Scientific Journal Of King Faisal University
Basic and Applied Sciences

ع

Scientific Journal of King Faisal University / Basic and Applied Sciences

Osteoclast Stimulatory Transmembrane Protein (OC‐STAMP): A Key Regulator in Osteoclast Fusion

(Mayyadah Abdullah Alkuwayti)

Abstract

The integrity of bone mass depends on the balance between osteoblastic bone formation and osteoclastic bone resorption. Osteoclasts derived from hematopoietic stem cells in bone marrow via a mechanism mediated mainly by two cytokines: the receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Osteoclast stimulatory transmembrane protein (OC‐STAMP) is a newly identified master fusogen that functions as a regulator of osteoclastogenesis. It is considered a key factor during macrophage fusion and differentiation. Osteoclast formation is mediated by a variety of factors and mechanisms other than OC-STAMP. Furthermore, numerous preclinical studies have investigated drugs that could target osteoclast differentiation, to allow better management of pathological bone metabolism. To improve understanding of osteoclast fusion and differentiation processes, this review will discuss recent findings on OC-STAMP and related signalling pathways.
KEYWORDS
Osteoblasts, osteoclastogenesis, RANKL, differentiation, DC-STAMP, osteoclast fusion molecules
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References

Anazawa, U., Hanaoka, H., Morioka, H., Morii, T. and Toyama, Y. (2004). Ultrastructural cytochemical and ultrastructural morphological differences between human multinucleated giant cells elicited by wear particles from hip prostheses and artificial ligaments at the knee. Ultrastruct Pathol , 28(5–6), 353–9. 
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. (1997). A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature, 390(6656), 175–9.
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. (2005). Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med , 202(9), 1261–9.
Bendixen, A.C., Shevde, N.K., Dienger, K.M., Willson, T.M., Funk, C.D. and Pike, J.W. (2001). IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor gamma 1. Proc Natl Acad Sci USA, 98(5), 2443–8.
Blair, H.C., Teitelbaum, S.L., Ghiselli, R. and Gluck, S. (1989). Osteoclastic bone resorption by a polarized vacuolar proton pump. Science, 245(4920), 855–7.
Blumenthal, R., Clague, M.J., Durell, S.R. and Epand, R.M. (2003). Membrane fusion. Chem Rev ,103(1), 53–69.
Boyce, B.F. (2013). Advances in osteoclast biology reveal potential new drug targets and new roles for osteoclasts. J Bone Miner Res, 28(4), 711–22.
Boyle, W.J., Simonet, W.S. and Lacey, D.L. (2003). Osteoclast differentiation and activation. Nature, 423(6937), 337–42.
Caetano-Lopes, J., Canhao, H. and Fonseca, J.E. (2007). Osteoblasts and bone formation. Acta Reumatol Port , 32(2), 103–10.
Chambers, T.J. (2000). Regulation of the differentiation and function of osteoclasts. J Pathol, 192(1), 4–13.
Chambers, T.J., Owens, J.M., Hattersley, G., Jat, P.S. and Noble, M.D. (1993). Generation of osteoclast-inductive and osteoclastogenic cell lines from the H-2KbtsA58 transgenic mouse. Proc Natl Acad Sci USA, 90(12), 5578–82.
Charles, J.F. and Aliprantis, A.O. (2014). Osteoclasts: More than 'bone eaters'. Trends Mol Med, 20(8), 449–59.
Chiu, Y.H. and Ritchlin, C.T. (2016). DC-STAMP: A Key Regulator in Osteoclast Differentiation. J Cell Physiol , 231(11), 2402–7.
Dai, X.M., Ryan, G.R., Hapel, A.J., Dominguez, M.G., Russell, R.G., Kapp, S., Sylvestre, V. and Stanley, E.R. (2002). Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood, 99(1), 111–20.
Dougall, W.C., Glaccum, M., Charrier, K., Rohrbach, K., Brasel, K., De Smedt, T., Daro, E., Smith, J., Tometsko, M.E., Maliszewski, C.R., Armstrong, A., Shen, V., Bain, S., Cosman, D., Anderson, D., Morrissey, P.J., Peschon, J.J. and Schuh, J. (1999). RANK is essential for osteoclast and lymph node development. Genes Dev ,13(18), 2412–24.
Florencio-Silva, R., Sasso, G.R., Sasso-Cerri, E., Simoes, M.J. and Cerri, P.S. (2015). Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. Biomed Res Int., 2015(n/a), 421746.
Fuller, K., Wong, B., Fox, S., Choi, Y. and Chambers, T.J. (1998). TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med, 188(5), 997–1001.
Hartgers, F.C., Vissers, J.L., Looman, M.W., van Zoelen, C., Huffine, C., Figdor, C. G. and Adema, G.J. (2000). DC-STAMP, a novel multimembrane-spanning molecule preferentially expressed by dendritic cells. Eur J Immunol, 30(12), 3585–90.
Hernandez, L.D., Hoffman, L.R., Wolfsberg, T.G. and White, J.M. (1996). Virus-cell and cell-cell fusion. Annu Rev Cell Dev Biol , 12(n/a), 627–61.
Hodge, J.M., Kirkland, M.A., Aitken, C.J., Waugh, C.M., Myers, D.E., Lopez, C.M., Adams, B.E. and Nicholson, G.C. (2004). Osteoclastic potential of human CFU-GM: Biphasic effect of GM-CSF. J Bone Miner Res, 19(2), 190–9.
Hwang, Y.S., Ma, G.T., Park, K.K. and Chung, W.Y. (2014). Lysophosphatidic acid stimulates osteoclast fusion through OC-STAMP and P2X7 receptor signaling. J Bone Miner Metab, 32(2), 110–22.
Ishibashi, T., Ding, L., Ikenaka, K., Inoue, Y., Miyado, K., Mekada, E. and Baba, H. (2004). Tetraspanin protein CD9 is a novel paranodal component regulating paranodal junctional formation. J Neurosci 24(1), 96–102.
Ishii, M., Iwai, K., Koike, M., Ohshima, S., Kudo-Tanaka, E., Ishii, T., Mima, T., Katada, Y., Miyatake, K., Uchiyama, Y. and Saeki, Y. (2006). RANKL-induced expression of tetraspanin CD9 in lipid raft membrane microdomain is essential for cell fusion during osteoclastogenesis. J Bone Miner Res, 21(6), 965–76.
Ishii, T., Ruiz-Torruella, M., Ikeda, A., Shindo, S., Movila, A., Mawardi, H., Albassam, A., Kayal, R.A., Al-Dharrab, A.A., Egashira, K., Wisitrasameewong, W., Yamamoto, K., Mira, A.I., Sueishi, K., Han, X., Taubman, M.A., Miyamoto, T. and Kawai, T. (2018). OC-STAMP promotes osteoclast fusion for pathogenic bone resorption in periodontitis via up-regulation of permissive fusogen CD9. FASEB J 32(7), 4016–30.
Kaji, K. and Kudo, A. (2004). The mechanism of sperm-oocyte fusion in mammals. Reproduction, 127(4), 423–9.
Kaji, K., Oda, S., Miyazaki, S. and Kudo, A. (2002). Infertility of CD9-deficient mouse eggs is reversed by mouse CD9, human CD9, or mouse CD81; polyadenylated mRNA injection developed for molecular analysis of sperm-egg fusion. Dev Biol, 247(2), 327–34.
Khan, U.A., Hashimi, S.M., Bakr, M.M., Forwood, M.R., and Morrison, N.A. (2013). Foreign body giant cells and osteoclasts are TRAP positive, have podosome-belts and both require OC-STAMP for cell fusion. J Cell Biochem, 114(8), 1772–8.
Kim, M.H., Park, M., Baek, S.H., Kim, H.J. and Kim, S.H. (2011). Molecules and signaling pathways involved in the expression of OC-STAMP during osteoclastogenesis. Amino Acids, 40(5), 1447–59.
Kodama, J., and Kaito, T. (2020). Osteoclast Multinucleation: Review of Current Literature. Int J Mol Sci, 2(16), 5685.
Kukita, T., Wada, N., Kukita, A., Kakimoto, T., Sandra, F., Toh, K., Nagata, K., Iijima, T., Horiuchi, M., Matsusaki, H., Hieshima, K., Yoshie, O. and Nomiyama, H. (2004). RANKL-induced DC-STAMP is essential for osteoclastogenesis. J Exp Med, 200(7), 941–6.
Kylmaoja, E., Nakamura, M. and Tuukkanen, J. (2016). Osteoclasts and remodeling based bone formation. Curr Stem Cell Res Ther, 11(8), 626–33.
Liu, Y.C., Zou, X.B., Chai, Y.F. and Yao, Y.M. (2014). Macrophage polarization in inflammatory diseases. Int J Biol Sci, 10(5), 520–9.
McNally, A.K. and Anderson, J.M. (1995). Interleukin-4 induces foreign body giant cells from human monocytes/macrophages. Differential lymphokine regulation of macrophage fusion leads to morphological variants of multinucleated giant cells. Am J Pathol, 147(5), 1487–99.
Mensah, K.A., Ritchlin, C.T. and Schwarz, E.M. (2010). RANKL induces heterogeneous DC-STAMP(lo) and DC-STAMP(hi) osteoclast precursors of which the DC-STAMP(lo) precursors are the master fusogens. J Cell Physiol, 223(1), 76–83.
Mills, C.D. (2015). Anatomy of a discovery: M1 and m2 macrophages. Front Immunol, 6(n/a), 212.
Miyamoto, H., Suzuki, T., Miyauchi, Y., Iwasaki, R., Kobayashi, T., Sato, Y., Miyamoto, K., Hoshi, H., Hashimoto, K., Yoshida, S., Hao, W., Mori, T., Kanagawa, H., Katsuyama, E., Fujie, A., Morioka, H., Matsumoto, M., Chiba, K., Takeya, M., Toyama, Y. and Miyamoto, T. (2012). Osteoclast stimulatory transmembrane protein and dendritic cell-specific transmembrane protein cooperatively modulate cell-cell fusion to form osteoclasts and foreign body giant cells. J Bone Miner Res, 27(6), 1289–97.
Miyamoto, T. (2013). STATs and macrophage fusion. JAKSTAT, 2(3), e24777.
Moreno, J.L., Mikhailenko, I., Tondravi, M.M. and Keegan, A.D. (2007). IL-4 promotes the formation of multinucleated giant cells from macrophage precursors by a STAT6-dependent, homotypic mechanism: Contribution of E-cadherin. J Leukoc Biol, 82(6), 1542–53.
Nakashima, T., Hayashi, M., Fukunaga, T., Kurata, K., Oh-Hora, M., Feng, J. Q., Bonewald, L.F., Kodama, T., Wutz, A., Wagner, E.F., Penninger, J.M. and Takayanagi, H. (2011). Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med, 17(10), 1231–4.
Parfitt, A.M. (2002). Targeted and nontargeted bone remodeling: Relationship to basic multicellular unit origination and progression. Bone, 30(1), 5–7.
Sipos, W., Pietschmann, P., Rauner, M., Kerschan-Schindl, K. and Patsch, J. (2009). Pathophysiology of osteoporosis. Wien Med Wochenschr, 159(9-10), 230–4.
Song, I., Kim, J.H., Kim, K., Jin, H.M., Youn, B.U. and Kim, N. (2009). Regulatory mechanism of NFATc1 in RANKL-induced osteoclast activation. FEBS Lett, 583(14), 2435–40.
Staege, H., Brauchlin, A., Schoedon, G. and Schaffner, A. (2001). Two novel genes FIND and LIND differentially expressed in deactivated and Listeria-infected human macrophages. Immunogenetics, 53(2), 105–13.
Szanto, A., Balint, B.L., Nagy, Z.S., Barta, E., Dezso, B., Pap, A., Szeles, L., Poliska, S., Oros, M., Evans, R.M., Barak, Y., Schwabe, J. and Nagy, L. (2010). STAT6 transcription factor is a facilitator of the nuclear receptor PPARgamma-regulated gene expression in macrophages and dendritic cells. Immunity, 33(5), 699–712.
Tachibana, I. and Hemler, M. E. (1999). Role of transmembrane 4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance. J Cell Biol ,146(4), 893–904.
Takagi, T., Inoue, H., Takahashi, N., Katsumata-Tsuboi, R. and Uehara, M. (2017a). Sulforaphane inhibits osteoclast differentiation by suppressing the cell-cell fusion molecules DC-STAMP and OC-STAMP. Biochem Biophys Res Commun, 483(1), 718–24.
Takagi, T., Inoue, H., Takahashi, N., Katsumata-Tsuboi, R. and Uehara, M. (2017b). Sulforaphene attenuates multinucleation of pre-osteoclasts by suppressing expression of cell-cell fusion-associated genes DC-STAMP, OC-STAMP, and Atp6v0d2. Biosci Biotechnol Biochem, 81(6), 1220–3.
Takayanagi, H. (2007). Osteoimmunology: Shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol, 7(4), 292–304.
Teitelbaum, S.L. and Ross, F.P. (2003). Genetic regulation of osteoclast development and function. Nat Rev Genet, 4(8), 638–49.
Willkomm, L. and Bloch, W. (2015). State of the art in cell-cell fusion. Methods Mol Biol, 1313(n/a), 1–19.
Wisitrasameewong, W., Kajiya, M., Movila, A., Rittling, S., Ishii, T., Suzuki, M., Matsuda, S., Mazda, Y., Torruella, M.R., Azuma, M.M., Egashira, K., Freire, M.O., Sasaki, H., Wang, C.Y., Han, X., Taubman, M.A. and Kawai, T. (2017). DC-STAMP Is an Osteoclast Fusogen Engaged in Periodontal Bone Resorption. J Dent Res, 96(6), 685–93.
Witwicka, H., Hwang, S.Y., Reyes-Gutierrez, P., Jia, H., Odgren, P.E., Donahue, L. R., Birnbaum, M.J. and Odgren, P.R. (2015). Studies of OC-STAMP in osteoclast fusion: A new knockout mouse model, rescue of cell fusion, and transmembrane structure. PLoS One, 10(6), e0128275.
Xing, L., Xiu, Y. and Boyce, B.F. (2012). Osteoclast fusion and regulation by RANKL-dependent and independent factors. World J Orthop, 3(12), 212–22.
Xiong, J., Onal, M., Jilka, R.L., Weinstein, R.S., Manolagas, S.C. and O'Brien, C.A. (2011). Matrix-embedded cells control osteoclast formation. Nat Med, 17(10), 1235–41.
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. and Suda, T. (2005). DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med, 202(3), 345–51.
Yang, M., Birnbaum, M.J., MacKay, C.A., Mason-Savas, A., Thompson, B. and Odgren, P.R. (2008). Osteoclast stimulatory transmembrane protein (OC-STAMP), a novel protein induced by RANKL that promotes osteoclast differentiation. J Cell Physiol, 215(2), 497–505.
Yuan, H., He, J., Zhang, G., Zhang, D., Kong, X. and Chen, F. (2017). Osteoclast stimulatory transmembrane protein induces a phenotypic switch in macrophage polarization suppressing an M1 pro-inflammatory state. Acta Biochim Biophys Sin (Shanghai), 49(10), 935–44.
Zhang, C., Dou, C.E., Xu, J. and Dong, S. (2014). DC-STAMP, the key fusion-mediating molecule in osteoclastogenesis. J Cell Physiol, 229(10), 1330–5.