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Rac1 GTPase regulates osteoclast differentiation through TRANCE-induced NF-κB activation

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Abstract

Signaling by tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) is essential for the differentiation of monocytes/macrophages into osteoclasts. We show here that TRANCE selectively activates Rac1, but not Rac2 in osteoclast precursors. Expression of a dominant interfering mutant of TNF receptor-associated factor (TRAF)6 blocks TRANCE-mediated Rac1 activation, indicating that Rac1 lies downstream of TRAF6. Osteoclast precursors expressing a dominant negative Rac1N17 are defective in TRANCE-induced IKK activation and IκBα degradation resulting in inhibition of NFκB-dependent reporter gene activity. In addition, Rac1 acts upstream of TAK1 to induce NF-κB activation and is required for the normal differentiation of osteoclast precursors. Thus, Rac1 may represent a key regulator for differentiation of osteoclasts through the activation of NF-κB.

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References

  1. Etienne-Manneville S, Hall A: Rho GTPases in cell biology. Nature 420: 629–635, 2002

    Article  PubMed  CAS  Google Scholar 

  2. Haataja L, Groffen J, Heisterkamp N: Characterization of Rac3, a novel member of the Rho family. J Biol Chem 272: 20384–20388, 1997

    Article  PubMed  CAS  Google Scholar 

  3. Gu Y, Byrne MC, Paranavitana NC, Aronow B, Siefring JE, D'Souza M, Horton HF, Quilliam LA, Williams DA: Rac2, a hematopoiesis-specific Rho GTPase, specifically regulates mast cell protease gene expression in bone marrow-derived mast cells. Mol Cell Biol 22: 7645–7657, 2002

    Article  PubMed  CAS  Google Scholar 

  4. Van Alst L, D'Souza-Schorey C: Rho GTPase and signaling networks. Genes Dev 11: 2295–2322, 1997

    Google Scholar 

  5. Walmsley MJ, Ooi SK, Reynolds LF, Smith SH, Ruf S, Mathiot A, Vanes L, Williams DA, Cancro MP, Tybulewicz VL: Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling. Science 302: 459–462, 2003

    Article  PubMed  CAS  Google Scholar 

  6. Li B, Yu H, Zheng W, Voll R, Na S, Roberts AW, Williams DA, Davis RJ, Ghosh S, Flavell RA: Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science 288: 2219–2222, 2000

    PubMed  CAS  Google Scholar 

  7. Razzouk S, Lieberherr M, Cournot G: Rac-GTPase, osteoclast cytoskeleton and bone resorption. Eur J Cell Biol 78: 249–255, 1999

    PubMed  CAS  Google Scholar 

  8. Faccio R, Novack DV, Zallone A, Ross FP, Teitelbaum SL: Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by β3 integrin. J Cell Biol 162: 499–509, 2003

    Article  PubMed  CAS  Google Scholar 

  9. Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS, Frankel WN, Lee SY, Choi Y: TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinases in T cells. J Biol Chem 272: 25910–25914, 1997

    Google Scholar 

  10. Anderson DM, Maraskovsky E, Billingsley WL, Dougall W, Tometsko ME, ERoux ER, Teepe MC, DuBose RF, Cosman D, Galibert L: A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390: 175–179, 1997

    Article  PubMed  CAS  Google Scholar 

  11. 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, Suda T: Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95: 3597–3602, 1998

    Article  PubMed  CAS  Google Scholar 

  12. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ: Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93: 165–176, 1998

    Article  PubMed  CAS  Google Scholar 

  13. Lee NK, Choi YG, Baik JY, Han SY, Jeong D, Bae YS, Kim N, Lee SY: A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 106: 852–859, 2005

    PubMed  CAS  Google Scholar 

  14. Wong BR, Besser D, Kim N, Arron JR, Vologodskaia M, Hanafusa H, Choi Y: TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell 4: 1041–1049, 1999

    Article  PubMed  CAS  Google Scholar 

  15. Benard V, Bohl BJ, Bokoch GM: Characterization of Rac and Cdc42 activation in chemoattractant-stimulated human neutrophils using a novel assay for active GTPases. J Biol Chem 274: 13198–13204, 1999

    Article  PubMed  CAS  Google Scholar 

  16. Jang HD, Yoon K, Shin YJ, Kim J, Lee SY: PIAS3 suppresses NF-κB-mediated transcription by interacting with the p65/RelA subunit. J Biol Chem 279: 24873–24880, 2004

    PubMed  CAS  Google Scholar 

  17. Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony A, Capparelli C, Van G, Kaufman S, van der Heiden A, Itie A, Wakeham A, Khoo W, Sasaki T, Cao Z, Penninger JM, Paige CJ, Lacey DL, Dunstan CR, Boyle WJ, Goeddel DV, Mak TW: TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 13: 1015–1024, 1999

    PubMed  CAS  Google Scholar 

  18. Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, Nakao K, Nakamura K, Katsuki M, Yamamoto T, Inoue J: Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4: 353–362, 1999

    Article  PubMed  CAS  Google Scholar 

  19. Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S, Inoue J: Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J 20: 1271–1280, 2001

    Article  PubMed  CAS  Google Scholar 

  20. Mizukami J, Takaesu G, Akatsuka H, Sakurai H, Ninomiya-Tsuji J, Matsumoto K, Sakurai N: Receptor activator of NF-κB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Mol Cell Biol 22: 992–1000, 2002

    Article  PubMed  CAS  Google Scholar 

  21. Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation. Nature 423: 337–342, 2003

    Article  PubMed  CAS  Google Scholar 

  22. Ahonen C, Manning E, Erickson LD, O'Connor B, Lind EF, Pullen SS, Kehry MR, Noelle RJ: The CD40-TRAF6 axis controls affinity maturation and the generation of long-lived plasma cells. Nat Immunol 3: 451–456, 2002

    Article  PubMed  CAS  Google Scholar 

  23. Wu H, Arron JR: TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays 25: 1096–1105, 2003

    Article  PubMed  CAS  Google Scholar 

  24. O'Neill LA: Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamil. Curr Top Microbiol Immunol 270: 47–61, 2002

    PubMed  Google Scholar 

  25. Kadono Y, Okada F, Perchonock C, Jang HD, Lee SY, Kim N, Choi Y: Strength of TRAF6 signalling determines osteoclastogenesis. EMBO Rep 6: 171–176, 2005

    Article  PubMed  CAS  Google Scholar 

  26. Ye H, Arron JR, Lamothe B, Cirilli M, Kobayashi T, Shevde NK, Segal D, Dzivenu OK, Vologodskaia M, Yim M, Du K, Singh S, Pike JW, Darnay BG, Choi Y, Wu H: Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418: 443–447, 2002

    Article  PubMed  CAS  Google Scholar 

  27. Arbibe L, Mira JP, Teusch N, Kline L, Guha M, Mackman N, Godowski PJ, Ulevitch RJ, Knaus UG: Toll-like receptor 2-mediated NF-κB activation requires a Rac1-dependent pathway. Nat Immunol 1: 533–540, 2000

    Article  PubMed  CAS  Google Scholar 

  28. Jefferies CA, O'Neill LA: Rac1 regulates interleukin 1-induced nuclear factor κB activation in an inhibitory protein κBα-independent manner by enhancing the ability of the p65 subunit to transactivate gene expression. J Biol Chem 275: 3114–3120, 2000

    Article  PubMed  CAS  Google Scholar 

  29. Jefferies C, Bowie A, Brady G, Cooke EL, Li X, O'Neill LA: Transactivation by the p65 subunit of NF-κB in response to interleukin-1 (IL-1) involves MyD88, IL-1 receptor-associated kinase 1, TRAF-6, and Rac1. Mol Cell Biol 21: 4544–4552, 2001

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul, 120-750, Korea

    Na Kyung Lee, Han Kyung Choi & Soo Young Lee

  2. Cell and Gene Therapy Research Institute, Pochon CHA University, CHA General Hospital, Seoul, 135-081, Korea

    Dong-Ku Kim

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  1. Na Kyung Lee
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  2. Han Kyung Choi
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  3. Dong-Ku Kim
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  4. Soo Young Lee
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Correspondence to Soo Young Lee.

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Lee, N.K., Choi, H.K., Kim, DK. et al. Rac1 GTPase regulates osteoclast differentiation through TRANCE-induced NF-κB activation. Mol Cell Biochem 281, 55–61 (2006). https://doi.org/10.1007/s11010-006-0333-y

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  • DOI: https://doi.org/10.1007/s11010-006-0333-y

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