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Characterization of the osteoblast-specific transmembrane protein IFITM5 and analysis of IFITM5-deficient mice

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Abstract

Interferon-inducible transmembrane protein 5 (IFITM5) is an osteoblast-specific membrane protein whose expression peaks around the early mineralization stage during the osteoblast maturation process. To investigate IFITM5 function, we first sought to identify which proteins interact with IFITM5. Liquid chromatography mass spectrometry revealed that FK506-binding protein 11 (FKBP11) co-immunoprecipitated with IFITM5. FKBP11 is the only protein it was found to interact with in osteoblasts, while IFITM5 interacts with several proteins in fibroblasts. FKBPs are involved in protein folding and immunosuppressant binding, but we could not be sure that IFITM5 participated in these activities when bound to FKBP11. Thus, we generated Ifitm5-deficient mice and analyzed their skeletal phenotypes. The skeletons, especially the long bones, of homozygous mutants (Ifitm5 −/−) were smaller than those of heterozygous mutants (Ifitm5 +/−), although we did not observe any significant differences in bone morphometric parameters. The effect of Ifitm5 deficiency on bone formation was more significant in newborns than in young and adult mice, suggesting that Ifitm5 deficiency might have a greater effect on prenatal bone development. Overall, the effect of Ifitm5 deficiency on bone formation was less than we expected. We hypothesize that this may have resulted from a compensatory mechanism in Ifitm5-deficient mice.

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References

  1. Hanagata N, Takemura T, Monkawa A, Ikoma T, Tanaka J (2007) Phenotype and gene expression pattern of osteoblast-like cells cultured on polystyrene and hydroxyapatite with pre-adsorbed type-I collagen. J Biomed Mater Res Part A 83A:362–371

    Article  CAS  Google Scholar 

  2. Lange UC, Saitou M, Western PS, Barton SC, Surani MA (2003) The fragilis interferon-inducible gene family of transmembrane proteins is associated with germ cell specification in mice. BMC Dev Biol 3:1–11

    Article  PubMed  CAS  Google Scholar 

  3. Evans SS, Lee DB, Han T, Tomasi TB, Evans RL (1990) Monoclonal antibody to the interferon-inducible protein Leu-13 triggers aggregation and inhibits proliferation of leukemic B cells. Blood 76:2583–2693

    PubMed  CAS  Google Scholar 

  4. Evans SS, Colla RP, Leasure JA, Lee DB (1993) IFN-α induces homotypic adhesion and Leu-13 expression in human B lymphoid cells. J Immunol 150:736–747

    PubMed  CAS  Google Scholar 

  5. Friedman RL, Manley SP, Mcahon M, Kerr IM, Stark GR (1984) Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell 38:745–755

    Article  PubMed  CAS  Google Scholar 

  6. Kelly JM, Gilbert CS, Stark GR, Kerr IM (1985) Differential regulation of interferon-induced mRNAs and c-myc mRNA by α- and β-interferons. Eur J Biochem 153:367–371

    Article  PubMed  CAS  Google Scholar 

  7. Bradbury LE, Kansas GS, Levy S, Evans RL, Tedder TF (1992) The CD19/CD21 signal transducing complex of human B lymphocytes induces the target of antiproliferative antibody-1 and Leu-13 molecules. J Immunol 149:2841–2850

    PubMed  CAS  Google Scholar 

  8. Deblandre GA, Marinx OP, Evans SS, Majjaj S, Leo O, Caput D, Huez GA, Wathelet MG (1995) Expression cloning of an interferon-inducible 17-kDa membrane protein implicated in the control of cell growth. J Biol Chem 270:23860–23866

    Article  PubMed  CAS  Google Scholar 

  9. Zucchi I, Montagna C, Susani L, Vezzoni P, Dulbecco R (1998) The rat gene homologous to the human gene 9-27 is involved in the development of the mammary gland. Proc Natl Acad Sci USA 95:1079–1084

    Article  PubMed  CAS  Google Scholar 

  10. Zucchi I, Montagna C, Susani L, Montesano R, Affer M, Zanotti S, Redolfi E, Vezzoni P, Dulbecco R (1999) Genetic dissection of dome formation in a mammary cell line: identification of two genes with opposing action. Proc Natl Acad Sci USA 96:13766–13770

    Article  PubMed  CAS  Google Scholar 

  11. Zucchi I, Bini L, Valaperta R, Ginestra A, Albani D, Susani L, Sanchez JC, Liberatori S, Magi B, Raggiaschi R, Hochstrasser DF, Pallini V, Vezzoni P, Dulbecco R (2001) Proteomic dissection of dome formation in a mammary cell line: role of tropomyosin-5b and maspin. Proc Natl Acad Sci USA 98:5608–5613

    Article  PubMed  CAS  Google Scholar 

  12. Zucchi I, Prinetti A, Scotti M, Valaperta R, Mento E, Reinbold R, Vezzoni P, Sonnino S, Albertini A, Dulbecco R (2004) Association of rat8 with Fyn protein kinase via lipid rafts is required for rat mammary cell differentiation in vitro. Proc Natl Acad Sci USA 101:1880–1885

    Article  PubMed  CAS  Google Scholar 

  13. Saitou M, Barton SC, Surani MA (2002) A molecular programme for the specification of germ cell fate in mice. Nature 418:293–300

    Article  PubMed  CAS  Google Scholar 

  14. Tanaka SS, Nagamatsu G, Tokitake Y, Kasa M, Tam PPL, Matsui Y (2004) Regulation of expression of mouse interferon-induced transmembrane protein like gene-3, Ifitm3 (mil-1, fragilis), in germ cells. Dev Dyn 230:651–659

    Article  PubMed  CAS  Google Scholar 

  15. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao Y-H, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764

    Article  PubMed  CAS  Google Scholar 

  16. Inada M, Yasui T, Nomura S, Miyake S, Deguchi K, Himeno M, Sato M, Yamagiwa H, Kimura T, Yasui N et al (1999) Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev Dyn 214:279–290

    Article  PubMed  CAS  Google Scholar 

  17. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29

    Article  PubMed  CAS  Google Scholar 

  18. Hauschka P, Lian J, Cole D, Gundberg C (1989) Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev 69:990–1047

    PubMed  CAS  Google Scholar 

  19. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, Smith E, Bonadio J, Goldstein S, Gundberg C, Bradley A, Karsenty G (1996) Increased bone formation in osteocalcin-deficient mice. Nature 382:448–452

    Article  PubMed  CAS  Google Scholar 

  20. Malaval L, Wade-Gueye NM, Boudiffa M, Fei J, Zirngibl R, Chen F, Laroche N, Roux J-P, Burt-Pichat B, Duboeuf F, Boivin G, Jurdic P, Lafage-Proust M-H, Amedee J, Vico L, Rossant J, Aubin J (2008) Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis. J Exp Med 205:1145–1153

    Article  PubMed  CAS  Google Scholar 

  21. Thomas G, Moffatt P, Salois P, Gaumond M-H, Gingras R, Godin E, Miao D, Goltzman D, Lancotot C (2003) Osteocrin, a novel bone-specific secreted protein that modulates the osteoblast phenotype. J Biol Chem 278:50563–50571

    Article  PubMed  CAS  Google Scholar 

  22. Rulten SL, Kinloch RA, Tateossian H, Robinson C, Gettins L, Kay JE (2006) The human FK506-binding proteins: characterization of human FKBP11. Mamm Genome 17:322–331

    Article  PubMed  CAS  Google Scholar 

  23. Kodama H, Amagai Y, Sudo H, Kasai S, Yamamoto S (1981) Establishment of a clonal osteogenetic cell line from newborn mouse calvaria. Jpn J Oral Biol 23:899–901

    Google Scholar 

  24. Sudo H, Kodama HA, Amagi Y, Yamamoto S, Kasai S (1983) In vitro differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria. J Cell Biol 96:191–198

    Article  PubMed  CAS  Google Scholar 

  25. Galat A (2003) Peptidyl prolyl cis/trans isomerases (immunophilins): biological diversity-targets-functions. Curr Top Med Chem 3:1315–1347

    Article  PubMed  CAS  Google Scholar 

  26. Moffatt P, Gaumond M-H, Salois P, Sellin K, Bessette M-C, Godin E, de Oliveira PT, Atkins GJ, Nanci A, Thomas G (2008) Bril, a novel bone-specific modulator of mineralization. J Bone Miner Res 23:1497–1508

    Article  PubMed  CAS  Google Scholar 

  27. Midura RJ, Wang A, Lovitch D, Law D, Powell K, Gorski JP (2004) Bone acidic glycoprotein-75 delineates the extracellular sites of future bone sialoprotein accumulation and apatite nucleation in osteoblastic cultures. J Biol Chem 279:25464–25473

    Article  PubMed  CAS  Google Scholar 

  28. Gorski JP, Wang A, Lovitch D, Law D, Powell K, Midura RJ (2004) Extracellular bone acidic glycoprotein-75 defines condensed mesenchyme regions to be mineralized and localizes with bone sialoprotein during intramembranous bone formation. J Biol Chem 279:25455–25463

    Article  PubMed  CAS  Google Scholar 

  29. Caplan AI, Pechak DG (1987) The cellular and molecular embryology of bone formation. In: Peck WA (ed) Bone and mineral research, vol 5. Elsevier, New York, pp 117–183

    Google Scholar 

  30. Kay JE (1996) Structure–function relationships in the FK506-binding protein (FKBP) family of peptidylprolyl cis–trans isomerases. Biochem J 314:361–385

    PubMed  CAS  Google Scholar 

  31. Galat A (1993) Peptidylproline cis–trans-isomerases: immunophilins. Eur J Biochem 216:689–707

    Article  PubMed  CAS  Google Scholar 

  32. Winslow MM, Pan MG, Starbuck M, Gallo EM, Deng L, Karsenty G, Crabtree GR (2006) Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell 10:771–782

    Article  PubMed  CAS  Google Scholar 

  33. Koga T, Matsui Y, Asagiri M, Kodama T, de Crombrugghe B, Nakashima K, Takayama H (2005) NFAT and Osterix cooperatively regulate bone formation. Nat Med 11:880–885

    Article  PubMed  CAS  Google Scholar 

  34. Tanaka SS, Yamaguchi YL, Tsoi B, Lickert H, Tam PP (2005) IFITM/Mil/fragilis family proteins IFITM and IFITM3 play distinct roles in mouse primordial germ cell homing and repulsion. Dev Cell 9:723–724

    Article  Google Scholar 

  35. Rubinstein E, Ziyyat A, Prenant M, Wrobel E, Wolf J-P, Levy S, Le Nauour F, Boucheix C (2006) Reduced fertility of female mice lacking CD81. Dev Biol 290:351–358

    Article  PubMed  CAS  Google Scholar 

  36. Brass AL, Huang I-C, Benita Y, John SP, Krishnan MN et al (2009) The IFITM5 proteins mediate cellular resistance to influenza A H1N1 virus, West nile virus, and dengue virus. Cell 139:1243–1254

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to Ms S. Kajiwara and M. Maeda for their technical assistance. We also would like to thank Dr. T. Koda for his useful advice in knockout mice analysis. Part of this research was funded by the Research Promotion Bureau of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

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Authors and Affiliations

  1. Nanotechnology Innovation Center, National Institute for Materials Science, 1-2-1 Sengen, Tsukuba, Ibaraki, 305-0047, Japan

    Nobutaka Hanagata, Xianglan Li, Hiromi Morita, Taro Takemura, Jie Li & Takashi Minowa

  2. Graduate School of Life Science, Hokkaido University, N10 W8, Kita-ku, Sapporo, 060-0810, Japan

    Nobutaka Hanagata

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  1. Nobutaka Hanagata
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Correspondence to Nobutaka Hanagata.

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Hanagata, N., Li, X., Morita, H. et al. Characterization of the osteoblast-specific transmembrane protein IFITM5 and analysis of IFITM5-deficient mice. J Bone Miner Metab 29, 279–290 (2011). https://doi.org/10.1007/s00774-010-0221-0

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  • DOI: https://doi.org/10.1007/s00774-010-0221-0

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