Osteoclast Differentiation Independent of the TRANCE-RANK-TRAF6 Axis

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2005 Sep 9

PMID 16147974

Citations 152

Authors

Nacksung Kim

Yuho Kadono

Masamichi Takami

Junwon Lee

Seoung-Hoon Lee

Fumihiko Okada

Jung Ha Kim

Takashi Kobayashi

Paul R Odgren

Hiroyasu Nakano

Wen-Chen Yeh

Sun-Kyeong Lee

Joseph A Lorenzo

Yongwon Choi

Affiliations

Soon will be listed here.

Abstract

Osteoclasts are derived from myeloid lineage cells, and their differentiation is supported by various osteotropic factors, including the tumor necrosis factor (TNF) family member TNF-related activation-induced cytokine (TRANCE). Genetic deletion of TRANCE or its receptor, receptor activator of nuclear factor kappaB (RANK), results in severely osteopetrotic mice with no osteoclasts in their bones. TNF receptor-associated factor (TRAF) 6 is a key signaling adaptor for RANK, and its deficiency leads to similar osteopetrosis. Hence, the current paradigm holds that TRANCE-RANK interaction and subsequent signaling via TRAF6 are essential for the generation of functional osteoclasts. Surprisingly, we show that hematopoietic precursors from TRANCE-, RANK-, or TRAF6-null mice can become osteoclasts in vitro when they are stimulated with TNF-alpha in the presence of cofactors such as TGF-beta. We provide direct evidence against the current paradigm that the TRANCE-RANK-TRAF6 pathway is essential for osteoclast differentiation and suggest the potential existence of alternative routes for osteoclast differentiation.

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References

Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S . Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med. 2000; 191(2):275-86. PMC: 2195746. DOI: 10.1084/jem.191.2.275. View

Kadono Y, Okada F, Perchonock C, Jang H, Lee S, Kim N . Strength of TRAF6 signalling determines osteoclastogenesis. EMBO Rep. 2005; 6(2):171-6. PMC: 1299255. DOI: 10.1038/sj.embor.7400345. View

Fuller K, Lean J, Bayley K, Wani M, Chambers T . A role for TGFbeta(1) in osteoclast differentiation and survival. J Cell Sci. 2000; 113 ( Pt 13):2445-53. DOI: 10.1242/jcs.113.13.2445. View

Kim N, Odgren P, Kim D, Marks Jr S, Choi Y . Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. Proc Natl Acad Sci U S A. 2000; 97(20):10905-10. PMC: 27122. DOI: 10.1073/pnas.200294797. View

Kim D, Mebius R, MacMicking J, Jung S, Cupedo T, Castellanos Y . Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J Exp Med. 2000; 192(10):1467-78. PMC: 2193182. DOI: 10.1084/jem.192.10.1467. View

Lam J, Takeshita S, Barker J, Kanagawa O, Ross F, Teitelbaum S . TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 2000; 106(12):1481-8. PMC: 387259. DOI: 10.1172/JCI11176. View

Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S . Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J. 2001; 20(6):1271-80. PMC: 145527. DOI: 10.1093/emboj/20.6.1271. View

Quinn J, Itoh K, Udagawa N, Hausler K, Yasuda H, Shima N . Transforming growth factor beta affects osteoclast differentiation via direct and indirect actions. J Bone Miner Res. 2001; 16(10):1787-94. DOI: 10.1359/jbmr.2001.16.10.1787. View

Pettit A, Ji H, von Stechow D, Muller R, Goldring S, Choi Y . TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol. 2001; 159(5):1689-99. PMC: 1867076. DOI: 10.1016/S0002-9440(10)63016-7. View

10.

Fuller K, Murphy C, Kirstein B, Fox S, Chambers T . TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology. 2002; 143(3):1108-18. DOI: 10.1210/endo.143.3.8701. View

11.

Armstrong A, Tometsko M, Glaccum M, Sutherland C, Cosman D, Dougall W . A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function. J Biol Chem. 2002; 277(46):44347-56. DOI: 10.1074/jbc.M202009200. View

12.

Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H . Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002; 3(6):889-901. DOI: 10.1016/s1534-5807(02)00369-6. View

13.

Kanazawa K, Azuma Y, Nakano H, Kudo A . TRAF5 functions in both RANKL- and TNFalpha-induced osteoclastogenesis. J Bone Miner Res. 2003; 18(3):443-50. DOI: 10.1359/jbmr.2003.18.3.443. View

14.

Boyle W, Simonet W, Lacey D . Osteoclast differentiation and activation. Nature. 2003; 423(6937):337-42. DOI: 10.1038/nature01658. View

15.

Walsh M, Choi Y . Biology of the TRANCE axis. Cytokine Growth Factor Rev. 2003; 14(3-4):251-63. DOI: 10.1016/s1359-6101(03)00027-3. View

16.

Kobayashi T, Walsh P, Walsh M, Speirs K, Chiffoleau E, King C . TRAF6 is a critical factor for dendritic cell maturation and development. Immunity. 2003; 19(3):353-63. DOI: 10.1016/s1074-7613(03)00230-9. View

17.

Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel D . TRAF6 is a signal transducer for interleukin-1. Nature. 1996; 383(6599):443-6. DOI: 10.1038/383443a0. View

18.

Fuller K, Wong B, Fox S, Choi Y, Chambers T . TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med. 1998; 188(5):997-1001. PMC: 2213394. DOI: 10.1084/jem.188.5.997. View

19.

Lomaga M, Yeh W, Sarosi I, Duncan G, Furlonger C, Ho A . TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999; 13(8):1015-24. PMC: 316636. DOI: 10.1101/gad.13.8.1015. View

20.

Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie M, Martin T . Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 1999; 20(3):345-57. DOI: 10.1210/edrv.20.3.0367. View