IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro

Journal of Bone and Mineral Metabolism

Volumn 32, Issue 4, 2014, Pages 378-392

  Kaneshiro, Shoichi ^a   Ebina, Kosuke ^a   Shi, Kenrin ^a   Higuchi, Chikahisa ^a   Hirao, Makoto ^b   Okamoto, Michio ^a   Koizumi, Kota ^a   Morimoto, Tokimitsu ^a   Yoshikawa, Hideki ^a   Hashimoto, Jun ^b  

^a OSAKA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b MINAMI OSAKA GENERAL HOSPITAL   (Japan)

Author keywords

Akt2; Interleukin 6; MEK2; Osteoblast differentiation; Signaling pathway

Indexed keywords

INTERLEUKIN 6; INTERLEUKIN 6 RECEPTOR; JANUS KINASE; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE 2; OSTEOCALCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B BETA; PROTEIN SH2; SMALL INTERFERING RNA; STAT3 PROTEIN; TRANSCRIPTION FACTOR OSTERIX; TRANSCRIPTION FACTOR RUNX2; AKT2 PROTEIN, MOUSE; MAP2K2 PROTEIN, MOUSE; PROTEIN KINASE B; PROTEIN TYROSINE PHOSPHATASE SHP 2; PTPN11 PROTEIN, MOUSE;

3T3 CELL LINE; ANIMAL CELL; ARTICLE; BONE MINERALIZATION; CALVARIA; CELL DIFFERENTIATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME INHIBITION; GENE EXPRESSION; GENE SILENCING; IN VITRO STUDY; INTRACELLULAR SIGNALING; NONHUMAN; OSTEOBLAST; PRIORITY JOURNAL; REGULATORY MECHANISM; ANIMAL; BONE DEVELOPMENT; CELL LINE; CYTOLOGY; DRUG EFFECTS; METABOLISM; MOUSE;

ANIMALS; CELL DIFFERENTIATION; CELL LINE; INTERLEUKIN-6; MAP KINASE KINASE 2; MICE; OSTEOBLASTS; OSTEOGENESIS; PROTEIN TYROSINE PHOSPHATASE, NON-RECEPTOR TYPE 11; PROTO-ONCOGENE PROTEINS C-AKT;

EID: 84904574649     PISSN: 09148779     EISSN: 14355604     Source Type: Journal    
DOI: 10.1007/s00774-013-0514-1     Document Type: Article

References (58)

1. Hashizume M, Mihara M (2011) The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis. Arthritis 2011:765624
2. Ito A, Itoh Y, Sasaguri Y, Morimatsu M, Mori Y (1992) Effects of interleukin-6 on the metabolism of connective tissue components in rheumatoid synovial fibroblasts. Arthritis Rheum 35:1197-1201
3. Nishimoto N, Kishimoto T (2004) Inhibition of IL-6 for the treatment of inflammatory diseases. Curr Opin Pharmacol 4:386-391 (Pubitemid 38987066)
4. De Benedetti F, Robbioni P, Massa M, Viola S, Albani S, Martini A (1992) Serum interleukin-6 levels and joint involvement in polyarticular and pauciarticular juvenile chronic arthritis. Clin Exp Rheumatol 10:493-498
5. De Benedetti F, Massa M, Pignatti P, Albani S, Novick D, Martini A (1994) Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest 93:2114-2119
6. Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, Yamaguchi A, Kishimoto T, Suda T, Kashiwazaki S (1996) Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 11:88-95 (Pubitemid 26026748)
7. Kwan Tat S, Padrines M, Theoleyre S, Heymann D, Fortun Y (2004) IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology. Cytokine Growth Factor Rev 15:49-60
8. Palmqvist P, Persson E, Conaway HH, Lerner UH (2002) IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol 169:3353-3362 (Pubitemid 35013185)
9. Le Goff B, Blanchard F, Berthelot JM, Heymann D, Maugars Y (2010) Role for interleukin-6 in structural joint damage and systemic bone loss in rheumatoid arthritis. Joint Bone Spine 77:201-205
10. Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, Sato K, Shimizu M, Maini R, Feldmann M et al (1988) Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 18:1797-1801 (Pubitemid 19011590)
11. Ohshima S, Saeki Y, Mima T, Sasai M, Nishioka K, Nomura S, Kopf M, Katada Y, Tanaka T, Suemura M, Kishimoto T (1998) Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci USA 95:8222-8226 (Pubitemid 28326094)
12. Dasgupta B, Corkill M, Kirkham B, Gibson T, Panayi G (1992) Serial estimation of interleukin 6 as a measure of systemic disease in rheumatoid arthritis. J Rheumatol 19:22-25
13. Poli V, Balena R, Fattori E, Markatos A, Yamamoto M, Tanaka H, Ciliberto G, Rodan GA, Costantini F (1994) Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J 13:1189-1196 (Pubitemid 24074725)
14. Yang X, Ricciardi BF, Hernandez-Soria A, Shi Y, Pleshko Camacho N, Bostrom MP (2007) Callus mineralization and maturation are delayed during fracture healing in interleukin-6 knockout mice. Bone 41:928-936 (Pubitemid 350116738)
15. Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, Zinkernagel R, Bluethmann H, Kohler G (1994) Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368:339-342 (Pubitemid 24104268)
16. De Benedetti F, Rucci N, Del Fattore A, Peruzzi B, Paro R, Longo M, Vivarelli M, Muratori F, Berni S, Ballanti P, Ferrari S, Teti A (2006) Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum 54:3551-3563 (Pubitemid 44737167)
17. Naka T, Nishimoto N, Kishimoto T (2002) The paradigm of IL-6: from basic science to medicine. Arthritis Res 4(Suppl 3):S233-S242
18. Wong PK, Campbell IK, Egan PJ, Ernst M, Wicks IP (2003) The role of the interleukin-6 family of cytokines in inflammatory arthritis and bone turnover. Arthritis Rheum 48:1177-1189 (Pubitemid 36554516)
19. Garnero P, Thompson E, Woodworth T, Smolen JS (2010) Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis Rheum 62:33-43
20. Franchimont N, Wertz S, Malaise M (2005) Interleukin-6: an osteotropic factor influencing bone formation? Bone 37:601-606 (Pubitemid 41476382)
21. Li YP, Stashenko P (1992) Proinflammatory cytokines tumor necrosis factor-alpha and IL-6, but not IL-1, down-regulate the osteocalcin gene promoter. J Immunol 148:788-794
22. Peruzzi B, Cappariello A, Del Fattore A, Rucci N, De Benedetti F, Teti A (2012) c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling. Nat Commun 3:630
23. Hughes FJ, Howells GL (1993) Interleukin-6 inhibits bone formation in vitro. Bone Miner 21:21-28 (Pubitemid 23161155)
24. Nishimura R, Moriyama K, Yasukawa K, Mundy GR, Yoneda T (1998) Combination of interleukin-6 and soluble interleukin-6 receptors induces differentiation and activation of JAK-STAT and MAP kinase pathways in MG-63 human osteoblastic cells. J Bone Miner Res 13:777-785 (Pubitemid 28224193)
25. Taguchi Y, Yamamoto M, Yamate T, Lin SC, Mocharla H, DeTogni P, Nakayama N, Boyce BF, Abe E, Manolagas SC (1998) Interleukin-6-type cytokines stimulate mesenchymal progenitor differentiation toward the osteoblastic lineage. Proc Assoc Am Physicians 110:559-574 (Pubitemid 28516131)
26. Ishihara K, Hirano T (2002) Molecular basis of the cell specificity of cytokine action. Biochim Biophys Acta 1592:281-296 (Pubitemid 35284884)
27. Takahashi-Tezuka M, Yoshida Y, Fukada T, Ohtani T, Yamanaka Y, Nishida K, Nakajima K, Hibi M, Hirano T (1998) Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase. Mol Cell Biol 18:4109-4117 (Pubitemid 28287934)
28. Hideshima T, Nakamura N, Chauhan D, Anderson KC (2001) Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 20:5991-6000 (Pubitemid 32955041)
29. Tu Y, Gardner A, Lichtenstein A (2000) The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses. Cancer Res 60:6763-6770
30. Chung TD, Yu JJ, Kong TA, Spiotto MT, Lin JM (2000) Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis in human prostate cancer cell lines. Prostate 42:1-7 (Pubitemid 30004869)
31. Qiu Y, Robinson D, Pretlow TG, Kung HJ (1998) Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 30-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells. Proc Natl Acad Sci USA 95:3644-3649
32. Chen RH, Chang MC, Su YH, Tsai YT, Kuo ML (1999) Interleukin-6 inhibits transforming growth factor-beta-induced apoptosis through the phosphatidylinositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways. J Biol Chem 274:23013-23019
33. Schmidt K, Schinke T, Haberland M, Priemel M, Schilling AF, Mueldner C, Rueger JM, Sock E, Wegner M, Amling M (2005) The high mobility group transcription factor Sox8 is a negative regulator of osteoblast differentiation. J Cell Biol 168:899-910 (Pubitemid 40397004)
34. Ratisoontorn C, Seto ML, Broughton KM, Cunningham ML (2005) In vitro differentiation profile of osteoblasts derived from patients with Saethre-Chotzen syndrome. Bone 36:627-634 (Pubitemid 40602256)
35. Hellmuth K, Grosskopf S, Lum CT, Wurtele M, Roder N, von Kries JP, Rosario M, Rademann J, Birchmeier W (2008) Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking. Proc Natl Acad Sci USA 105:7275-7280 (Pubitemid 351754468)
36. Ernst M, Inglese M, Waring P, Campbell IK, Bao S, Clay FJ, Alexander WS, Wicks IP, Tarlinton DM, Novak U, Heath JK, Dunn AR (2001) Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. J Exp Med 194:189-203 (Pubitemid 32673352)
37. Itoh S, Udagawa N, Takahashi N, Yoshitake F, Narita H, Ebisu S, Ishihara K (2006) A critical role for interleukin-6 family-mediated Stat3 activation in osteoblast differentiation and bone formation. Bone 39:505-512 (Pubitemid 44149269)
38. Sims NA (2004) Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways. J Clin Investig 113:379-389
39. Kawamura N, Kugimiya F, Oshima Y, Ohba S, Ikeda T et al (2007) Akt1 in osteoblasts and osteoclasts controls bone remodeling. PLoS One 2:e1058
40. Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T, Roninson I, Weng W, Suzuki R, Tobe K, Kadowaki T, Hay N (2001) Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev 15:2203-2208 (Pubitemid 32843832)
41. Yang ZZ, Tschopp O, Hemmings-Mieszczak M, Feng J, Brodbeck D, Perentes E, Hemmings BA (2003) Protein kinase B alpha/Akt1 regulates placental development and fetal growth. J Biol Chem 278:32124-32131 (Pubitemid 37048402)
42. Vandoorne K, Magland J, Plaks V, Sharir A, Zelzer E, Wehrli F, Hemmings BA, Harmelin A, Neeman M (2010) Bone vascularization and trabecular bone formation are mediated by PKB alpha/Akt1 in a gene-dosage-dependent manner: in vivo and ex vivo MRI. Magn Reson Med 64:54-64
43. Choi YH, Choi HJ, Lee KY, Oh JW (2012) Akt1 regulates phosphorylation and osteogenic activity of Dlx3. Biochem Biophys Res Commun 425:800-805
44. Mukherjee A, Rotwein P (2012) Selective signaling by Akt1 controls osteoblast differentiation and osteoblast-mediated osteoclast development. Mol Cell Biol 32:490-500
45. Mukherjee A, Wilson EM, Rotwein P (2010) Selective signaling by Akt2 promotes bone morphogenetic protein 2-mediated osteoblast differentiation. Mol Cell Biol 30:1018-1027
46. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, Smith E, Bonadio J, Goldstein S, Gundberg C, Bradley A, Karsenty G (1996) Increased bone formation in osteocalcin-deficient mice. Nature 382:448-452 (Pubitemid 26264860)
47. Higuchi C, Myoui A, Hashimoto N, Kuriyama K, Yoshioka K, Yoshikawa H, Itoh K (2002) Continuous inhibition of MAPK signaling promotes the early osteoblastic differentiation and mineralization of the extracellular matrix. J Bone Miner Res 17:1785-1794
48. Chaudhary LR, Avioli LV (2000) Extracellular-signal regulated kinase signaling pathway mediates downregulation of type I procollagen gene expression by FGF-2, PDGF-BB, and okadaic acid in osteoblastic cells. J Cell Biochem 76:354-359 (Pubitemid 30078444)
49. Lin FH, Chang JB, Brigman BE (2011) Role of mitogen-activated protein kinase in osteoblast differentiation. J Orthop Res 29:204-210
50. Ge C, Xiao G, Jiang D, Franceschi RT (2007) Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J Cell Biol 176:709-718 (Pubitemid 46333984)
51. Matsushita T, Chan YY, Kawanami A, Balmes G, Landreth GE, Murakami S (2009) Extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis. Mol Cell Biol 29:5843-5857
52. Schindeler A, Little DG (2006) Ras-MAPK signaling in osteogenic differentiation: friend or foe? J Bone Miner Res 21:1331-1338 (Pubitemid 44300039)
53. Sims NA, Jenkins BJ, Quinn JM, Nakamura A, Glatt M, Gillespie MT, Ernst M, Martin TJ (2004) Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways. J Clin Invest 113:379-389 (Pubitemid 38544182)
54. Duplomb L, Baud'huin M, Charrier C, Berreur M, Trichet V, Blanchard F, Heymann D (2008) Interleukin-6 inhibits receptor activator of nuclear factor kappaB ligand-induced osteoclastogenesis by diverting cells into the macrophage lineage: key role of Serine727 phosphorylation of signal transducer and activator of transcription 3. Endocrinology 149:3688-3697 (Pubitemid 351919592)
55. Yamanaka Y, Nakajima K, Fukada T, Hibi M, Hirano T (1996) Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation. EMBO J 15:1557-1565 (Pubitemid 26112377)
56. Nakajima K, Yamanaka Y, Nakae K, Kojima H, Ichiba M, Kiuchi N, Kitaoka T, Fukada T, Hibi M, Hirano T (1996) A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J 15:3651-3658 (Pubitemid 26239777)
57. Hirano T, Matsuda T, Nakajima K (1994) Signal transduction through gp130 that is shared among the receptors for the interleukin 6 related cytokine subfamily. Stem Cells 12:262-277
58. Krause A, Scaletta N, Ji JD, Ivashkiv LB (2002) Rheumatoid arthritis synoviocyte survival is dependent on Stat3. J Immunol 169:6610-6616 (Pubitemid 36903515)