Abstract
Introduction
In bone tissue, bone resorption by osteoclasts and bone formation by osteoblasts are repeated continuously. Osteoclasts are multinucleated cells that derive from monocyte-/macrophage-lineage cells and resorb bone. In contrast, osteoblasts mediate osteoclastogenesis by expressing receptor activator of nuclear factor-kappa B ligand (RANKL), which is expressed as a membrane-associated cytokine. Osteoprotegerin (OPG) is a soluble RANKL decoy receptor that is predominantly produced by osteoblasts and which prevents osteoclast formation and osteoclastic bone resorption by inhibiting the RANKL–RANKL receptor interaction.
Materials and Methods
In this review, we would like to summarize our experimental results on signal transduction that regulates the expression of RANKL and OPG.
Results
Using OPG gene-deficient mice, we have demonstrated that OPG and sclerostin produced by osteocytes play an important role in the maintenance of cortical and alveolar bone. In addition, it was shown that osteoclast-derived leukemia inhibitory factor (LIF) reduces the expression of sclerostin in osteocytes and promotes bone formation. WP9QY (W9) is a peptide that was designed to be structurally similar to one of the cysteine-rich TNF-receptortype-I domains. Addition of the W9 peptide to bone marrow culture simultaneously inhibited osteoclast differentiation and stimulated osteoblastic cell proliferation. An anti-sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) antibody inhibited multinucleated osteoclast formation induced by RANKL and macrophage colony-stimulating factor (M-CSF). Pit-forming activity of osteoclasts was also inhibited by the anti-Siglec-15 antibody. In addition, anti-Siglec-15 antibody treatment stimulated the appearance of osteoblasts in cultures of mouse bone marrow cells in the presence of RANKL and M-CSF.
Conclusions
Bone mass loss depends on the RANK–RANKL–OPG system, which is a major regulatory system of osteoclast differentiation induction, activation, and survival.
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References
Rodan GA, Martin TJ (1981) Role of osteoblasts in hormonal control of bone resorption—a hypothesis. Calcif Tissue Int 33:349–351. https://doi.org/10.1007/BF02409454
Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, Koga T, Martin TJ, Suda T (1990) Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acid Sci 87:7260–7264. https://doi.org/10.1073/pnas.87.18.7260
Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A, Jane MM, Jone M, Suda T (1987) Osteoblastic cells are involved in osteoclast formation. Endocrinology 123:2600–2602. https://doi.org/10.1210/endo-123-5-2600
Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345:442–444. https://doi.org/10.1038/345442a0
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 (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acid Sci 95:3597–3602. https://doi.org/10.1073/pnas.95.7.3597
Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ (1999) Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endoc Rev 20:345–357. https://doi.org/10.1210/edrv.20.3.0367
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319. https://doi.org/10.1016/s0092-8674(00)80209-3
Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M, Kanno T, Murakami A, Tsuda E, Morinaga T, Higashio K (1998) Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 139:1329–1337. https://doi.org/10.1210/endo.139.3.5837
Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323. https://doi.org/10.1038/16852
Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, Daro E, Smith J, Tometsko ME, Maliszewski CR, Armstrong A, Shen V, Bain S, Cosman D, Anderson D, Morrissey PJ, Peschon JJ, Schuh J (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13:2412–2424. https://doi.org/10.1101/gad.13.18.2412
Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268. https://doi.org/10.1101/gad.12.9.1260
Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, Sato Y, Nakagawa N, Yasuda H, Mochizuki S, Gomibuchi T, Yano K, Shim N, Washida N, Tsuda E, Morinaga T, Higashino K, Ozawa H (1998) Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commum 247:610–625. https://doi.org/10.1006/bbrc.1998.8697
Zebaze RM, Libanati C, McClung MR, Zanchetta JR, Kendler DL, Høiseth A, Wang A, Ghasem-Zadeh A, Seeman E (2016) Denosumab reduces cortical porosity of the proximal femoral shaft in postmenopausal women with osteoporosis. J Bone Miner Res 31:1827–1834. https://doi.org/10.1002/jbmr.2855
Koide M, Kobayashi Y, Ninomiya T, Nakamura M, Yasuda H, Arai Y, Okahashi N, Yoshinari N, Takahashi N, Udagawa N (2013) Osteoprotegerin-deficient male mice as a model for severe alveolar bone loss. Comparison with RANKL-overexpressing transgenic male mice. Endocrinology 154:773–782. https://doi.org/10.1210/en.2012-1928
Nakamura M, Udagawa N, Matsuura S, Mogi M, Nakamura H, Horiuchi H, Saito N, Hiraoka BY, Kobayashi Y, Takaoka K, Ozawa H, Miyazawa H, Takahashi N (2003) Osteoprotegerin regulates bone formation through a coupling mechanism with bone resorption. Endocrinology 144:5441–5449. https://doi.org/10.1210/en.2003-0717
Yamamoto Y, Udagawa N, Matsuura S, Nakamichi Y, Horiuchi H, Hosoya A, Nakamura M, Ozawa H, Takaoka K, Penninger JM, Noguchi T, Takahashi N (2006) Osteoblasts provide a suitable microenvironment for the action of receptor activator of nuclear factor-κB ligand. Endocrinology 147:3366–3374. https://doi.org/10.1210/en.2006-0216
Weivoda MM, Ruan M, Pederson L, Hachfeld C, Davey RA, Zajac JD, Westendorf JJ, Khosla S, Oursler MJ (2016) Osteoclast TGF-β receptor signaling induces Wnt1 secretion and couples bone resorption to bone formation. J Bone Miner Res 31:76–85. https://doi.org/10.1002/jbmr.2586
Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ (2008) Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci USA 105:20764–20769. https://doi.org/10.1073/pnas.0805133106
Irie N, Takada Y, Watanabe Y, Matsuzaki Y, Naruse C, Asano M, Iwakura Y, Suda T, Matsuo K (2009) Bidirectional signaling through ephrinA2-ephA2 enhances osteoclastogenesis and suppresses osteoblastogenesis. J Biol Chem 284:14637–14644. https://doi.org/10.1074/jbc.M807598200
Takyar FM, Tonna S, Ho PW, Crimeen-Irwin B, Baker EK, Martin TJ, Sims NA (2013) EphrinB2/ephB4 inhibition in the osteoblast lineage modifies the anabolic response to parathyroid hormone. J Bone Miner Res 28:912–925. https://doi.org/10.1002/jbmr.1820
Negishi-Koga T, Shinohara M, Komatsu N, Bito H, Kodama T, Friedel RH, Takayanagi H (2011) Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat Med 17:1473–1480. https://doi.org/10.1038/nm.2489
Xie H, Cui Z, Wang L, Xia Z, Hu Y et al (2014) PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat Med 20:1270–1278. https://doi.org/10.1038/nm.3668
Ota K, Quint P, Ruan M, Pederson L, Westendorf JJ, Khosla S, Oursler MJ (2013) TGF-β induces Wnt10b in osteoclasts from female mice to enhance coupling to osteoblasts. Endocrinology 154:3745–3752. https://doi.org/10.1210/en.2013-1272
Takeshita S, Fumoto T, Matsuoka K, Park KA, Aburatani H, Kato S, Ito M, Ikeda K (2013) Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation. J Clin Invest 123:3914–3924. https://doi.org/10.1172/JCI69493
Matsuoka K, Park KA, Ito M, Ikeda K, Takeshita S (2014) Osteoclast-derived complement component 3a stimulates osteoblast differentiation. J Bone Miner Res 29:1522–1530. https://doi.org/10.1002/jbmr.2187
Lotinun S, Kiviranta R, Matsubara AJA, Neff L, Lüth A, Koskivirta I, Kleuser B, Vacher J, Vuorio E, Horne WC, Baron R (2013) Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest 123:666–681. https://doi.org/10.1172/JCI64840
Hayashi M, Nakashima T, Taniguchi M, Kodama T, Kumanogoh A, Takayanagi H (2012) Osteoprotection by semaphorin 3A. Nature 485:69–74. https://doi.org/10.1038/nature11000
Furuya Y, Inagaki A, Khan M, Mori K, Penninger JM, Nakamura M, Udagawa N, Aoki K, Ohya K, Uchida K, Yasuda H (2013) Stimulation of bone formation in cortical bone of mice treated with a preceptor activator of nuclear factor-κB ligand (RANKL)-binding peptide that possesses osteoclastogenesis inhibitory activity. J Biol Chem 288:5562–5571. https://doi.org/10.1074/jbc.M112.426080
Ikebuchi Y, Aoki S, Honma M, Hayashi M, Sugamori Y, Khan M, Kariya Y, Kato G, Tabata Y, Penninger JM, Udagawa N, Aoki K, Suzuki H (2018) Coupling of bone resorption and formation by RANKL reverse signalling. Nature 561:195–200. https://doi.org/10.1038/s41586-018-0482-7
Shoji-Matsunaga A, Ono T, Hayashi M, Takayanagi H, Moriyama K, Nakashima T (2017) Osteocyte regulation of orthodontic force-mediated tooth movement via RANKL expression. Sci Rep 7:8753. https://doi.org/10.1038/s41598-017-09326-7
Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887. https://doi.org/10.1074/jbc.M413274200
Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192. https://doi.org/10.1038/nm.3074
Li X, Ominsky MS, Niu QT, Sun N, Daugherty B et al (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869
Li X, Ominsky MS, Warmington KS, Morony S, Gong J et al (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578–588. https://doi.org/10.1359/jbmr.080216
Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (2008) Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 283:5866–5875. https://doi.org/10.1074/jbc.M705092200
Leupin O, Kramer I, Collette NM, Loots GG, Natt F, Kneissel M, Keller H (2007) Control of the SOST bone enhancer by PTH using MEF2 transcription factors. J Bone Miner Res 22:1957–1967. https://doi.org/10.1359/jbmr.070804
Galea GL, Sunters A, Meakin LB, Zaman G, Sugiyama T, Lanyon LE, Price JS (2011) Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4. FEBS Lett 585:2450–2454. https://doi.org/10.1016/j.febslet.2011.06.019
Walker EC, McGregor NE, Poulton IJ, Solano M, Pompolo S, Fernandes TJ, Constable MJ, Nicholson GC, Zhang JG, Nicola NA, Gillespie MT, Martin TJ, Sims NA (2010) Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice. J Clin Invest 120:582–592. https://doi.org/10.1172/JCI40568
Poulton IJ, McGregor NE, Pompolo S, Walker EC, Sims NA (2012) Contrasting roles of leukemia inhibitory factor in murine bone development and remodeling involve region-specific changes in vascularization. J Bone Miner Res 27:586–595. https://doi.org/10.1002/jbmr.1485
Walker EC, McGregor NE, Poulton IJ et al (2008) Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling. J Bone Miner Res 23:2025–2032. https://doi.org/10.1359/jbmr.080706
Cornish J, Callon K, King A, Edgar S, Reid IR (1993) The effect of leukemia inhibitory factor on bone in vivo. Endocrinology 132:1359–1366. https://doi.org/10.1210/endo.132.3.8440191
Sims NA, Martin TJ (2015) Coupling signals between the osteoclast and osteoblast: how are messages transmitted between these temporary visitors to the bone surface? Front Endocrinol 6:41. https://doi.org/10.3389/fendo.2015.00041
Ota K, Quint P, Weivoda MM, Ruan M, Pederson L, Westendorf JJ, Khosla S, Oursler MJ (2013) Transforming growth factorβ1 induces CXCL16 and leukemia inhibitory factor expression in osteoclasts to modulate migration of osteoblast progenitors. Bone 57:68–75. https://doi.org/10.1016/j.bone.2013.07.023
Koide M, Kobayashi Y, Yamashita T, Uehara S, Nakamura M, Hiraoka BY, Ozaki Y, Iimura T, Yasuda H, Takahashi N, Udagawa N (2017) Bone Formation is coupled to resorption via suppression of sclerostin expression by osteoclasts. J Bone Miner Res 32:2074–2086. https://doi.org/10.1002/jbmr.3175
Udagawa N, Takahashi N, Yasuda H, Mizuno A, Itoh K, Ueno Y, Shinki T, Gillespie MT, Martin TJ, Higashio K, Suda T (2000) Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function. Endocrinology 141:3478–3484. https://doi.org/10.1210/endo.141.9.7634
Takasaki W, Kajino Y, Kajino K, Murali R, Greene MI (1997) Structure-based design and characterization of exocyclic peptidomimetics that inhibit TNF alpha binding to its receptor. Nat Biotechnol 15:1266–1270. https://doi.org/10.1038/nbt1197-1266
Aoki K, Saito H, Itzstein C, Ishiguro M, Shibata T, Blanque R, Mian AH, Takahashi M, Suzuki Y, Yoshimatsu M, Yamaguchi A, Deprez P, Mollat P, Murali R, Ohya K, Horne WC, Baron R (2006) A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss. J Clin Invest 116:1525–1534. https://doi.org/10.1172/JCI22513
Nakamura M, Nakamichi Y, Mizoguchi T, Koide M, Yamashita T, Ara T, Nakamura H, Penninger JM, Furuya Y, Yasuda H, Udagawa N (2017) The W9 peptide directly stimulates osteoblast differentiation via RANKL signaling. J Oral Biosci 59:146–151
Ishida N, Hayashi K, Hoshijima M, Ogawa T, Koga S, Miyatake Y, Kumegawa M, Kimura T, Takeya T (2002) Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator. J Biol Chem 277:41147–41156. https://doi.org/10.1074/jbc.M205063200
Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3:889–901. https://doi.org/10.1016/s1534-5807(02)00369-6
Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, Morita I, Wagner EF, Mak TW, Serfling E, Takayanagi H (2005) Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med 202:1261–1269. https://doi.org/10.1084/jem.20051150
Aliprantis AO, Ueki Y, Sulyanto R, Park A, Sigrist KS, Sharma SM, Ostrowski MC, Olsen BR, Glimcher LH (2008) NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest 118:3775–3789. https://doi.org/10.1172/JCI35711
Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T, Taniguchi T, Takayanagi H, Takai T (2004) Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428:758–763. https://doi.org/10.1038/nature02444
Kaifu T, Nakahara J, Inui M, Mishima K, Momiyama T, Kaji M, Sugahara A, Koito H, Ujike-Asai A, Nakamura A, Kanazawa K, Tan-Takeuchi K, Iwasaki K, Yokoyama W, Kudo A, Fujiwara M, Asou H, Takai T (2003) Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest 111:323–332. https://doi.org/10.1172/JCI16923
Hiruma Y, Hirai T, Tsuda E (2011) Siglec-15, a member of the sialic acid-binding lectin, is a novel regulator for osteoclast differentiation. Biochem Biophy Res Commun 409:424–429. https://doi.org/10.1016/j.bbrc.2011.05.015
Ishida-Kitagawa N, Tanaka K, Bao X, Kimura T, Miura T, Kitaoka Y, Hayashi K, Sato M, Maruoka M, Ogawa T, Miyoshi J, Takeya T (2012) Siglec-15 protein regulates formation of functional osteoclasts in concert with DNAX-activating protein of 12 kDa (DAP12). J Biol Chem 287:17493–17502. https://doi.org/10.1074/jbc.M111.324194
Kameda Y, Takahata M, Komatsu M, Mikuni S, Hatakeyama S, Shimizu T, Angata T, Kinjo M, Minami A, Iwasaki N (2013) Siglec-15 regulaters osteoclast differentiation by modulating RANKL-induced phosphatidylinositol 3-kinase/Akt and Erk pathways in association with signaling adaptor DAP12. J Bone Miner Res 28:2463–2475. https://doi.org/10.1002/jbmr.1989
Hiruma Y, Tsuda E, Maeda N, Okada A, Kabasawa N, Miyamoto M, Hattori H, Fukuda C (2013) Impaired osteoclast differentiation and function and mild osteopetrosis development in Siglec-15-deficient mice. Bone 53:87–93. https://doi.org/10.1016/j.bone.2012.11.036
Stuible M, Moraitis A, Fortin A, Saragosa S, Kalbakji A, Filion M, Tremblay GB (2014) Mechanism and function of monoclonal antibodies targeting siglec-15 for therapeutic inhibition of osteoclastic bone resorption. J Biol Chem 289:6498–6512. https://doi.org/10.1074/jbc.M113.494542
Udagawa N, Uehara S, Koide M, Arai A, Mizoguchi T, Nakamura M, Kobayashi Y, Takahashi N, Fukuda C, Tsuda E (2017) Anti-Siglec-15 antibody inhibits bone-resorbing activity of osteoclasts and stimulates osteoblast differentiation. J Bone Miner Res Suppl 32:349
Fukuda C, Okada A, Karibe T, Hinuma Y, Kumakura S, Tsuda E (2017) A novel bone formation-sparing anti-resorptive agent, DS-1501a, increased BMD and bone biomechanical properties of cortical bone in ovariectomized cynomolgus monkeys. J Bone Miner Res 32:112
Fukuda C, Tsuda E, Okada A, Amizuka N, Hasegawa T, Karibe T, Hinuma Y, Takagi N, Kumakura S (2017) Anti-Siglec-15 antibody reduced bone resorption while maintaining bone formation in ovariectomized (OVX) rats and monkeys. J Bone Miner Res 32:112
Dishy V, Kang D, Warren V, Maxwell W, Levinson B, Kochan J, He L, Baz-Hecht M, Fukuda C, Koga J, Tsuda E, Watanabe K (2017) A phase 1, subject and investigator blinded, sponsor unblended, placebocontrolled, radamized, 2 part, sequential, single ascending dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of DS-1501a in healthy young subjects and healthy postmenopausal woman. J Bone Miner Res 32:107–108
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This work was supported by JSPS KAKENHI (Grant nos 19K10395, 17K19776, 16H05508, 16K11818, 15K11377, and 15K15688).
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Eisuke Tsuda and Chie Fukuda are employees of Daiichi Sankyo Co., Ltd. The other authors (Nobuyuki Udagawa, Masanori Koide, Midori Nakamura, Yuko Nakamichi, Teruhito Yamashita, Shunsuke Uehara, and Yasuhiro Koide) have financial interest and/or other relationship with Daiichi Sankyo Co., Ltd. Yuriko Furuya and Hisataka Yasuda are employees of Oriental Yeast Co., Ltd.
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Udagawa, N., Koide, M., Nakamura, M. et al. Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Miner Metab 39, 19–26 (2021). https://doi.org/10.1007/s00774-020-01162-6
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DOI: https://doi.org/10.1007/s00774-020-01162-6