Gonzales Baird A, Doetschman T (1995) Abnormal bone growth and selective translational regulation in the basic fibroblast growth factor (FGF-2) transgenic mice. Mol Biol Cell 6: 1861–1873PubMedGoogle Scholar
  21. Copp Ai (1995) Death before birth: clues from gene knock-out and mutations. Trends Genet 11: 87–93PubMedCrossRefGoogle Scholar
  22. Corral D, Amling M, Priemel M, Neff L, Chung U, Kronenberg HM, Baron R, Karsenty G (1997) Reversible ablation of osteoblasts: An animal model of osteoporosis. J Bone Min Res 12: S120Google Scholar
  23. Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH, Blaese RM (1992) In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 256: 1550–1552PubMedCrossRefGoogle Scholar
  24. Delling G (1987) Bone morphology in primary hyperparathyroidism A qualitative and quantitative study of 391 cases Appl Pathol 5: 157–159Google Scholar
  25. Delling G, Amling M (1995) Biomechanical stability of the skeleton — it is not only bone mass, but also bone structure that counts. Nephrol Dial Transplant 10: 601–606PubMedGoogle Scholar
  26. Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P (1996) Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84: 911–921PubMedCrossRefGoogle Scholar
  27. Dostal LA, Toverud SU (1984) Effect of vitamin D3 on duodenal calcium ab- sorption in vivo during early development. Am J Physiol 246: G528 - G534PubMedGoogle Scholar
  28. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dustan C, Smith E, Bonadio J, Goldstein S, Grundberg C, Bradley A, Kasenty G (1996) Increased bone formation in osteocalcin-deficient mice. Nature 382: 448–452PubMedCrossRefGoogle Scholar
  29. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Osf2/Cbfal: a transcriptional activator of osteoblast differentiation. Cell 89: 747–745PubMedCrossRefGoogle Scholar
  30. Erlebacher A, Filvaroff EH, Gitelman SE, Derynck R (1995) Towards a molecular understanding of skeletal development. Cell 80: 371–378PubMedCrossRefGoogle Scholar
  31. Felix R, Cecchini MG, Fleisch H (1990) Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology 127: 2592–2594PubMedCrossRefGoogle Scholar
  32. Golden AJ, Brugge S (1988) The src oncogene. In: Reddy EP, Skalka AM, Curran T (eds) The oncogene handbook. Elsiver, Amsterdam, pp 149–173Google Scholar
  33. Goltzman D, Hendy GN, Banville D(1989) Parathyroid hormone-like peptide: molecular characterization and biological properties. Trends Endocrinol Metabol 1: 39–44Google Scholar
  34. Gordon JW, Scangos GA, Plotkin DJ, Barbosa JA, Ruddle FH (1980) Genetic transformation of mouse embryos by microinjection of purified DNA. Proc Natl Acad Sci USA 77: 7380–7384PubMedCrossRefGoogle Scholar
  35. Grigoriadis AE, Schellander K, Wang ZQ, Wagner EF (1993) Osteoblasts are target cells for transformation in c-fos transgenic mice. J Cell Biol 122: 685–701PubMedCrossRefGoogle Scholar
  36. Grigoriadis AE, Wang ZQ, Cecchini MG, Hofstetter W, Felix R, Fleisch H, Wagner E F (1994) Fos: A key regulator of osteoclast-macrophage lineage determination and bone formation. Science 266: 443–448Google Scholar
  37. Gu H, Marth JD, Orban PC, Mossmann H, Rajewsky K (1994) Deletion of dna polymerase b gene segment in t cells using cell type-specific gene targeting. Science 265: 103–105PubMedCrossRefGoogle Scholar
  38. Hamel W, Magnelli L, Chiarugi VP, Israel MA (1996) Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells. Cancer Res 56: 2697–2702PubMedGoogle Scholar
  39. Hardy MH (1992) The secret life of the hair follicle. Trends Genet 8: 55–61PubMedGoogle Scholar
  40. Hentz MW, Amling MJ, David P, Neff L, van Lohuizen M, Baron R, Delling G (1997) Overexpression and altered subnuclear localization of the transcriptional repressor Bmi-1 in osteosarcoma. J Bone Miner Res 12:S 140Google Scholar
  41. Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, S J Korsmeyer (1993) Bcl-2 functions in an antioxidative pathway to prevent apoptosis. Cell 75: 241–251PubMedCrossRefGoogle Scholar
  42. Horne WC, Neff L, Lomri A, Levy JB, Baron R (1992) Osteoclasts express high levels of pp60c-src in association with intracellular membranes. J Cell Biol 119: 1003–1013PubMedCrossRefGoogle Scholar
  43. Jansen M (1934) Über atypische Chondrodystrophie (Achondroplasie) und über eine noch nicht beschriebene angeborene Wachstumsstörung des Knochensystems: Metaphysäre Dysostosis. Z Orthop Chir 61: 253–286Google Scholar
  44. Jensen BL (1990) Somatic development in cleidocranial dysplasia. Am J Med Gen 35: 69–74CrossRefGoogle Scholar
  45. Jove R, Hanafusa H (1987) Cell transformation by the viral src oncogene. Ann Rev Cell Biol 3: 31–56PubMedCrossRefGoogle Scholar
  46. Jüppner H (1996) Jansen’s metaphyseal chondrodysplasia. A disorder due to a PTH/PTHrP receptor gene mutation. Trends Endocrinol Metabol 7: 157–162CrossRefGoogle Scholar
  47. Jüppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski LF, Hock J, Potts JT, Kronenberg HM, Segre GV (1991)A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254: 1024–1026Google Scholar
  48. Jüppner H, Abou-Samra AB, Uneno S, Gu WX, Potts JT, Segre GV (1988) The parathyroid hormone-like peptide associated with humoral hypercalcemia of malignancy and parathyroid hormone bind to the same receptor on the plasma membrane of ROS 17/28 cells. J Biol Chem 263: 8557–8560PubMedGoogle Scholar
  49. Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VLJ, Kronenberg HM, Mulligan RC (1994) Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 8: 277–289PubMedCrossRefGoogle Scholar
  50. Kilby NJ, Snaith MR, Murray JA (1993) Site specific recombinase: tools for genome engineering. Trends Genet 9: 413–421PubMedCrossRefGoogle Scholar
  51. Kodama H, Yamasaki A, Nose M, Nuda S, Ohgame Y, Abe M, Kumegawa M, Suda T (1991)Congenital osteoclast deficiency in osteopetrotic (op/op) mice is cured by injections of macrophage colony-stimulating factor. J Exp Med 173: 269–274Google Scholar
  52. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T (1997) Targeted disruption of CBFA 1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89: 755–764PubMedCrossRefGoogle Scholar
  53. Korsmeyer SJ (1992) Bc1–2 initiates a new category of oncogenes: regulators of cell death. Blood 80: 879–886PubMedGoogle Scholar
  54. Kronenberg HM, Bringhurst FR, Nussbaum S, Jüppner H, Abou-Samra A-B, Segre G, Potts JT (1993) Parathyroid hormone: Biosynthesis, secretion, chemistry, and action. In: Mundy GR, Martin TJ (eds) Handbook of experimental pharmacology: physiology and pharmacology of bone. Springer-Verlag, Berlin, Heidelberg, New York, pp 507–549CrossRefGoogle Scholar
  55. Kühn R, Schwenk F, Aguet M, Rajewsky K (1995) Inducible gene targeting in mice. Science 269: 1427–1429PubMedCrossRefGoogle Scholar
  56. Lakso M, Sauer B, Mosinger BJ, Lee EJ, Manning RW, Yu SH, Mulder KL, Westphal H (1992) Targeted oncogene activation by site specific recombinases in transgenic mice. Proc Natl Acad Sci USA 89: 6232–6236PubMedCrossRefGoogle Scholar
  57. Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro A, Karperien M, Defize LHK, Ho C, Mulligan RC, Abou-Samra AB, Jüppner H, Segre GV, Kronenberg HM (1996) PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273: 663–666PubMedCrossRefGoogle Scholar
  58. Li Y, Lacerda DA, Warman ML, Beier ML, Yoshioka H, Ninomiya Y, Oxford JT, Morris NP, Andrikopoulos K, Ramirez F, Wardell BB, Lifferth GD, Teuscher C, Woodward SR, Tayler BA, Seegmiller RE, Olsen BR (1995) A fibrillar collagen gene, Coll 1al, is essential for skeletal morphogenesis. Cell 80: 423–430PubMedCrossRefGoogle Scholar
  59. Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, Demay MB (1997) Targeted ablation of vitamin D receptor: an animal model of vitamin d-dependent rickets type II with alopecia. Proc Natl Acad Sci USA 94: 9831–9835PubMedCrossRefGoogle Scholar
  60. Lowe C, Yoneda T, Boyce BF, Chen H, Mundy GR, Soriano P (1993) Osteopetrosis in src-deficient mice is due to an autonomous defect of osteoclast. Proc Natl Acad Sci USA 90: 4485–4489PubMedCrossRefGoogle Scholar
  61. Mangin M, Webb AC, Dreyer BE, Posillico JT, Ikeda K, Weir E C, Stewart AF, Bander NH, Milstone L, Barton DE, Francke U, Broadus AE (1988) Identification of a cDNA encoding a parathyroid hormone-like peptide from human tumor associated with humoral hypercalcemia of malignancy. Proc Natl Acad Sci USA 85: 597–601PubMedCrossRefGoogle Scholar
  62. Muenke M, Schell U (1995) Fibroblast-growth-factor receptor mutations in human skeletal disorders. Trends Genet 11: 308–313PubMedCrossRefGoogle Scholar
  63. Mullins LJ, Kotelevtseva N, Boyd AC, Mullins JJ (1997) Efficient cre-lox linearisation of bacs: applications to physical mapping and generation of transgenic animals. Nucleis Acids Res 25: 2539–2540CrossRefGoogle Scholar
  64. Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Henn W, Knoll JHM, Owen MJ, Mertelsmann R, Zabel BU, Olsen BR (1997) Mutations involving the transcription factor CBFA 1 cause cleidocranial dysplasia. Cell 89: 773–779PubMedCrossRefGoogle Scholar
  65. Nakayama K, Nakayama K-I, Negishi I, Kuida K, Sawa H, Loh DY (1994) Targeted disruption of Bc1–2ab in mice: occurence of gray hair, polycystic kidney disease, and lymphocytopenia. Proc Natl Acad Sci USA 91: 3700–3704PubMedCrossRefGoogle Scholar
  66. Ogawa E, Maruyama M, Kagoshima H, Inuzuka M, Lu J, Satake M, Shigesada K, Ito Y (1993) PEBP2/PEA2 represents a family of transcription factors homologous to the products of Drosophila runt gene and the human AML1 gene. Proc Natl Acad Sci USA 90: 6859–6863PubMedCrossRefGoogle Scholar
  67. Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bc1–2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74: 609–619Google Scholar
  68. Otto F, Thornell AP, Crompton T, Dencel A, Gilmour KC, Rosewell IR, Stamp GWH, Beddington RSP, Mundlos S, Olsen BR, Selby PB, Owen MJ (1997) Cbfa 1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89: 765–771PubMedCrossRefGoogle Scholar
  69. Pluck A (1996) Conditional mutagenesis in mice: the cre/loxP recombination system. Int J Exp Path 77: 269–278Google Scholar
  70. Posi M, Amling M, Neff L, Grahl K, Baron R, Delling G (1996) Coexpression of PTHrP and Bc1–2 correlates with the degree of malignancy of chondro genic tumors. J Bone Miner Res 11: S113Google Scholar
  71. Reimhold AM, Grusby MJ, Kosaras B, Fries JWU, Mori R, Maniwa S, Clauss IM, Collins T, Sidam RL, Glimcher M, Glimcher LH (1996) Chondrodysplasia and neurological abnormalities in the ATF-2-deficient mice. Nature 379: 262–265CrossRefGoogle Scholar
  72. Rousseau F, Bonaventure J, Legeal-Mallet L, Pelet A, Rozet J-M, Maroteaux P, Le Merrer M, Munnich A (1994) Mutations in the gene encoding fibroblast growth factorreceptor-3 in achondroplasia. Nature 371: 252–254PubMedCrossRefGoogle Scholar
  73. Rousseau F, Saugier P, Le Merrer M, Munnich A, Delezoide A-L, Maroteaux P, Bonaventure J, Narcy F, Sanak M (1995) Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. Nat Genet 10: 11–12PubMedCrossRefGoogle Scholar
  74. Schipani E, Kruse K, Jüppner H (1995) A constitutively active mutant PTHPTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268: 98–100PubMedCrossRefGoogle Scholar
  75. Shiang R, Thompson LM, Zhu Y-Z, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ (1994) Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78: 335–342PubMedCrossRefGoogle Scholar
  76. Snell GD (1929) Dwarf, a new mendelian recessive character of the house mouse. Proc Natl Acad Sci USA 15: 733–734PubMedCrossRefGoogle Scholar
  77. Soriano P, Montgomery C, Geske R, Bradley A (1991)Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64: 693–702Google Scholar
  78. St-Onge L, Furth PA, Gruss P (1996) Temporal control of the cre recombinase in transgenic mice by a tetracycline responsive promoter. Nucleic Acids Res 24: 3875–3877PubMedCrossRefGoogle Scholar
  79. Strewler GJ, Stern PH, Jacobs JW, Eveloff J, Klein RF, Leung SC, Rosenblatt M, Nissenson RA (1987) Parathyroid hormone-like protein from human renal carcinoma cells Structural and functional homology with parathyroid hormone. J Clin Invest 80: 1803–1807PubMedCrossRefGoogle Scholar
  80. Suva LJ, Winslow GA, Wettenhall RE H, Hammonds RG, Moseley JM, Diefenbach-Jagger H, Rodda CP, Kemp BE, Rodriguez H, Chen E Y, Hudson PJ, Martin TJ, Wood WI (1987) A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science 237: 893–896PubMedCrossRefGoogle Scholar
  81. Tanaka S, Amling M, Neff L, Peymann A, Uhlmann E, Levy JB, Baron R (1996) c-Cbl is downstream of c-Src in a signaling pathway necessary for bone resorption. Nature 383: 528–531Google Scholar
  82. Tanaka S, Neff L, Baron R, Levy JB (1995) Tyrosine phosphorylation and translocation of the c-Cbl protein after activation of tyrosine kinase signaling pathways. J Biol Chem 270: 14347–14351PubMedCrossRefGoogle Scholar
  83. Tanaka S, Takahashi N, Udagawa N, Sasaki T, Fukui Y, Kurokawa T, Suda T ( 1992 Osteoclasts express high levels of p60c-src, preferentially on ruffled border membranes. FEBS Lett 313: 85–89PubMedCrossRefGoogle Scholar
  84. van der Lugt NMT, Domen J, Linder K, van Roon M, Robanus-Maandag E, to Riele H, Van der Valk M, Deschamps J, Sofroniew M, van Lohuizen M, Berns A (1994) Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with targeted deletion of the bmi-1 proto-oncogene. Genes Dev 8: 757–769PubMedCrossRefGoogle Scholar
  85. van de Stolpe A, Karperien M, Lswik CWGM, Jüppner H, Segre GV, Abou Samra A-B, de Laat SW, Defize LHK (1993) Parathyroid hormone-related peptide as an endogenous inducer of parietal endoderm differentiation. J Cell Biol 120: 235–243PubMedCrossRefGoogle Scholar
  86. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75: 229–240PubMedCrossRefGoogle Scholar
  87. Vikkula M, Mariman E CM, Lui VCH, Zhidkova NI, Tiller GE, Goldring MB, van Beersum SE C, de Waal Malefijt M, van den Hoogen FHJ, Ropers HH, Mayne R, Cheah KSE, Olsen BR, Warman ML, Brunner HG (1995) Autosomal dominant and recessive osteochondrodysplasias associated with the Co111A2 locus. Cell 80: 431–437PubMedCrossRefGoogle Scholar
  88. Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ (1996) Regulation of rate of cartilage differentiation by indian hedgehog and PTHrelated protein. Science 273: 613–622PubMedCrossRefGoogle Scholar
  89. Wang Z-Q, Ovitt C, Grigoriadis AE, Möhle-Steinlein U, Wither U, Wagner E F ( 1992 Bone and haematopoietic defects in mice lacking c-fos. Nature 360: 741–745PubMedCrossRefGoogle Scholar
  90. Weir E C, Philbrick WM, Amling M, Neff L, Baron R, Broadus AE (1996) Targeted overexpression of parathyroid hormone-related peptide in chondrocytes delays chondrocyte differentiation and endochondral bone formation. Proc Natl Acad Sci USA 93: 10240–10245PubMedCrossRefGoogle Scholar
  91. Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW, Ahmed-Ansari A, Sell KW, Pollard JW, Stanley E R (1990) Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA 87: 4828–4832PubMedCrossRefGoogle Scholar
  92. Wysolmerski JJ, Broadus AE, Zhou J, Fuchs E, Milstone LM, Philbrick WM (1994) Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes with hair follicle development. Proc Natl Acad Sci USA 91: 1133–1137PubMedCrossRefGoogle Scholar
  93. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD (1990) The murine mutation osteopetrosis is in the coding region of macrophage colony stimulating factor. Nature 345: 442–444PubMedCrossRefGoogle Scholar
  94. Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, Kawakami T, Arioka K, Sato H, Uchiyama Y, Masushige S, Fukamizu A, Matsumoto T, Kato S (1997) Mice lacking in the vitamin d receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 16: 391–396PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • M. Amling
  • M. W. Hentz
  • M. Priemel
  • G. Delling

There are no affiliations available

Personalised recommendations