Abstract
Osteoclasts and foreign body giant cells (FBGCs) are derived from common progenitors and share properties such as multi-nucleation capacity induced by cell–cell fusion; however, mechanisms underlying lineage determination between these cells remain unclear. Here we show that, under inflammatory conditions, osteoclasts are stimulated in a manner similar to M1 macrophages, while formation of FBGCs, which exhibit M2-like phenotypes, is inhibited in a manner similar to that seen in M1/M2 macrophage polarization. FBGC/osteoclast polarization was inhibited by conditional knockout of tumor necrosis factor receptor associated factor 6 (Traf6) in adults in vivo and in vitro. Traf6-null mice were previously reported to die soon after birth, but we found that Traf6 deletion in adults did not cause lethality but rather inhibited osteoclast activation and prevented FBGC inhibition under inflammatory conditions. Accordingly, basal osteoclastogenesis was significantly inhibited by Traf6 deletion in vivo and in vitro and accompanied by increased bone mass. Lipopolysaccharide-induced osteoclast formation and osteolysis were significantly inhibited in Traf6 conditional knockout mice. Our results suggest that Traf6 plays a crucial role in regulating M1 osteoclast and M2 FBGC polarization and is a potential therapeutic target in blocking FBGC inhibition, antagonizing osteolysis in inflammatory conditions, and increasing bone mass without adverse effects in adults.
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References
Marwick C (2000) Implant recommendations (in Eng). JAMA 283:869
Tang L, Eaton JW (1995) Inflammatory responses to biomaterials (in Eng). Am J Clin Pathol 103:466–471
Tang L, Eaton JW (1999) Natural responses to unnatural materials: a molecular mechanism for foreign body reactions (in Eng). Mol Med 5:351–358
Anderson JM (1988) Inflammatory response to implants (in Eng). ASAIO Trans 34:101–107
Anderson JM, Rodriguez A, Chang DT (2008) Foreign body reaction to biomaterials (in Eng). Semin Immunol 20:86–100. https://doi.org/10.1016/j.smim.2007.11.004
Aronson M, Elberg SS (1962) Fusion of peritoneal histocytes with formation of giant cells (in Eng). Nature 193:399–400
Yagi M, Miyamoto T, Sawatani Y, Iwamoto K, Hosogane N, Fujita N, Morita K, Ninomiya K, Suzuki T, Miyamoto K, Oike Y, Takeya M, Toyama Y, Suda T (2005) DC-STAMP is essential for cell–cell fusion in osteoclasts and foreign body giant cells (in Eng). J Exp Med 202:345–351. https://doi.org/10.1084/jem.20050645
Yagi M, Ninomiya K, Fujita N, Suzuki T, Iwasaki R, Morita K, Hosogane N, Matsuo K, Toyama Y, Suda T, Miyamoto T (2007) Induction of DC-STAMP by alternative activation and downstream signaling mechanisms (in Eng). J Bone Miner Res 22:992–1001. https://doi.org/10.1359/jbmr.070401
Lee SH, Rho J, Jeong D, Sul JY, Kim T, Kim N, Kang JS, Miyamoto T, Suda T, Lee SK, Pignolo RJ, Koczon-Jaremko B, Lorenzo J, Choi Y (2006) v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation (in Eng). Nat Med 12:1403–1409. https://doi.org/10.1038/nm1514
Saginario C, Sterling H, Beckers C, Kobayashi R, Solimena M, Ullu E, Vignery A (1998) MFR, a putative receptor mediating the fusion of macrophages (in Eng). Mol Cell Biol 18:6213–6223
Han X, Sterling H, Chen Y, Saginario C, Brown EJ, Frazier WA, Lindberg FP, Vignery A (2000) CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation (in Eng). J Biol Chem 275:37984–37992. https://doi.org/10.1074/jbc.M002334200
Sterling H, Saginario C, Vignery A (1998) CD44 occupancy prevents macrophage multinucleation (in Eng). J Cell Biol 143:837–847
Cui W, Ke JZ, Zhang Q, Ke HZ, Chalouni C, Vignery A (2006) The intracellular domain of CD44 promotes the fusion of macrophages (in Eng). Blood 107:796–805. https://doi.org/10.1182/blood-2005-05-1902
Helming L, Gordon S (2009) Molecular mediators of macrophage fusion (in Eng). Trends Cell Biol 19:514–522. https://doi.org/10.1016/j.tcb.2009.07.005
Miyamoto H, Suzuki T, Miyauchi Y, Iwasaki R, Kobayashi T et al (2012) Osteoclast stimulatory transmembrane protein and dendritic cell-specific transmembrane protein cooperatively modulate cell–cell fusion to form osteoclasts and foreign body giant cells (in Eng). J Bone Miner Res 27:1289–1297. https://doi.org/10.1002/jbmr.1575
Zhao Q, Topham N, Anderson JM, Hiltner A, Lodoen G, Payet CR (1991) Foreign-body giant cells and polyurethane biostability: in vivo correlation of cell adhesion and surface cracking (in Eng). J Biomed Mater Res 25:177–183. https://doi.org/10.1002/jbm.820250205
MacLauchlan S, Skokos EA, Meznarich N, Zhu DH, Raoof S, Shipley JM, Senior RM, Bornstein P, Kyriakides TR (2009) Macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9 (in Eng). J Leukoc Biol 85:617–626. https://doi.org/10.1189/jlb.1008588
Katsuyama E, Miyamoto H, Kobayashi T, Sato Y, Hao W, Kanagawa H, Fujie A, Tando T, Watanabe R, Morita M, Miyamoto K, Niki Y, Morioka H, Matsumoto M, Toyama Y, Miyamoto T (2015) Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells. J Biol Chem 290:716–726. https://doi.org/10.1074/jbc.M114.568360
Mantovani A, Sica A, Locati M (2005) Macrophage polarization comes of age (in Eng). Immunity 23:344–346. https://doi.org/10.1016/j.immuni.2005.10.001
Lawrence T, Natoli G (2011) Transcriptional regulation of macrophage polarization: enabling diversity with identity (in Eng). Nat Rev Immunol 11:750–761. https://doi.org/10.1038/nri3088
Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas (in Eng). J Clin Invest 122:787–795. https://doi.org/10.1172/jci59643
Scudiero I, Zotti T, Ferravante A, Vessichelli M, Vito P, Stilo R (2011) Alternative splicing of CARMA2/CARD14 transcripts generates protein variants with differential effect on NF-kappaB activation and endoplasmic reticulum stress-induced cell death (in Eng). J Cell Physiol 226:3121–3131. https://doi.org/10.1002/jcp.22667
Zotti T, Uva A, Ferravante A, Vessichelli M, Scudiero I, Ceccarelli M, Vito P, Stilo R (2011) TRAF7 protein promotes Lys-29-linked polyubiquitination of IkappaB kinase (IKKgamma)/NF-kappaB essential modulator (NEMO) and p65/RelA protein and represses NF-kappaB activation (in Eng). J Biol Chem 286:22924–22933. https://doi.org/10.1074/jbc.M110.215426
Zotti T, Vito P, Stilo R (2012) The seventh ring: exploring TRAF7 functions (in Eng). J Cell Physiol 227:1280–1284. https://doi.org/10.1002/jcp.24011
Wajant H, Grell M, Scheurich P (1999) TNF receptor associated factors in cytokine signaling (in Eng). Cytokine Growth Factor Rev 10:15–26
Inoue J, Ishida T, Tsukamoto N, Kobayashi N, Naito A, Azuma S, Yamamoto T (2000) Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling (in Eng). Exp Cell Res 254:14–24. https://doi.org/10.1006/excr.1999.4733
Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C et al (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling (in Eng). Genes Dev 13:1015–1024
Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, Nakao K, Nakamura K, Katsuki M, Yamamoto T, Inoue J (1999) Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice (in Eng). Genes Cells 4:353–362
Gohda J, Matsumura T, Inoue J (2004) Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling (in Eng). J Immunol 173:2913–2917
Akiyama T, Maeda S, Yamane S, Ogino K, Kasai M, Kajiura F, Matsumoto M, Inoue J (2005) Dependence of self-tolerance on TRAF6-directed development of thymic stroma (in Eng). Science (New York, NY) 308:248–251. https://doi.org/10.1126/science.1105677
Muto G, Kotani H, Kondo T, Morita R, Tsuruta S, Kobayashi T, Luche H, Fehling HJ, Walsh M, Choi Y, Yoshimura A (2013) TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity (in Eng). PLoS One 8:e74639. https://doi.org/10.1371/journal.pone.0074639
Kobayashi T, Kim TS, Jacob A, Walsh MC, Kadono Y, Fuentes-Panana E, Yoshioka T, Yoshimura A, Yamamoto M, Kaisho T, Akira S, Monroe JG, Choi Y (2009) TRAF6 is required for generation of the B-1a B cell compartment as well as T cell-dependent and -independent humoral immune responses (in Eng). PLoS One 4:e4736. https://doi.org/10.1371/journal.pone.0004736
Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T, Komatsu N, Kodama T, Takayanagi H (2015) Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163:975–987. https://doi.org/10.1016/j.cell.2015.10.013
Yang S, Fujikado N, Kolodin D, Benoist C, Mathis D (2015) Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance (in Eng). Science (New York, NY) 348:589–594. https://doi.org/10.1126/science.aaa7017
Yagi M, Miyamoto T, Toyama Y, Suda T (2006) Role of DC-STAMP in cellular fusion of osteoclasts and macrophage giant cells (in Eng). J Bone Miner Metab 24:355–358. https://doi.org/10.1007/s00774-006-0697-9
Jeganathan S, Fiorino C, Naik U, Sun HS, Harrison RE (2014) Modulation of osteoclastogenesis with macrophage M1- and M2-inducing stimuli (in Eng). PLoS One 9:e104498. https://doi.org/10.1371/journal.pone.0104498
Xiong Q, Zhang L, Ge W, Tang P (2016) The roles of interferons in osteoclasts and osteoclastogenesis. Joint Bone Spine 83:276–281. https://doi.org/10.1016/j.jbspin.2015.07.010
Jimi E, Akiyama S, Tsurukai T, Okahashi N, Kobayashi K, Udagawa N, Nishihara T, Takahashi N, Suda T (1999) Osteoclast differentiation factor acts as a multifunctional regulator in murine osteoclast differentiation and function. J Immunol 163:434–442
Lomaga MA, Henderson JT, Elia AJ, Robertson J, Noyce RS, Yeh WC, Mak TW (2000) Tumor necrosis factor receptor-associated factor 6 (TRAF6) deficiency results in exencephaly and is required for apoptosis within the developing CNS (in Eng). J Neurosci 20:7384–7393
Drachman DB (1994) Myasthenia gravis (in Eng). N Engl J Med 330:1797–1810. https://doi.org/10.1056/nejm199406233302507
Brune B, Weigert A, Dehne N (2015) Macrophage polarization in the tumor microenvironment (in Eng). Redox Biol 5:419. https://doi.org/10.1016/j.redox.2015.09.028
Martinez FO, Gordon S (2015) The evolution of our understanding of macrophages and translation of findings toward the clinic (in Eng). Expert Rev Clin Immunol 11:5–13. https://doi.org/10.1586/1744666x.2015.985658
Teitelbaum SL (2016) Therapeutic implications of suppressing osteoclast formation versus function (in Eng). Rheumatology (Oxford, England) 55:61–63. https://doi.org/10.1093/rheumatology/kew350
Acknowledgements
T. Miyamoto was supported by a grant from the Japan Agency for Medical Research and Development and a grant-in-aid for Scientific Research in Japan. K. Miyamoto and Y. Sato were supported by a grant-in-aid for Scientific Research in Japan. This study was supported in part by a grant from the Translational Research Network Program and a grant-in-aid for Scientific Research.
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Oya, A., Katsuyama, E., Morita, M. et al. Tumor necrosis factor receptor-associated factor 6 is required to inhibit foreign body giant cell formation and activate osteoclasts under inflammatory and infectious conditions. J Bone Miner Metab 36, 679–690 (2018). https://doi.org/10.1007/s00774-017-0890-z
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DOI: https://doi.org/10.1007/s00774-017-0890-z