International Journal of Oral Biology

The Korean Academy of Oral Biology (대한구강생물학회)
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Negative regulators in RANKL-induced osteoclastogenesis

  • Lee, Jun-Won (Medical Research Center for Gene Regulation, Chonnam National University Medical School) ;
  • Kim, Kab-Sun (Medical Research Center for Gene Regulation, Chonnam National University Medical School) ;
  • Kim, Nack-Sung (Medical Research Center for Gene Regulation, Chonnam National University Medical School)
  • Published : 2007.03.31
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Abstract

Receptor activator of nuclear factor ${\kappa}B$ ligand (RANKL) induces osteoclast formation from hematopoietic cells via up-regulation of positive regulators, including $NF-{\kappa}B$, c-Fos, microphthalmia transcription factor (Mitf), PU.1, and nuclear factor of activated T cells (NFAT) c1. In addition to the positive regulation by these transcription factors, RANKL appears to regulate negative regulators such as MafB and inhibitors of differentiation (Ids). Ids and MafB are abundantly expressed in osteoclast precursors, bone marrowderived monocyte/macrophage lineage cells (BMMs). Expression levels of these genes are significantly reduced by RANKL during osteoclastogenesis. Overexpression of these genes in BMMs inhibits the formation of tartarate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts by down-regulation of NFATc1 and osteoclast-associated receptor (OSCAR), which are important for osteoclast differentiation. Furthermore, reduced expression of these genes enhances osteoclastogenesis and increases expression of NFATc1 and OSCAR. Taken together, RANKL induces osteoclastogenesis via up-regulation of positive regulators as well as down-regulation of negative regulators.

Keywords

References

  1. ANDERSON, D. M., MARASKOVSKY, E., BILLINGSLEY, W. L., DOUGALL, W. C., TOMETSKO, M. E., ROUX, E. R., TEEPE, M. C., DUBOSE, R. F., COSMAN, D. and GALIBERT, L. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 390:175-9, 1997 https://doi.org/10.1038/36593
  2. ASAGIRI, M., SATO, K., USAMI, T., OCHI, S., NISHINA, H., YOSHIDA, H., MORITA, I., WAGNER, E. F., MAK, T. W., SERFLING, E. and TAKAYANAGI, H. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med. 202:1261-9, 2005 https://doi.org/10.1084/jem.20051150
  3. BENEZRA, R., DAVIS, R. L., LOCKSHON, D., TURNER, D. L. and WEINTRAUB, H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell. 61:49-59, 1990 https://doi.org/10.1016/0092-8674(90)90214-Y
  4. BLANK, V. and ANDREWS, N. C. The Maf transcription factors: regulators of differentiation. Trends Biochem Sci. 22:437-41, 1997 https://doi.org/10.1016/S0968-0004(97)01105-5
  5. BOYLE, W. J., SIMONET, W. S. and LACEY, D. L. Osteoclast differentiation and activation. Nature. 423:337-42, 2003 https://doi.org/10.1038/nature01658
  6. CORDES, S. P. and BARSH, G. S. The mouse segmentation gene kr encodes a novel basic domain-leucine zipper transcription factor. Cell. 79:1025-34, 1994 https://doi.org/10.1016/0092-8674(94)90033-7
  7. EICHMANN, A., GRAPIN-BOTTON, A., KELLY, L., GRAF, T., LE DOUARIN, N. M. and SIEWEKE, M. The expression pattern of the mafB/kr gene in birds and mice reveals that the kreisler phenotype does not represent a null mutant. Mech Dev. 65:111-22, 1997 https://doi.org/10.1016/S0925-4773(97)00063-4
  8. HIROTANI, H., TUOHY, N. A., WOO, J. T., STERN, P. H. and CLIPSTONE, N. A. The calcineurin/nuclear factor of activated T cells signaling pathway regulates osteoclastogenesis in RAW264.7 cells. J Biol Chem. 279:13984-92, 2004 https://doi.org/10.1074/jbc.M213067200
  9. HODGKINSON, C. A., MOORE, K. J., NAKAYAMA, A., STEINGRIMSSON, E., COPELAND, N. G., JENKINS, N. A. and ARNHEITER, H. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell. 74: 395-404, 1993 https://doi.org/10.1016/0092-8674(93)90429-T
  10. IOTSOVA, V., CAAMANO, J., LOY, J., YANG, Y., LEWIN, A. and BRAVO, R. Osteopetrosis in mice lacking NFkappaB1 and NF-kappaB2. Nat Med. 3:1285-9, 1997 https://doi.org/10.1038/nm1197-1285
  11. ISHIKAWA, S., ARASE, N., SUENAGA, T., SAITA, Y., NODA, M., KURIYAMA, T., ARASE, H. and SAITO, T. Involvement of FcRgamma in signal transduction of osteoclast-associated receptor (OSCAR). Int Immunol. 16: 1019-25, 2004 https://doi.org/10.1093/intimm/dxh103
  12. KELLY, L. M., ENGLMEIER, U., LAFON, I., SIEWEKE, M. H. and GRAF, T. MafB is an inducer of monocytic differentiation. Embo J. 19:1987-97, 2000 https://doi.org/10.1093/emboj/19.9.1987
  13. KIM, K., KIM, J. H., LEE, J., JIN, H. M., KOOK, H., KIM, K. K., LEE, S. Y. and KIM, N. MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood. DOI 10.1182/blood-2006-09-048249, 2007
  14. KIM, K., KIM, J. H., LEE, J., JIN, H. M., LEE, S. H., FISHER, D. E., KOOK, H., KIM, K. K., CHOI, Y. and KIM, N. Nuclear factor of activated T cells c1 induces osteoclastassociated receptor gene expression during tumor necrosis factor-related activation-induced cytokine-mediated osteoclastogenesis. J Biol Chem. 280:35209-16, 2005 https://doi.org/10.1074/jbc.M505815200
  15. KIM, N., TAKAMI, M., RHO, J., JOSIEN, R. and CHOI, Y. A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J Exp Med. 195:201-9, 2002 https://doi.org/10.1084/jem.20011681
  16. KIM, Y., SATO, K., ASAGIRI, M., MORITA, I., SOMA, K. and TAKAYANAGI, H. Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis. J Biol Chem. 280:32905-13, 2005 https://doi.org/10.1074/jbc.M505820200
  17. KOGA, T., INUI, M., INOUE, K., KIM, S., SUEMATSU, A., KOBAYASHI, E., IWATA, T., OHNISHI, H., MATOZAKI, T., KODAMA, T., TANIGUCHI, T., TAKAYANAGI, H. and TAKAI, T. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature. 428:758-63, 2004 https://doi.org/10.1038/nature02444
  18. LACEY, D. L., TIMMS, E., TAN, H. L., KELLEY, M. J., DUNSTAN, C. R., BURGESS, T., ELLIOTT, R., COLOMBERO, A., ELLIOTT, G., SCULLY, S., HSU, H., SULLIVAN, J., HAWKINS, N., DAVY, E., CAPPARELLI, C., ELI, A., QIAN, Y. X., KAUFMAN, S., SAROSI, I., SHALHOUB, V., SENALDI, G., GUO, J., DELANEY, J. and BOYLE, W. J. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 93: 165-76, 1998 https://doi.org/10.1016/S0092-8674(00)81569-X
  19. LASORELLA, A., UO, T. and IAVARONE, A. Id proteins at the cross-road of development and cancer. Oncogene. 20:8326-33, 2001 https://doi.org/10.1038/sj.onc.1205093
  20. LEE, J., KIM, K., KIM, J. H., JIN, H. M., CHOI, H. K., LEE, S. H., KOOK, H., KIM, K. K., YOKOTA, Y., LEE, S. Y., CHOI, Y. and KIM, N. Id helix-loop-helix proteins negatively regulate TRANCE-mediated osteoclast differentiation. Blood. 107:2686-93, 2006 https://doi.org/10.1182/blood-2005-07-2798
  21. LEE, Z. H. and KIM, H. H. Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochem Biophys Res Commun. 305:211-4, 2003 https://doi.org/10.1016/S0006-291X(03)00695-8
  22. LUCHIN, A., PURDOM, G., MURPHY, K., CLARK, M. Y., ANGEL, N., CASSADY, A. I., HUME, D. A. and OSTROWSKI, M. C. The microphthalmia transcription factor regulates expression of the tartrate-resistant acid phosphatase gene during terminal differentiation of osteoclasts. J Bone Miner Res. 15:451-60, 2000 https://doi.org/10.1359/jbmr.2000.15.3.451
  23. LUCHIN, A., SUCHTING, S., MERSON, T., ROSOL, T. J., HUME, D. A., CASSADY, A. I. and OSTROWSKI, M. C. Genetic and physical interactions between Microphthalmia transcription factor and PU.1 are necessary for osteoclast gene expression and differentiation. J Biol Chem. 276: 36703-10, 2001 https://doi.org/10.1074/jbc.M106418200
  24. MANSKY, K. C., SANKAR, U., HAN, J. and OSTROWSKI, M. C. Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NFkappa B ligand signaling. J Biol Chem. 277:11077-83, 2002 https://doi.org/10.1074/jbc.M111696200
  25. MASSARI, M. E. and MURRE, C. Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol. 20:429-40, 2000 https://doi.org/10.1128/MCB.20.2.429-440.2000
  26. MERCK, E., GAILLARD, C., GORMAN, D. M., MONTEROJULIAN, F., DURAND, I., ZURAWSKI, S. M., MENETRIERCAUX, C., CARRA, G., LEBECQUE, S., TRINCHIERI, G. and BATES, E. E. OSCAR is an FcRgamma-associated receptor that is expressed by myeloid cells and is involved in antigen presentation and activation of human dendritic cells. Blood. 104:1386-95, 2004 https://doi.org/10.1182/blood-2004-03-0850
  27. MOCSAI, A., HUMPHREY, M. B., VAN ZIFFLE, J. A., HU, Y., BURGHARDT, A., SPUSTA, S. C., MAJUMDAR, S., LANIER, L. L., LOWELL, C. A. and NAKAMURA, M. C. The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc Natl Acad Sci U S A. 101:6158-63, 2004
  28. MOTOHASHI, H., SHAVIT, J. A., IGARASHI, K., YAMAMOTO, M. and ENGEL, J. D. The world according to Maf. Nucleic Acids Res. 25:2953-59, 1997 https://doi.org/10.1093/nar/25.15.2953
  29. MOTYCKOVA, G., WEILBAECHER, K. N., HORSTMANN, M., RIEMAN, D. J., FISHER, D. Z. and FISHER, D. E. Linking osteopetrosis and pycnodysostosis: regulation of cathepsin K expression by the microphthalmia transcription factor family. Proc Natl Acad Sci U S A. 98:5798-803, 2001
  30. SIEWEKE, M. H., TEKOTTE, H., FRAMPTON, J. and GRAF, T. MafB is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation. Cell. 85:49-60, 1996 https://doi.org/10.1016/S0092-8674(00)81081-8
  31. SIMON, M. C. PU.1 and hematopoiesis: lessons learned from gene targeting experiments. Semin Immunol. 10:111-8, 1998 https://doi.org/10.1006/smim.1998.0112
  32. SINGH, H., DEKOTER, R. P. and WALSH, J. C. PU.1, a shared transcriptional regulator of lymphoid and myeloid cell fates. Cold Spring Harb Symp Quant Biol. 64:13-20, 1999
  33. SO, H., RHO, J., JEONG, D., PARK, R., FISHER, D. E., OSTROWSKI, M. C., CHOI, Y. and KIM, N. Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. J Biol Chem. 278:24209-16, 2003 https://doi.org/10.1074/jbc.M302940200
  34. SUDA, T., TAKAHASHI, N., UDAGAWA, N., JIMI, E., GILLESPIE, M. T. and MARTIN, T. J. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 20:345-57, 1999 https://doi.org/10.1210/er.20.3.345
  35. TAKAYANAGI, H. Mechanistic insight into osteoclast differentiation in osteoimmunology. J Mol Med. 83:170-9, 2005 https://doi.org/10.1007/s00109-004-0612-6
  36. TAKAYANAGI, H., KIM, S., KOGA, T., NISHINA, H., ISSHIKI, M., YOSHIDA, H., SAIURA, A., ISOBE, M., YOKOCHI, T., INOUE, J., WAGNER, E. F., MAK, T. W., KODAMA, T. and TANIGUCHI, T. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 3:889-901, 2002 https://doi.org/10.1016/S1534-5807(02)00369-6
  37. TEITELBAUM, S. L. Bone resorption by osteoclasts. Science. 289:1504-8, 2000 https://doi.org/10.1126/science.289.5484.1504
  38. TEITELBAUM, S. L. and ROSS, F. P. Genetic regulation of osteoclast development and function. Nat Rev Genet. 4: 638-49, 2003 https://doi.org/10.1038/nrg1122
  39. WAGNER, E. F. and EFERL, R. Fos/AP-1 proteins in bone and the immune system. Immunol Rev. 208:126-40, 2005 https://doi.org/10.1111/j.0105-2896.2005.00332.x
  40. WANG, Z. Q., OVITT, C., GRIGORIADIS, A. E., MOHLESTEINLEIN, U., RUTHER, U. and WAGNER, E. F. Bone and haematopoietic defects in mice lacking c-fos. Nature. 360:741-5, 1992 https://doi.org/10.1038/360741a0
  41. WONG, B. R., RHO, J., ARRON, J., ROBINSON, E., ORLINICK, J., CHAO, M., KALACHIKOV, S., CAYANI, E., BARTLETT, F. S., 3RD, FRANKEL, W. N., LEE, S. Y. and CHOI, Y. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun Nterminal kinase in T cells. J Biol Chem. 272:25190-4, 1997 https://doi.org/10.1074/jbc.272.40.25190
  42. YASUDA, H., SHIMA, N., NAKAGAWA, N., YAMAGUCHI, K., KINOSAKI, M., MOCHIZUKI, S., TOMOYASU, A., YANO, K., GOTO, M., MURAKAMI, A., TSUDA, E., MORINAGA, T., HIGASHIO, K., UDAGAWA, N., TAKAHASHI, N. and SUDA, T. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesisinhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 95:3597-602, 1998