Drugs

, Volume 73, Issue 2, pp 101–115 | Cite as

Mitogen-Activated Protein Kinases as Therapeutic Targets for Rheumatoid Arthritis

Leading Article

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which imbalances in pro- and anti-inflammatory cytokines promote the induction of autoimmunity, inflammation and joint destruction. Methotrexate, the standard disease-modifying anti-rheumatic drug (DMARD), has shown a gradual loss of efficacy in a significant proportion of patients, probably due to the onset of drug resistance, and thus it was hoped that the development of biologics would revolutionise RA management. Even though biologics have improved the therapy of patients refractive to DMARDs, they require parenteral administration and may leave patients open to serious infection and cancer. Therefore, attention has also been focused on inhibitors of mitogen-activated protein kinases (MAPKs), signalling enzymes that play key roles in pathogenic cytokine production, and their downstream effector pathways, in order to create safe and effective oral drugs. This article therefore provides an overview of the structure and function of MAPKs and their role in the pathogenesis of RA as context to describing the advances in the development of specific, druggable MAPK inhibitors. Their potential as therapies in the management of RA is also discussed.

Notes

Acknowledgments

Both authors planned, drafted and revised the manuscript in collaboration. They thank the UK Medical Research Council for their support and declare no conflict of interest.

References

  1. 1.
    McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19.PubMedCrossRefGoogle Scholar
  2. 2.
    McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429–42.PubMedCrossRefGoogle Scholar
  3. 3.
    Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 2008;118(11):3537–45.PubMedCrossRefGoogle Scholar
  4. 4.
    Cai L, Yin JP, Starovasnik MA, Hogue DA, Hillan KJ, Mort JS, et al. Pathways by which interleukin 17 induces articular cartilage breakdown in vitro and in vivo. Cytokine. 2001;16(1):10–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Muller-Ladner U, Pap T, Gay RE, Neidhart M, Gay S. Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2005;1(2):102–10.PubMedCrossRefGoogle Scholar
  6. 6.
    Zhou FH, Foster BK, Zhou XF, Cowin AJ, Xian CJ. TNF-alpha mediates p38 MAP kinase activation and negatively regulates bone formation at the injured growth plate in rats. J Bone Miner Res. 2006;21(7):1075–88.PubMedCrossRefGoogle Scholar
  7. 7.
    Thompson RN, Watts C, Edelman J, Esdaile J, Russell AS. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol. 1984;11(6):760–3.PubMedGoogle Scholar
  8. 8.
    Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med. 1985;312(13):818–22.PubMedCrossRefGoogle Scholar
  9. 9.
    Williams HJ, Willkens RF, Samuelson CO Jr, Alarcon GS, Guttadauria M, Yarboro C, et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthr Rheum. 1985;28(7):721–30.CrossRefGoogle Scholar
  10. 10.
    Morgan C, Lunt M, Brightwell H, Bradburn P, Fallow W, Lay M, et al. Contribution of patient related differences to multidrug resistance in rheumatoid arthritis. Ann Rheum Dis. 2003;62(1):15–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Scott DL. Biologics-based therapy for the treatment of rheumatoid arthritis. Clin Pharmacol Ther. 2012;91(1):30–43.PubMedCrossRefGoogle Scholar
  12. 12.
    Hot A, Miossec P. Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes. Ann Rheum Dis. 2011;70(5):727–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Kumar S, Boehm J, Lee JC. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov. 2003;2(9):717–26.PubMedCrossRefGoogle Scholar
  14. 14.
    Cohen S. Small molecular therapies for rheumatoid arthritis: where do we stand? Expert Opin Investig Drugs. 2012;21(1):23–31.PubMedCrossRefGoogle Scholar
  15. 15.
    Liu JO. The yins of T cell activation. Sci STKE. 2005;4(265):re1.Google Scholar
  16. 16.
    Harnett MM, Katz E, Ford CA. Differential signalling during B-cell maturation. Immunol Lett. 2005;98(1):33–44.PubMedCrossRefGoogle Scholar
  17. 17.
    Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004;21(4):467–76.PubMedCrossRefGoogle Scholar
  18. 18.
    Goodridge HS, Harnett W, Liew FY, Harnett MM. Differential regulation of interleukin-12 p40 and p35 induction via Erk mitogen-activated protein kinase-dependent and -independent mechanisms and the implications for bioactive IL-12 and IL-23 responses. Immunology. 2003;109(3):415–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Feng GJ, Goodridge HS, Harnett MM, Wei XQ, Nikolaev AV, Higson AP, et al. Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP kinase. J Immunol. 1999;163(12):6403–12.PubMedGoogle Scholar
  20. 20.
    Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372(6508):739–46.PubMedCrossRefGoogle Scholar
  21. 21.
    Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Annu Rev Immunol. 2002;20:55–72.PubMedCrossRefGoogle Scholar
  22. 22.
    Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22(2):153–83.PubMedCrossRefGoogle Scholar
  23. 23.
    Canagarajah BJ, Khokhlatchev A, Cobb MH, Goldsmith EJ. Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell. 1997;90(5):859–69.PubMedCrossRefGoogle Scholar
  24. 24.
    Turjanski AG, Vaque JP, Gutkind JS. MAP kinases and the control of nuclear events. Oncogene. 2007;26(22):3240–53.PubMedCrossRefGoogle Scholar
  25. 25.
    Biondi RM, Nebreda AR. Signalling specificity of Ser/Thr protein kinases through docking-site-mediated interactions. Biochem J. 2003;372(Pt 1):1–13.PubMedCrossRefGoogle Scholar
  26. 26.
    Tanoue T, Nishida E. Molecular recognitions in the MAP kinase cascades. Cell Signal. 2003;15(5):455–62.PubMedCrossRefGoogle Scholar
  27. 27.
    Akella R, Moon TM, Goldsmith EJ. Unique MAP Kinase binding sites. Biochim Biophys Acta. 2008;1784(1):48–55.PubMedCrossRefGoogle Scholar
  28. 28.
    Powers JC, Asgian JL, Ekici OD, James KE. Irreversible inhibitors of serine, cysteine, and threonine proteases. Chem Rev. 2002;102(12):4639–750.PubMedCrossRefGoogle Scholar
  29. 29.
    Morrison DK, Davis RJ. Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu Rev Cell Dev Biol. 2003;19:91–118.PubMedCrossRefGoogle Scholar
  30. 30.
    Raman M, Chen W, Cobb MH. Differential regulation and properties of MAPKs. Oncogene. 2007;26(22):3100–12.PubMedCrossRefGoogle Scholar
  31. 31.
    Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993;7(11):2135–48.PubMedCrossRefGoogle Scholar
  32. 32.
    Ortega-Perez I, Cano E, Were F, Villar M, Vazquez J, Redondo JM. c-Jun N-terminal kinase (JNK) positively regulates NFATc2 transactivation through phosphorylation within the N-terminal regulatory domain. J Biol Chem. 2005;280(21):20867–78.PubMedCrossRefGoogle Scholar
  33. 33.
    Cavigelli M, Dolfi F, Claret FX, Karin M. Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. EMBO J. 1995;14(23):5957–64.PubMedGoogle Scholar
  34. 34.
    van Dam H, Wilhelm D, Herr I, Steffen A, Herrlich P, Angel P. ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. EMBO J. 1995;14(8):1798–811.PubMedGoogle Scholar
  35. 35.
    Treisman R. Journey to the surface of the cell: Fos regulation and the SRE. EMBO J. 1995;14(20):4905–13.PubMedGoogle Scholar
  36. 36.
    Fuchs SY, Adler V, Pincus MR, Ronai Z. MEKK1/JNK signaling stabilizes and activates p53. Proc Natl Acad Sci USA. 1998;95(18):10541–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Lu G, Kang YJ, Han J, Herschman HR, Stefani E, Wang Y. TAB-1 modulates intracellular localization of p38 MAP kinase and downstream signaling. J Biol Chem. 2006;281(9):6087–95.PubMedCrossRefGoogle Scholar
  38. 38.
    Saxena M, Mustelin T. Extracellular signals and scores of phosphatases: all roads lead to MAP kinase. Semin Immunol. 2000;12(4):387–96.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhou B, Wang ZX, Zhao Y, Brautigan DL, Zhang ZY. The specificity of extracellular signal-regulated kinase 2 dephosphorylation by protein phosphatases. J Biol Chem. 2002;277(35):31818–25.PubMedCrossRefGoogle Scholar
  40. 40.
    Camps M, Nichols A, Arkinstall S. Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J. 2000;14(1):6–16.PubMedGoogle Scholar
  41. 41.
    Masuda K, Shima H, Watanabe M, Kikuchi K. MKP-7, a novel mitogen-activated protein kinase phosphatase, functions as a shuttle protein. J Biol Chem. 2001;276(42):39002–11.PubMedCrossRefGoogle Scholar
  42. 42.
    Karlsson M, Mathers J, Dickinson RJ, Mandl M, Keyse SM. Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal. J Biol Chem. 2004;279(40):41882–91.PubMedCrossRefGoogle Scholar
  43. 43.
    Jeffrey KL, Brummer T, Rolph MS, Liu SM, Callejas NA, Grumont RJ, et al. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol. 2006;7(3):274–83.PubMedCrossRefGoogle Scholar
  44. 44.
    Fransen J, van Riel PL. Outcome measures in inflammatory rheumatic diseases. Arthr Res Ther. 2009;11(5):244.CrossRefGoogle Scholar
  45. 45.
    Nah SS, Won HJ, Ha E, Kang I, Cho HY, Hur SJ, et al. Epidermal growth factor increases prostaglandin E2 production via ERK1/2 MAPK and NF-kappaB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis. Rheumatol Int. 2010;30(4):443–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Yoo JK, Kwon H, Khil LY, Zhang L, Jun HS, Yoon JW. IL-18 induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways. J Immunol. 2005;175(12):8280–6.PubMedGoogle Scholar
  47. 47.
    Kim YG, Lee CK, Kim SH, Cho WS, Mun SH, Yoo B. Interleukin-32gamma enhances the production of IL-6 and IL-8 in fibroblast-like synoviocytes via Erk1/2 activation. J Clin Immunol. 2010;30(2):260–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Schett G, Tohidast-Akrad M, Smolen JS, Schmid BJ, Steiner CW, Bitzan P, et al. Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthr Rheum. 2000;43(11):2501–12.CrossRefGoogle Scholar
  49. 49.
    Geppert TD, Whitehurst CE, Thompson P, Beutler B. Lipopolysaccharide signals activation of tumor necrosis factor biosynthesis through the ras/raf-1/MEK/MAPK pathway. Mol Med. 1994;1(1):93–103.PubMedGoogle Scholar
  50. 50.
    Barchowsky A, Frleta D, Vincenti MP. Integration of the NF-kappaB and mitogen-activated protein kinase/AP-1 pathways at the collagenase-1 promoter: divergence of IL-1 and TNF-dependent signal transduction in rabbit primary synovial fibroblasts. Cytokine. 2000;12(10):1469–79.PubMedCrossRefGoogle Scholar
  51. 51.
    Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest. 2001;108(1):73–81.PubMedGoogle Scholar
  52. 52.
    Pelletier JP, Fernandes JC, Brunet J, Moldovan F, Schrier D, Flory C, et al. In vivo selective inhibition of mitogen-activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes. Arthr Rheum. 2003;48(6):1582–93.CrossRefGoogle Scholar
  53. 53.
    Liacini A, Sylvester J, Li WQ, Huang W, Dehnade F, Ahmad M, et al. Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes. Exp Cell Res. 2003;288(1):208–17.PubMedCrossRefGoogle Scholar
  54. 54.
    Thiel MJ, Schaefer CJ, Lesch ME, Mobley JL, Dudley DT, Tecle H, et al. Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms. Arthr Rheum. 2007;56(10):3347–57.CrossRefGoogle Scholar
  55. 55.
    Singh K, Deshpande P, Pryshchep S, Colmegna I, Liarski V, Weyand CM, et al. ERK-dependent T cell receptor threshold calibration in rheumatoid arthritis. J Immunol. 2009;183(12):8258–67.PubMedCrossRefGoogle Scholar
  56. 56.
    Lindstrom TM, Robinson WH. A multitude of kinases: which are the best targets in treating rheumatoid arthritis? Rheum Dis Clin North Am. 2010;36(2):367–83.PubMedCrossRefGoogle Scholar
  57. 57.
    Ohori M, Kinoshita T, Okubo M, Sato K, Yamazaki A, Arakawa H, et al. Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex. Biochem Biophys Res Commun. 2005;336(1):357–63.PubMedCrossRefGoogle Scholar
  58. 58.
    Ohori M. ERK inhibitors as a potential new therapy for rheumatoid arthritis. Drug News Perspect. 2008;21(5):245–50.PubMedCrossRefGoogle Scholar
  59. 59.
    Ohori M, Takeuchi M, Maruki R, Nakajima H, Miyake H. FR180204, a novel and selective inhibitor of extracellular signal-regulated kinase, ameliorates collagen-induced arthritis in mice. Naunyn Schmiedebergs Arch Pharmacol. 2007;374(4):311–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Das S, Cho J, Lambertz I, Kelliher MA, Eliopoulos AG, Du K, et al. Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and stimulus-specific manner. J Biol Chem. 2005;280(25):23748–57.PubMedCrossRefGoogle Scholar
  61. 61.
    Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH, et al. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell. 2000;103(7):1071–83.PubMedCrossRefGoogle Scholar
  62. 62.
    Hall JP, Kurdi Y, Hsu S, Cuozzo J, Liu J, Telliez JB, et al. Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood. J Biol Chem. 2007;282(46):33295–304.PubMedCrossRefGoogle Scholar
  63. 63.
    Green N, Hu Y, Janz K, Li HQ, Kaila N, Guler S, et al. Inhibitors of tumor progression loci-2 (Tpl2) kinase and tumor necrosis factor alpha (TNF-alpha) production: selectivity and in vivo antiinflammatory activity of novel 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles. J Med Chem. 2007;50(19):4728–45.PubMedCrossRefGoogle Scholar
  64. 64.
    Liacini A, Sylvester J, Li WQ, Zafarullah M. Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biol. 2002;21(3):251–62.PubMedCrossRefGoogle Scholar
  65. 65.
    Sundarrajan M, Boyle DL, Chabaud-Riou M, Hammaker D, Firestein GS. Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK. Arthr Rheum. 2003;48(9):2450–60.CrossRefGoogle Scholar
  66. 66.
    Inoue T, Hammaker D, Boyle DL, Firestein GS. Regulation of JNK by MKK-7 in fibroblast-like synoviocytes. Arthr Rheum. 2006;54(7):2127–35.CrossRefGoogle Scholar
  67. 67.
    Lee SI, Boyle DL, Berdeja A, Firestein GS. Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway. Arthr Res Ther. 2012;14(1):R38.CrossRefGoogle Scholar
  68. 68.
    Maroney AC, Finn JP, Bozyczko-Coyne D, O’Kane TM, Neff NT, Tolkovsky AM, et al. CEP-1347 (KT7515), an inhibitor of JNK activation, rescues sympathetic neurons and neuronally differentiated PC12 cells from death evoked by three distinct insults. J Neurochem. 1999;73(5):1901–12.PubMedGoogle Scholar
  69. 69.
    Maroney AC, Finn JP, Connors TJ, Durkin JT, Angeles T, Gessner G, et al. Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J Biol Chem. 2001;276(27):25302–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Cui J, Zhang M, Zhang YQ, Xu ZH. JNK pathway: diseases and therapeutic potential. Acta Pharmacol Sin. 2007;28(5):601–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Wang W, Ma C, Mao Z, Li M. JNK inhibition as a potential strategy in treating Parkinson’s disease. Drug News Perspect. 2004;17(10):646–54.PubMedCrossRefGoogle Scholar
  72. 72.
    Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA. 2001;98(24):13681–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Ruckle T, Biamonte M, Grippi-Vallotton T, Arkinstall S, Cambet Y, Camps M, et al. Design, synthesis, and biological activity of novel, potent, and selective (benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-terminal kinase. J Med Chem. 2004;47(27):6921–34.PubMedCrossRefGoogle Scholar
  74. 74.
    Gaillard P, Jeanclaude-Etter I, Ardissone V, Arkinstall S, Cambet Y, Camps M, et al. Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase. J Med Chem. 2005;48(14):4596–607.PubMedCrossRefGoogle Scholar
  75. 75.
    Denninger K, Rasmussen S, Larsen JM, Orskov C, Seier Poulsen S, Sorensen P, et al. JNK1, but not JNK2, is required in two mechanistically distinct models of inflammatory arthritis. Am J Pathol. 2011;179(4):1884–93.PubMedCrossRefGoogle Scholar
  76. 76.
    Koller M, Hayer S, Redlich K, Ricci R, David JP, Steiner G, et al. JNK1 is not essential for TNF-mediated joint disease. Arthr Res Ther. 2005;7(1):R166–73.CrossRefGoogle Scholar
  77. 77.
    Gee E, Milkiewicz M, Haas TL. p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress-induced angiogenesis. J Cell Physiol. 2010;222(1):120–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Rousseau D, Cannella D, Boulaire J, Fitzgerald P, Fotedar A, Fotedar R. Growth inhibition by CDK-cyclin and PCNA binding domains of p21 occurs by distinct mechanisms and is regulated by ubiquitin-proteasome pathway. Oncogene. 1999;18(30):4313–25.PubMedCrossRefGoogle Scholar
  79. 79.
    Duch A, de Nadal E, Posas F. The p38 and Hog1 SAPKs control cell cycle progression in response to environmental stresses. FEBS Lett. 2012;586(18):2925–31.PubMedCrossRefGoogle Scholar
  80. 80.
    Joaquin M, Gubern A, Gonzalez-Nunez D, Josue Ruiz E, Ferreiro I, de Nadal E, et al. The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress. EMBO J. 2012;31(13):2952–64.PubMedCrossRefGoogle Scholar
  81. 81.
    Yoshizuka N, Chen RM, Xu Z, Liao R, Hong L, Hu WY, et al. A novel function of p38-regulated/activated kinase in endothelial cell migration and tumor angiogenesis. Mol Cell Biol. 2012;32(3):606–18.PubMedCrossRefGoogle Scholar
  82. 82.
    Lee JC, Young PR. Role of CSB/p38/RK stress response kinase in LPS and cytokine signaling mechanisms. J Leukoc Biol. 1996;59(2):152–7.PubMedGoogle Scholar
  83. 83.
    Tokuda H, Kanno Y, Ishisaki A, Takenaka M, Harada A, Kozawa O. Interleukin (IL)-17 enhances tumor necrosis factor-alpha-stimulated IL-6 synthesis via p38 mitogen-activated protein kinase in osteoblasts. J Cell Biochem. 2004;91(5):1053–61.PubMedCrossRefGoogle Scholar
  84. 84.
    Westra J, Limburg PC, de Boer P, van Rijswijk MH. Effects of RWJ 67657, a p38 mitogen activated protein kinase (MAPK) inhibitor, on the production of inflammatory mediators by rheumatoid synovial fibroblasts. Ann Rheum Dis. 2004;63(11):1453–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Campbell J, Ciesielski CJ, Hunt AE, Horwood NJ, Beech JT, Hayes LA, et al. A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. J Immunol. 2004;173(11):6928–37.PubMedGoogle Scholar
  86. 86.
    Young P, McDonnell P, Dunnington D, Hand A, Laydon J, Lee J. Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level. Agents Actions. 1993;39 Spec No:C67–9.Google Scholar
  87. 87.
    Baldassare JJ, Bi Y, Bellone CJ. The role of p38 mitogen-activated protein kinase in IL-1 beta transcription. J Immunol. 1999;162(9):5367–73.PubMedGoogle Scholar
  88. 88.
    Chae HJ, Chae SW, Chin HY, Bang BG, Cho SB, Han KS, et al. The p38 mitogen-activated protein kinase pathway regulates interleukin-6 synthesis in response to tumor necrosis factor in osteoblasts. Bone. 2001;28(1):45–53.PubMedCrossRefGoogle Scholar
  89. 89.
    Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL. IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest. 2005;115(2):282–90.PubMedGoogle Scholar
  90. 90.
    Rossa C, Ehmann K, Liu M, Patil C, Kirkwood KL. MKK3/6-p38 MAPK signaling is required for IL-1beta and TNF-alpha-induced RANKL expression in bone marrow stromal cells. J Interferon Cytokine Res. 2006;26(10):719–29.PubMedCrossRefGoogle Scholar
  91. 91.
    Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, et al. IL-6 is produced by osteoblasts and induces bone resorption. J Immunol. 1990;145(10):3297–303.PubMedGoogle Scholar
  92. 92.
    Thouverey C, Caverzasio J. The p38alpha MAPK positively regulates osteoblast function and postnatal bone acquisition. Cell Mol Life Sci. 2012;69(18):3115–25.PubMedCrossRefGoogle Scholar
  93. 93.
    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). J Biol Chem. 2000;275(40):31155–61.PubMedCrossRefGoogle Scholar
  94. 94.
    McLay LM, Halley F, Souness JE, McKenna J, Benning V, Birrell M, et al. The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy. Bioorg Med Chem. 2001;9(2):537–54.PubMedCrossRefGoogle Scholar
  95. 95.
    Mbalaviele G, Anderson G, Jones A, De Ciechi P, Settle S, Mnich S, et al. Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. J Pharmacol Exp Ther. 2006;317(3):1044–53.PubMedCrossRefGoogle Scholar
  96. 96.
    Medicherla S, Ma JY, Mangadu R, Jiang Y, Zhao JJ, Almirez R, et al. A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis. J Pharmacol Exp Ther. 2006;318(1):132–41.PubMedCrossRefGoogle Scholar
  97. 97.
    Nishikawa M, Myoui A, Tomita T, Takahi K, Nampei A, Yoshikawa H. Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthr Rheum. 2003;48(9):2670–81.CrossRefGoogle Scholar
  98. 98.
    Badger AM, Griswold DE, Kapadia R, Blake S, Swift BA, Hoffman SJ, et al. Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthr Rheum. 2000;43(1):175–83.CrossRefGoogle Scholar
  99. 99.
    Korb A, Tohidast-Akrad M, Cetin E, Axmann R, Smolen J, Schett G. Differential tissue expression and activation of p38 MAPK alpha, beta, gamma, and delta isoforms in rheumatoid arthritis. Arthr Rheum. 2006;54(9):2745–56.CrossRefGoogle Scholar
  100. 100.
    Fijen JW, Zijlstra JG, De Boer P, Spanjersberg R, Tervaert JW, Van Der Werf TS, et al. Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers. Clin Exp Immunol. 2001;124(1):16–20.PubMedCrossRefGoogle Scholar
  101. 101.
    Parasrampuria DA, de Boer P, Desai-Krieger D, Chow AT, Jones CR. Single-dose pharmacokinetics and pharmacodynamics of RWJ 67657, a specific p38 mitogen-activated protein kinase inhibitor: a first-in-human study. J Clin Pharmacol. 2003;43(4):406–13.PubMedCrossRefGoogle Scholar
  102. 102.
    Genovese MC, Cohen SB, Wofsy D, Weinblatt ME, Firestein GS, Brahn E, et al. A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis. J Rheumatol. 2011;38(5):846–54.PubMedCrossRefGoogle Scholar
  103. 103.
    Haddad JJ. VX-745. Vertex pharmaceuticals. Curr Opin Investig Drugs. 2001;2(8):1070–6.PubMedGoogle Scholar
  104. 104.
    Damjanov N, Kauffman RS, Spencer-Green GT. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies. Arthr Rheum. 2009;60(5):1232–41.CrossRefGoogle Scholar
  105. 105.
    Goldstein DM, Kuglstatter A, Lou Y, Soth MJ. Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J Med Chem. 2010;53(6):2345–53.PubMedCrossRefGoogle Scholar
  106. 106.
    Schreiber S, Feagan B, D’Haens G, Colombel JF, Geboes K, Yurcov M, et al. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006;4(3):325–34.PubMedCrossRefGoogle Scholar
  107. 107.
    Hill RJ, Dabbagh K, Phippard D, Li C, Suttmann RT, Welch M, et al. Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. J Pharmacol Exp Ther. 2008;327(3):610–9.PubMedCrossRefGoogle Scholar
  108. 108.
    Cohen SB, Cheng TT, Chindalore V, Damjanov N, Burgos-Vargas R, Delora P, et al. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthr Rheum. 2009;60(2):335–44.CrossRefGoogle Scholar
  109. 109.
    Lee MR, Dominguez C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem. 2005;12(25):2979–94.PubMedCrossRefGoogle Scholar
  110. 110.
    Fabbro D, Ruetz S, Buchdunger E, Cowan-Jacob SW, Fendrich G, Liebetanz J, et al. Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacol Ther. 2002;93(2–3):79–98.PubMedCrossRefGoogle Scholar
  111. 111.
    Fischer S, Koeberle SC, Laufer SA. p38alpha mitogen-activated protein kinase inhibitors, a patent review (2005–2011). Expert Opin Ther Pat. 2011;21(12):1843–66.PubMedCrossRefGoogle Scholar
  112. 112.
    Angell RM, Angell TD, Bamborough P, Bamford MJ, Chung CW, Cockerill SG, et al. Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes. Bioorg Med Chem Lett. 2008;18(15):4433–7.PubMedCrossRefGoogle Scholar
  113. 113.
    Badger AM, Bradbeer JN, Votta B, Lee JC, Adams JL, Griswold DE. Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther. 1996;279(3):1453–61.PubMedGoogle Scholar
  114. 114.
    Borsch-Haubold AG, Pasquet S, Watson SP. Direct inhibition of cyclooxygenase-1 and -2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase. J Biol Chem. 1998;273(44):28766–72.PubMedCrossRefGoogle Scholar
  115. 115.
    Goldstein DM, Gabriel T. Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development. Curr Top Med Chem. 2005;5(10):1017–29.PubMedCrossRefGoogle Scholar
  116. 116.
    Pettus LH, Wurz RP, Xu S, Herberich B, Henkle B, Liu Q, et al. Discovery and evaluation of 7-alkyl-1,5-bis-aryl-pyrazolopyridinones as highly potent, selective, and orally efficacious inhibitors of p38alpha mitogen-activated protein kinase. J Med Chem. 2010;53(7):2973–85.PubMedCrossRefGoogle Scholar
  117. 117.
    Nikas SN, Drosos AA. SCIO-469 Scios Inc. Curr Opin Investig Drugs. 2004;5(11):1205–12.PubMedGoogle Scholar
  118. 118.
    Mavunkel BJ, Chakravarty S, Perumattam JJ, Luedtke GR, Liang X, Lim D, et al. Indole-based heterocyclic inhibitors of p38alpha MAP kinase: designing a conformationally restricted analogue. Bioorg Med Chem Lett. 2003;13(18):3087–90.PubMedCrossRefGoogle Scholar
  119. 119.
    Genovese MC. Inhibition of p38: has the fat lady sung? Arthr Rheum. 2009;60(2):317–20.CrossRefGoogle Scholar
  120. 120.
    Schieven GL. The p38alpha kinase plays a central role in inflammation. Curr Top Med Chem. 2009;9(11):1038–48.PubMedCrossRefGoogle Scholar
  121. 121.
    Tong SE, Daniels SE, Black P, Chang S, Protter A, Desjardins PJ. Novel p38alpha mitogen-activated protein kinase inhibitor shows analgesic efficacy in acute postsurgical dental pain. J Clin Pharmacol. 2012;52(5):717–28.PubMedCrossRefGoogle Scholar
  122. 122.
    Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, et al. Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem. 2003;86(6):1534–44.PubMedCrossRefGoogle Scholar
  123. 123.
    Ji RR, Suter MR. p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain. 2007;3:33.PubMedCrossRefGoogle Scholar
  124. 124.
    Weisman MH. Newly diagnosed rheumatoid arthritis. Ann Rheum Dis. 2002;61(4):287–9.PubMedCrossRefGoogle Scholar
  125. 125.
    Karcher SC, Laufer SA. Successful structure-based design of recent p38 MAP kinase inhibitors. Curr Top Med Chem. 2009;9(7):655–76.PubMedCrossRefGoogle Scholar
  126. 126.
    Vertex moves to re-allocate resources from VX-745 in p38 MAP kinase program to accelerate development of second generation drug candidates VX-702 and VX-850 (media release). 24 Sep 2012 (online). http://www.prnewswire.com/news-releases/vertex-moves-to-re-allocate-resources-from-vx-745-in-p38-map-kinase-program-to-accelerate-development-of-second-generation-drug-candidates-vx-702-and-vx-850-72104487.html. Accessed 11 Jan 2013.
  127. 127.
    Vertext pharmaceuticals reports third quarter 2001 financial results (media release). 24 Oct 2001 (online). http://investors.vrtx.com/releasedetail.cfm?releaseid=62799. Accessed 11 Jan 2013.
  128. 128.
    Vertext pharmaceuticals initiates phase II clinical study in rheumatoid arthritis with investigational oral p38 MAP kinase inhibitor VX-702 (media release). 10 June 2005. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=233067. Accessed 11 Jan 2013.
  129. 129.
    Isoquinoline inhibitors of p38: EPO patent EP1414455 http://patent.ipexl.com/EP/EP1414455.html. Accessed 11 Jan 2013.
  130. 130.
    Trejo A, Arzeno H, Browner M, Chanda S, Cheng S, Comer DD, et al. Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase. J Med Chem. 2003;46(22):4702–13.PubMedCrossRefGoogle Scholar
  131. 131.
    Alten RE, Zerbini C, Jeka S, Irazoque F, Khatib F, Emery P, et al. Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy. Ann Rheum Dis. 2010;69(2):364–7.PubMedCrossRefGoogle Scholar
  132. 132.
    Aston NM, Bamborough P, Buckton JB, Edwards CD, Holmes DS, Jones KL, et al. p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression. J Med Chem. 2009;52(20):6257–69.PubMedCrossRefGoogle Scholar
  133. 133.
    Ostenfeld T, Krishen A, Lai RY, Bullman J, Baines AJ, Green J, Anand P, Kelly M. Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study. Eur J Pain. 2012. doi: 10.1002/j.1532-2149.2012.00256.x.
  134. 134.
  135. 135.
    Kim C, Cheng CY, Saldanha SA, Taylor SS. PKA-I holoenzyme structure reveals a mechanism for cAMP-dependent activation. Cell. 2007;130(6):1032–43.PubMedCrossRefGoogle Scholar
  136. 136.
    Kim C, Sano Y, Todorova K, Carlson BA, Arpa L, Celada A, et al. The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nat Immunol. 2008;9(9):1019–27.PubMedCrossRefGoogle Scholar
  137. 137.
    Cheung PC, Campbell DG, Nebreda AR, Cohen P. Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha. EMBO J. 2003;22(21):5793–805.PubMedCrossRefGoogle Scholar
  138. 138.
    Opar A. Kinase inhibitors attract attention as oral rheumatoid arthritis drugs. Nat Rev Drug Discov. 2010;9(4):257–8.PubMedCrossRefGoogle Scholar
  139. 139.
    Koeberle SC, Romir J, Fischer S, Koeberle A, Schattel V, Albrecht W, et al. Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor. Nat Chem Biol. 2012;8(2):141–3.CrossRefGoogle Scholar
  140. 140.
    Hammaker D, Firestein GS. “Go upstream, young man”: lessons learned from the p38 saga. Ann Rheum Dis. 2010;69(Suppl. 1):i77–82.PubMedCrossRefGoogle Scholar
  141. 141.
    Bonilla-Hernan MG, Miranda-Carus ME, Martin-Mola E. New drugs beyond biologics in rheumatoid arthritis: the kinase inhibitors. Rheumatology (Oxford). 2011;50(9):1542–50.CrossRefGoogle Scholar
  142. 142.
    Schieven GL, Zhang RF, Pitt S, Shen DR, Cao J, Sack J, et al. BMS-582949 is a dual action p38 kinase inhibitor well suited to avoid resistance mechanisms that increase p38 activation in cells. Arthr Rheum. 2010;62(10 Suppl.):S629–30.Google Scholar
  143. 143.
    Genovese MC, Gao L, Yin J, Smith S, Weinblatt ME, Smolen JS, et al. Proof of concept study for a potent p38 MAPK dual action inhibitor BMS-582949 in subjects with RA receiving concomitant methotrexate. Arthr Rheum. 2010;62(10 Suppl.):S469–70.Google Scholar
  144. 144.
    Gaestel M, Kotlyarov A, Kracht M. Targeting innate immunity protein kinase signalling in inflammation. Nat Rev Drug Discov. 2009;8(6):480–99.PubMedCrossRefGoogle Scholar
  145. 145.
    Guma M, Hammaker D, Topolewski K, Corr M, Boyle DL, Karin M, et al. Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKKk-6. Arthr Rheum. 2012;64(9):2887–95.CrossRefGoogle Scholar
  146. 146.
    Hammaker D, Boyle DL, Firestein GS. Synoviocyte innate immune responses: TANK-binding kinase-1 as a potential therapeutic target in rheumatoid arthritis. Rheumatology (Oxford). 2012;51(4):610–8.CrossRefGoogle Scholar
  147. 147.
    Engstrom W, Ward A, Moorwood K. The role of scaffold proteins in JNK signalling. Cell Prolif. 2010;43(1):56–66.PubMedCrossRefGoogle Scholar
  148. 148.
    Gallagher TF, Seibel GL, Kassis S, Laydon JT, Blumenthal MJ, Lee JC, et al. Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. Bioorg Med Chem. 1997;5(1):49–64.PubMedCrossRefGoogle Scholar
  149. 149.
    Liverton NJ, Butcher JW, Claiborne CF, Claremon DA, Libby BE, Nguyen KT, et al. Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. J Med Chem. 1999;42(12):2180–90.PubMedCrossRefGoogle Scholar
  150. 150.
    Koeberle SC, Fischer S, Schollmeyer D, Schattel V, Grutter C, Rauh D, et al. Design, synthesis, and biological evaluation of novel disubstituted dibenzosuberones as highly potent and selective inhibitors of p38 mitogen activated protein kinase. J Med Chem. 2012;55(12):5868–77.PubMedCrossRefGoogle Scholar
  151. 151.
    Liu C, Lin J, Wrobleski ST, Lin S, Hynes J, Wu H, et al. Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][ 1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38alpha MAP kinase inhibitor for the treatment of inflammatory diseases. J Med Chem. 2010;53(18):6629–39.PubMedCrossRefGoogle Scholar
  152. 152.
    Bode JG, Ehlting C, Haussinger D. The macrophage response towards LPS and its control through the p38(MAPK)-STAT3 axis. Cell Signal. 2012;24(6):1185–94.PubMedCrossRefGoogle Scholar
  153. 153.
    Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9(8):537–49.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, MVLSUniversity of GlasgowGlasgowUK

Personalised recommendations