대한의생명과학회지 (Biomedical Science Letters)

  • 제23권4호
  • /
  • Pages.295-302
  • /
  • 2017
  • /
  • 1738-3226(pISSN)
  • /
  • 2288-7415(eISSN)
대한의생명과학회 (The Korean Society for Biomedical Laboratory Sciences)
권호 표지
DOI QR코드

DOI QR Code

RANK Signaling Pathways and Key Molecules Inducing Osteoclast Differentiation

  • Lee, Na Kyung (Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University)
  • 투고 : 2017.12.05
  • 심사 : 2017.12.15
  • 발행 : 2017.12.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Mononuclear osteoclast precursors derived from hematopoietic progenitors fuse together and then become multinucleated mature osteoclasts by macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-${\kappa}B$ ligand (RANKL). Especially, the binding of RANKL to its receptor RANK provides key signals for osteoclast differentiation and bone-resorbing function. RANK transduces intracellular signals by recruiting adaptor molecules such as TNFR-associated factors (TRAFs), which then activate mitogen activated protein kinases (MAPKs), Src/PI3K/Akt pathway, nuclear factor-${\kappa}B$ (NF-${\kappa}B$) and finally amplify NFATc1 activation for the transcription and activation of osteoclast marker genes. This review will briefly describe RANKL-RANK signaling pathways and key molecules critical for osteoclast differentiation.

키워드

참고문헌

  1. Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux 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. 1997. 390: 175-179. https://doi.org/10.1038/36593
  2. Arron JR, Vologodskaia M, Wong BR, Naramura M, Kim N, Gu H, Choi Y. A positive regulatory role for Cbl family proteins in tumor necrosis factor-related activation-induced cytokine (trance) and CD40L-mediated Akt activation. Journal of Biological Chemistry. 2001. 276: 30011-30017. https://doi.org/10.1074/jbc.M100414200
  3. Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, Morita I, Wagner EF, Mak TW, Serfling E, Takayanagi H. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. Journal of Experimental Medicine. 2005. 202: 1261-1269. https://doi.org/10.1084/jem.20051150
  4. Aubin JE. Regulation of osteoblast formation and function. Reviews in Endocrine & Metabolic Disorders. 2001. 2: 81-94. https://doi.org/10.1023/A:1010011209064
  5. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes & Development. 1998. 12: 1260-1268. https://doi.org/10.1101/gad.12.9.1260
  6. Chambers TJ. Regulation of the differentiation and function of osteoclasts. Journal of Pathology. 2000. 192: 4-13. https://doi.org/10.1002/1096-9896(2000)9999:9999<::AID-PATH645>3.0.CO;2-Q
  7. Chellaiah M, Fitzgerald C, Alvarez U, Hruska K. C-Src is required for stimulation of gelsolin-associated phosphatidylinositol 3-kinase. Journal of Biological Chemistry. 1998. 273: 11908-11916. https://doi.org/10.1074/jbc.273.19.11908
  8. Darnay BG, Haridas V, Ni J, Moore PA, Aggarwal BB. Characterization of the intracellular domain of receptor activator of NFkappaB (RANK). interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappaB and c-Jun N-terminal kinase. Journal of Biological Chemistry. 1998. 273: 20551-20555. https://doi.org/10.1074/jbc.273.32.20551
  9. David JP, Sabapathy K, Hoffmann O, Idarraga MH, Wagner EF. JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms. Journal of Cell Science. 2002. 115: 4317-4325. https://doi.org/10.1242/jcs.00082
  10. Duran A, Serrano M, Leitges M, Flores JM, Picard S, Brown JP, Moscat J, Diaz-Meco MT. The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Developmental Cell. 2004. 6: 303-309. https://doi.org/10.1016/S1534-5807(03)00403-9
  11. Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, Elliott R, Scully S, Voura EB, Lacey DL, Boyle WJ, Khokha R, Penninger JM. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 2000. 103: 41-50. https://doi.org/10.1016/S0092-8674(00)00103-3
  12. Feng H, Cheng T, Steer JH, Joyce DA, Pavlos NJ, Leong C, Kular J, Liu J, Feng X, Zheng MH, Xu J. Myocyte enhancer factor2 and microphthalmia-associated transcription factor cooperate with NFATc1 to transactivate the V-ATPase d2 promoter during RANKL-induced osteoclastogenesis. Journal of Biological Chemistry. 2009. 284: 14667-14676. https://doi.org/10.1074/jbc.M901670200
  13. Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF, Siebenlist U. Requirement for NF-kappaB in osteoclast and B-cell development. Genes & Development. 1997. 11: 3482-3496. https://doi.org/10.1101/gad.11.24.3482
  14. Fuller K, Wong B, Fox S, Choi Y, Chambers TJ. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. Journal of Experimental Medicine. 1998. 188: 997-1001. https://doi.org/10.1084/jem.188.5.997
  15. Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996. 273: 1236-1238. https://doi.org/10.1126/science.273.5279.1236
  16. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002. 109: S81-96. https://doi.org/10.1016/S0092-8674(02)00703-1
  17. Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P, Debouck C, Kola I. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. Journal of Bone and Mineral Research. 1999. 14: 1654-1663. https://doi.org/10.1359/jbmr.1999.14.10.1654
  18. Grigoriadis AE, Wang ZQ, Cecchini MG, Hofstetter W, Felix R, Fleisch HA, Wagner EF. c-Fos: a key regulator of osteoclast macrophage lineage determination and bone remodeling. Science. 1994. 266: 443-448. https://doi.org/10.1126/science.7939685
  19. Hauer J, Puschner S, Ramakrishnan P, Simon U, Bongers M, Federle C, Engelmann H. TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAFbinding TNFRs. Proceedings of the National Academy of Sciences of the United States of America. 2005. 102: 2874-2879. https://doi.org/10.1073/pnas.0500187102
  20. Hayden MS, Ghosh S. Signaling to NF-kappa B. Genes & Development. 2004. 18: 2195-2224. https://doi.org/10.1101/gad.1228704
  21. He Y, Staser K, Rhodes SD, Liu Y, Wu X, Park SJ, Yuan J, Yang X, Li X, Jiang L, Chen S, Yang FC. Erk1 positively regulates osteoclast differentiation and bone resorptive activity. PLOS One. 2011. 6: e24780. https://doi.org/10.1371/journal.pone.0024780
  22. Inoue JI, Ishida T, Tsukamoto N, Kobayashi N, Naito A, Azuma S, Yamamoto T. Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Experimental Cell Research. 2000. 254: 14-24. https://doi.org/10.1006/excr.1999.4733
  23. Iotsova V, Caamano J, Loy J, Yang Y, Lewin A, Bravo R. Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nature Medicine. 1997. 3: 1285-1289. https://doi.org/10.1038/nm1197-1285
  24. Johnson MR, Polymeropoulos MH, Vos HL, Ortiz de Luna RI, Francomano CA. A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis. Genome Research. 1996. 6: 1050-1055. https://doi.org/10.1101/gr.6.11.1050
  25. Kanazawa K, Kudo A. TRAF2 is essential for TNF-alpha-induced osteoclastogenesis. Journal of Bone and Mineral Research. 2005. 20: 840-847.
  26. Kanazawa K, Azuma Y, Nakano H, Kudo A. TRAF5 functions in both RANKL- and TNF alpha-induced osteoclastogenesis. Journal of Bone and Mineral Research. 2003. 18: 443-450. https://doi.org/10.1359/jbmr.2003.18.3.443
  27. Kashiwada M, Shirakata Y, Inoue JI, Nakano H, Okazaki K, Okumura K, Yamamoto T, Nagaoka H, Takemori T. Tumor necrosis factor receptor-associated factor 6 (TRAF6) stimulates extracellular signal-regulated kinase (ERK) activity in CD40 signaling along a ras-independent pathway. Journal of Experimental Medicine. 1998. 187: 237-244. https://doi.org/10.1084/jem.187.2.237
  28. Kim N, Kadono Y, Takami M, Lee J, Lee SH, Okada F, Kim JH, Kobayashi T, Odgren PR, Nakano H, Yeh WC, Lee SK, Lorenzo JA, Choi Y. Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis. Journal of Experimental Medicine. 2005. 202: 589-595. https://doi.org/10.1084/jem.20050978
  29. Kim K, Lee SH, Ha KJ, Choi Y, Kim N. NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Molecular Endocrinology. 2008. 22: 176-185. https://doi.org/10.1210/me.2007-0237
  30. 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. The EMBO Journal. 2001. 20: 1271-1280. https://doi.org/10.1093/emboj/20.6.1271
  31. 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. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature. 2004. 428: 758-763. https://doi.org/10.1038/nature02444
  32. 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. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999. 397: 315-323. https://doi.org/10.1038/16852
  33. 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. 1998. 93: 165-176. https://doi.org/10.1016/S0092-8674(00)81569-X
  34. Lee NK, Choi YG, Baik JY, Han SY, Jeong DW, Bae YS, Kim N, Lee SY. A crucial role for reactive oxygen species in RANKLinduced osteoclast differentiation. Blood. 2005. 106: 852-859. https://doi.org/10.1182/blood-2004-09-3662
  35. Lee SE, Woo KM, Kim SY, Kim HM, Kwack K, Lee ZH, Kim HH. The phosphatidylinositol 3-kinase, p38, and extracellular signalregulated kinase pathways are involved in osteoclast differentiation. Bone. 2002. 30: 71-77.
  36. Li F, Matsuo K, Xing L, Boyce BF. Over-expression of activated NFATc1 plus RANKL rescues the osteoclastogenesis defect of NF-${\kappa}B$ p50/p52 double knockout splenocytes. Journal of Bone and Mineral Research. 2004. 19: S2. https://doi.org/10.1002/jbmr.5650191302
  37. Li X, Udagawa N, Itoh K, Suda K, Murase Y, Nishihara T, Suda T, Takahashi N. p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function. Endocrinology. 2002. 143: 3105-3113. https://doi.org/10.1210/endo.143.8.8954
  38. Lin J, Lee D, Choi Y, Lee SY. The scaffold protein RACK1 mediates the RANKL-dependent activation of p38 MAPK in osteoclast precursors. Science Signaling. 2015. 8: ra54. https://doi.org/10.1126/scisignal.2005867
  39. Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony S, 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 & Development. 1999. 13: 1015-1024. https://doi.org/10.1101/gad.13.8.1015
  40. Luchin A, Purdom G, Murphy K, Clark MY, Angel N, Cassady AI, Hume DA, Ostrowski MC. The microphthalmia transcription factor regulates expression of the tartrate-resistant acid phosphatase gene during terminal differentiation of osteoclasts. Journal of Bone and Mineral Research. 2000. 15: 451-460.
  41. Luchin A, Suchting S, Merson T, Rosol TJ, Hume DA, Cassady AI, Ostrowski MC. Genetic and physical interactions between microphthalmia transcription factor and PU.1 are necessary for osteoclast gene expression and differentiation. Journal of Biological Chemistry. 2001. 276: 36703-36710. https://doi.org/10.1074/jbc.M106418200
  42. Mansky KC, Sankar U, Han J, Ostrowski MC. Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling. Journal of Biological Chemistry. 2002. 277: 11077-11083. https://doi.org/10.1074/jbc.M111696200
  43. Marx J. Coming to grips with bone loss. Science. 2004. 305: 1420-1422. https://doi.org/10.1126/science.305.5689.1420
  44. Matsumoto M, Kogawa M, Wada S, Takayanagi H, Tsujimoto M, Katayama S, Hisatake K, Nogi Y. Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. Journal of Biological Chemistry. 2004. 279: 45969-45979. https://doi.org/10.1074/jbc.M408795200
  45. Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). Journal of Biological Chemistry. 2000. 275: 31155-31161. https://doi.org/10.1074/jbc.M001229200
  46. Matsuo K, Galson DL, Zhao C, Peng L, Laplace C, Wang KZ, Bachler MA, Amano H, Aburatani H, Ishikawa H, Wagner EF. Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. Journal of Biological Chemistry. 2004. 279: 26475-26480. https://doi.org/10.1074/jbc.M313973200
  47. Mizukami J, Takaesu G, Akatsuka H, Sakurai H, Ninomiya-Tsuji J, Matsumoto K, Sakurai N. Receptor activator of NF-kappaB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Molecular and Cellular Biology. 2002. 22: 992-1000. https://doi.org/10.1128/MCB.22.4.992-1000.2002
  48. Mocsai A, Humphrey MB, Van Ziffle JA, Hu Y, Burghardt A, Spusta SC, Majumdar S, Lanier LL, Lowell CA, Nakamura MC. The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proceedings of the National Academy of Sciences of the United States of America. 2004. 101: 6158-6163. https://doi.org/10.1073/pnas.0401602101
  49. Moon JB, Kim JH, Kim K, Youn BU, Ko A, Lee SY, Kim N. Akt induces osteoclast differentiation through regulating the $GSK3{\beta}$/NFATc1 signaling cascade. Journal of Immunology. 2012. 188: 163-169. https://doi.org/10.4049/jimmunol.1101254
  50. 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 signaling and lymph node organogenesis in TRAF6-deficient mice. Genes to Cells. 1999. 4: 353-362. https://doi.org/10.1046/j.1365-2443.1999.00265.x
  51. Novack DV, Yin L, Hagen-Stapleton A, Schreiber RD, Goeddel DV, Ross FP, Teitelbaum SL. The IkappaB function of NFkappaB2 p100 controls stimulated osteoclastogenesis. Journal of Experimental Medicine. 2003. 198: 771-781. https://doi.org/10.1084/jem.20030116
  52. Roberts HC, Knott L, Avery NC, Cox TM, Evans MJ, Hayman AR. Altered collagen in tartrate-resistant acid phosphatase (TRAP)-deficient mice: a role for TRAP in bone collagen metabolism. Calcified Tissue International. 2007. 80: 400-410. https://doi.org/10.1007/s00223-007-9032-2
  53. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997. 89: 309-319. https://doi.org/10.1016/S0092-8674(00)80209-3
  54. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocrine Review. 1999. 20: 345-357. https://doi.org/10.1210/edrv.20.3.0367
  55. Sugatani T, Alvarez U, Hruska KA. PTEN regulates RANKL- and osteopontin-stimulated signal transduction during osteoclast differentiation and cell motility. Journal of Biological Chemistry. 2003. 278: 5001-5008. https://doi.org/10.1074/jbc.M209299200
  56. 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. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Developmental Cell. 2002. 3: 889-901. https://doi.org/10.1016/S1534-5807(02)00369-6
  57. Takeshita S, Namba N, Zhao JJ, Jiang Y, Genant HK, Silva MJ, Brodt MD, Helgason CD, Kalesnikoff J, Rauh MJ, Humphries RK, Krystal G, Teitelbaum SL, Ross FP. SHIP-deficient mice are severely osteoporotic due to increased numbers of hyperresorptive osteoclasts. Nature Medicine. 2002. 8: 943-949. https://doi.org/10.1038/nm752
  58. Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000. 289:1504-1508. https://doi.org/10.1126/science.289.5484.1504
  59. Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochemistry Journal. 2000. 346: 561-576.
  60. Walsh MC, Choi Y. Biology of the TRANCE axis. Cytokine & Growth Factor Reviews. 2003. 14: 251-263. https://doi.org/10.1016/S1359-6101(03)00027-3
  61. 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. Molecular Cell. 1999. 4: 1041-1049. https://doi.org/10.1016/S1097-2765(00)80232-4
  62. Wong BR, Josien R, Lee SY, Sauter B, Li HL, Steinman RM, Choi Y. TRANCE (tumor necrosis factor [TNF]-related activationinduced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. Journal of Experimental Medicine. 1997. 186: 2075-2080. https://doi.org/10.1084/jem.186.12.2075
  63. Xing L, Bushnell TP, Carlson L, Tai Z, Tondravi M, Siebenlist U, Young F, Boyce BF. NF-kappaB p50 and p52 expression is not required for RANK expressing osteoclast progenitor formation but is essential for RANK- and cytokine mediated osteoclastogenesis. Journal of Bone and Mineral Research. 2002. 17. 1200-1210. https://doi.org/10.1359/jbmr.2002.17.7.1200
  64. Yamamoto A, Miyazaki T, Kadono Y, Takayanagi H, Miura T, Nishina H, Katada T, Wakabayashi K, Oda H, Nakamura K, Tanaka S. Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand. Journal of Bone and Mineral Research. 2002. 17: 612-621. https://doi.org/10.1359/jbmr.2002.17.4.612
  65. Yamashita T, Yao Z, Li F, Zhang Q, Badell IR, Schwarz EM, Takeshita S, Wagner EF, Noda M, Matsuo K, Xing L, Boyce BF. NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factorinduced osteoclast precursor differentiation by activating c-Fos and NFATc1. Journal of Biological Chemistry. 2007. 282:18245-18253. https://doi.org/10.1074/jbc.M610701200