Journal of Bone and Mineral Metabolism

, Volume 30, Issue 3, pp 293–303 | Cite as

Overexpression of receptor for hyaluronan-mediated motility (RHAMM) in MC3T3-E1 cells induces proliferation and differentiation through phosphorylation of ERK1/2

  • Hiroko Hatano
  • Hideo Shigeishi
  • Yasusei Kudo
  • Koichiro Higashikawa
  • Kei Tobiume
  • Takashi Takata
  • Nobuyuki Kamata
Original Article

Abstract

Receptor for hyaluronan (HA)-mediated motility (RHAMM) was first described as a soluble HA binding protein released by sub-confluent migrating cells. We previously found that RHAMM was highly expressed and plays an important role in proliferation in the human cementifying fibroma (HCF) cell line, which we previously established. HCF is a benign fibro-osseous neoplasm of the jaw and is composed of fibrous tissue containing varying amounts of mineralized material. However, the pathogenesis of HCF is not clear. In this paper, we examined the roles of RHAMM in osteoblastic cells. We generated RHAMM-overexpressing MC3T3-E1 cells and examined the cell proliferation and differentiation of osteoblastic cells. In MC3T3-E1 cells, overexpressing RHAMM was located intracellular and activated ERK1/2. Interestingly, the ERK1/2 activated by RHAMM overexpression promoted cell proliferation and suppressed the differentiation of osteoblastic cells. Our findings strongly suggest that RHAMM may play a key role in the osteoblastic differentiation process. The rupture of balance from differentiation to proliferation induced by RHAMM overexpression may link to the pathogenesis of bone neoplasms such as HCF.

Keywords

Cementifying fibroma RHAMM HA ERK Proliferation 

Abbreviations

RHAMM

Receptor for hyaluronan-mediated motility

ERK

Extracellular regulated kinase

HA

Hyaluronan

MAPK

Mitogen activated protein kinase

Notes

Acknowledgments

This work was supported by a Grant-in-Aid for JSPS fellows (No. 22-6035) from the Japan Society for the Promotion of Science (JSPS).

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

774_2011_318_MOESM1_ESM.pptx (84 kb)
Supplementary material 1 (PPTX 84 kb)

References

  1. 1.
    Waldron CA (1993) Fibro-osseous lesions of the jaws. J Oral Maxillofac Surg 51:828–835PubMedCrossRefGoogle Scholar
  2. 2.
    Su L, Weathers DR, Waldron CA (1997) Distinguishing features of focal cemento-osseous dysplasia and cemento-ossifying fibromas. II. A clinical and radiologic spectrum of 316 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:540–549PubMedCrossRefGoogle Scholar
  3. 3.
    Kudo Y, Hiraoka M, Kitagawa S, Miyauchi M, Kakuo S, Zhao M, Ide T, Takata T (2002) Establishment of human cementifying fibroma cell lines by transfection with temperature-sensitive simian virus-40 T-antigen gene and hTERT gene. Bone 30:712–717PubMedCrossRefGoogle Scholar
  4. 4.
    Hatano H, Shigeishi H, Kudo Y, Higashikawa K, Tobiume K, Takata T, Kamata N (2011) RHAMM/ERK interaction induces proliferative activities of cementifying fibroma cells through a mechanism based on the CD44–EGFR. Lab Invest 91:379–391PubMedCrossRefGoogle Scholar
  5. 5.
    Turley EA (1982) Purification of a hyaluronate-binding protein fraction that modifies cell social behavior. Biochem Biophys Res Commun 108:1016–1024PubMedCrossRefGoogle Scholar
  6. 6.
    Maxwell CA, McCarthy J, Turley E (2008) Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions? J Cell Sci 121:925–932PubMedCrossRefGoogle Scholar
  7. 7.
    Wang C, Entwistle J, Hou G, Li Q, Turley EA (1996) The characterization of a human RHAMM cDNA: conservation of the hyaluronan-binding domains. Gene 174:299–306PubMedCrossRefGoogle Scholar
  8. 8.
    Crainie M, Belch AR, Mant MJ, Pilarski LM (1999) Overexpression of the receptor for hyaluronan-mediated motility (RHAMM) characterizes the malignant clone in multiple myeloma: identification of three distinct RHAMM variants. Blood 93:1684–1696PubMedGoogle Scholar
  9. 9.
    Zhang S, Chang MC, Zylka D, Turley S, Harrison R, Turley EA (1998) The hyaluronan receptor RHAMM regulates extracellular-regulated kinase. J Biol Chem 273:11342–11348PubMedCrossRefGoogle Scholar
  10. 10.
    Entwistle J, Zhang S, Yang B, Wong C, Li Q, Hall CL, A J, Mowat M, Greenberg AH, Turley EA (1995) Characterization of the murine gene encoding the hyaluronan receptor RHAMM. Gene 163:233–238Google Scholar
  11. 11.
    Masellis-Smith A, Belch AR, Mant MJ, Turley EA, Pilarski LM (1996) Hyaluronan-dependent motility of B cells and leukemic plasma cells in blood, but not of bone marrow plasma cells, in multiple myeloma: alternate use of receptor for hyaluronan-mediated motility (RHAMM) and CD44. Blood 87:1891–1899PubMedGoogle Scholar
  12. 12.
    Tolg C, Hamilton SR, Nakrieko KA, Kooshesh F, Walton P, McCarthy JB, Bissell MJ, Turley EA (2006) Rhamm−/− fibroblasts are defective in CD44-mediated ERK1, 2 motogenic signaling, leading to defective skin wound repair. J Cell Biol 175:1017–1028PubMedCrossRefGoogle Scholar
  13. 13.
    Hamilton SR, Fard SF, Paiwand FF, Tolg C, Veiseh M, Wang C, McCarthy JB, Bissell MJ, Koropatnick J, Turley EA (2007) The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1, 2 that sustain high basal motility in breast cancer cells. J Biol Chem 282:16667–16680PubMedCrossRefGoogle Scholar
  14. 14.
    Assmann V, Jenkinson D, Marshall JF, Hart IR (1999) The intracellular hyaluronan receptor RHAMM/IHABP interacts with microtubules and actin filaments. J Cell Sci 112:3943–3954PubMedGoogle Scholar
  15. 15.
    Maxwell CA, Keats JJ, Crainie M, Sun X, Yen T, Shibuya E, Hendzel M, Chan G, Pilarski LM (2003) RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability. Mol Biol Cell 14:2262–2276PubMedCrossRefGoogle Scholar
  16. 16.
    Turley EA, Noble PW, Bourguignon LY (2002) Signaling properties of hyaluronan receptors. J Biol Chem 277:4589–4592PubMedCrossRefGoogle Scholar
  17. 17.
    Maxwell CA, Keats JJ, Belch AR, Pilarski LM, Reiman T (2005) Receptor for hyaluronan-mediated motility correlates with centrosome abnormalities in multiple myeloma and maintains mitotic integrity. Cancer Res 65:850–860PubMedGoogle Scholar
  18. 18.
    Mohapatra S, Yang X, Wright JA, Turley EA, Greenberg AH (1996) Soluble hyaluronan receptor RHAMM induces mitotic arrest by suppressing Cdc2 and cyclin B1 expression. J Exp Med 183:1663–1668PubMedCrossRefGoogle Scholar
  19. 19.
    Hall CL, Wang C, Lange LA, Turley EA (1994) Hyaluronan and the hyaluronan receptor RHAMM promote focal adhesion turnover and transient tyrosine kinase activity. J Cell Biol 126:575–588PubMedCrossRefGoogle Scholar
  20. 20.
    Nakayama K, Tamura Y, Suzawa M, Harada S, Fukumoto S, Kato M, Miyazono K, Rodan GA, Takeuchi Y, Fujita T (2003) Receptor tyrosine kinases inhibit bone morphogenetic protein-Smad responsive promoter activity and differentiation of murine MC3T3-E1 osteoblast-like cells. J Bone Miner Res 18:827–835PubMedCrossRefGoogle Scholar
  21. 21.
    Higuchi C, Myoui A, Hashimoto N, Kuriyama K, Yoshioka K, Yoshikawa H, Itoh K (2002) Continuous inhibition of MAPK signaling promotes the early osteoblastic differentiation and mineralization of the extracellular matrix. J Bone Miner Res 17:1785–1794PubMedCrossRefGoogle Scholar
  22. 22.
    Schindeler A, Little DG (2006) Ras-MAPK signaling in osteogenic differentiation: friend or foe? J Bone Miner Res 21:1331–1338PubMedCrossRefGoogle Scholar
  23. 23.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408PubMedCrossRefGoogle Scholar
  24. 24.
    Hall CL, Yang B, Yang X, Zhang S, Turley M, Samuel S, Lange LA, Wang C, Curpen GD, Savani RC, Greenberg AH, Turley EA (1995) Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell 82:19–26PubMedCrossRefGoogle Scholar
  25. 25.
    Bajorath J, Greenfield B, Munro SB, Day AJ, Aruffo A (1998) Identification of CD44 residues important for hyaluronan binding and delineation of the binding site. J Biol Chem 273:338–343PubMedCrossRefGoogle Scholar
  26. 26.
    Entwistle J, Hall CL, Turley EA (1996) HA receptors: regulators of signalling to the cytoskeleton. J Cell Biochem 61:569–577PubMedCrossRefGoogle Scholar
  27. 27.
    Zlobec I, Terracciano L, Tornillo L, Günthert U, Vuong T, Jass JR, Lugli A (2008) Role of RHAMM within the hierarchy of well-established prognostic factors in colorectal cancer 57:1413–1419Google Scholar
  28. 28.
    Yamano Y, Uzawa K, Shinozuka K, Fushimi K, Ishigami T, Nomura H, Ogawara K, Shiiba M, Yokoe H, Tanzawa H (2008) Hyaluronan-mediated motility: a target in oral squamous cell carcinoma. Int J Oncol 32:1001–1009PubMedGoogle Scholar
  29. 29.
    Tolg C, Poon R, Fodde R, Turley EA, Alman BA (2003) Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor). Oncogene 22:6873–6882PubMedCrossRefGoogle Scholar
  30. 30.
    Roberts PJ, Der CJ (2007) Targeting the Raf–MEK–ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2011

Authors and Affiliations

  • Hiroko Hatano
    • 1
  • Hideo Shigeishi
    • 1
  • Yasusei Kudo
    • 2
  • Koichiro Higashikawa
    • 1
  • Kei Tobiume
    • 1
  • Takashi Takata
    • 2
  • Nobuyuki Kamata
    • 1
  1. 1.Department of Oral and Maxillofacial Surgery, Division of Cervico-Gnathostomatology, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan
  2. 2.Department of Oral and Maxillofacial Pathobiology, Division of Frontier Medical Science, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan

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