185
Views
43
CrossRef citations to date
0
Altmetric
Special Topic: NF-κB, Immunity and Cancer

Targeting NF-κB: A Promising Molecular Therapy in Inflammatory Arthritis

&
Pages 351-374 | Published online: 03 Aug 2009

REFERENCES

  • Firestein G. S. Evolving concepts of rheumatoid arthritis. Nature 200; 423: 356–361
  • Pelletier J. P., Martel-Pelletier J., Abramson S. Osteoarthritis, an inflammatory disease. Potential implication for the selection of new therapeutic targets. Arthritis Rheum 2001; 44: 1237–1247
  • Firestein G. S., Manning A. M. Signal transduction and transcription factors in rheumatic disease. Arthritis Rheum 1999; 42: 609–621
  • Li Q., Verma I. M. NF-κ B regulation in the immune system. Nat Rev Immunol 2002; 2: 725–734
  • Silverman N., Maniatis T. NF-κB signaling pathways in mammalian and insect innate immunity. Genes Dev 2001; 15: 2321–2342
  • Ghosh S., Karin M. Missing pieces in the NF-κ B puzzle. Cell 2002; 109: S81–S96
  • Bouwmeester T., Bauch A. H Ruffner, P.O Angrand et al. A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol 2004; 6: 97–105
  • Hayden M. S., Ghosh S. Shared principles in NF-kappaB signaling. Cell 2008; 132: 344–362
  • Udalova I. A., Mott R., Field D., Kwiatkowski D. Quantitative prediction of NF-κ B DNA–protein interactions. Proc Natl Acad Sci USA 2002; 99: 8167–8172
  • Dejardin E., et al. The lymphotoxin–β receptor induces different patterns of gene expression via two NF-κ B pathways. Immunity 2002; 17: 525–535
  • Yamamoto Y., Gaynor R. B. IκB kinases: key regulators of the NF-κ B pathway. Trends Biochem Sci 2004; 29: 72–79
  • Yamaoka S., et al. Complementation cloning of NEMO, a component of the IKK complex essential for NF-κ B activation. Cell 1998; 93: 1231–1240
  • Häcker H., Karin M. Regulation and function of IKK and IKK–related kinases. Sci STKE 2006; 357: re13
  • Yamamoto Y., Verma U. N., Prajapati S., Kwak Y. T., Gaynor R. B. Histone H3 phosphorylation by IKK–alpha is critical for cytokine–induced gene expression. Nature 2003; 423: 655–659
  • Anest J. L., Hanson P. C., Cogswell K. A., Steinbrecher Strahl B. D., Baldwin A. S. A nucleosomal function for IkappaB kinase–alpha in NF–kappaB–dependent gene expression. Nature 2003; 423: 659–663
  • Dejardin E. The alternative NF–kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem Pharmacol 2006; 72: 1161–1179
  • Roman-Blas J. A., Jimenez S. A. NF-kappaB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage 2006; 14: 839–848
  • Uwe S. Anti–inflammatory interventions of NF-kappaB signaling: potential applications and risks. Biochem Pharmacol 2008; 75: 1567–1579
  • Groesdonk H. V., Schlottmann S., Richter F., Georgieff M., Senftleben U. Escherichia coli prevents phagocytosis–induced death of macrophages via classical NF–kappaB signaling, a link to T–cell activation. Infect Immun 2006; 74: 5989–6000
  • Hayden M. S., West A. P., Ghosh S. NF-kappaB and the immune response. Oncogene 2006; 25: 6758–6780
  • Zanetti M., Castiglioni P., Schoenberger S., Gerloni M. The role of relB in regulating the adaptive immune response. Ann N Y Acad Sci 2003; 987: 249–257
  • Theilgaard-Mönch K., Jacobsen L. C., Borup R., Rasmussen T., Bjerregaard M. D., Nielsen F. C., Cowland J. B., Borregaard N. The transcriptional program of terminal granulocytic differentiation. Blood 2005; 105: 1785–1796
  • McDonald P. P., Bald A., Cassatella M. A. Activation of the NF–kappaB pathway by inflammatory stimuli in human neutrophils. Blood 1997; 89: 3421–3433
  • Horwitz B. H., Zelazowski P., Shen Y., Wolcott K. M., Scott M. L., Baltimore D., Snapper C. M. The p65 subunit of NF–kappa B is redundant with p50 during B cell proliferative responses, and is required for germline CH transcription and class switching to IgG3. J Immunol 1999; 162: 1941–1946
  • Weih F., Caamaño J. Regulation of secondary lymphoid organ development by the nuclear factor–kappaB signal transduction pathway. Immunol Rev 2003; 195: 91–105
  • Ware C. F. Network communications: lymphotoxins, LIGHT, and TNF. Annu Rev Immunol 2005; 23: 787–819
  • Handel M. L., McMorrow L. B., Gravallese E. M. Nuclear factor-kappaB n rheumatoid synovium: localization of p50 and p65. Arthritis Rheum 1995; 38: 1762–1770
  • Benito M. J., Murphy E., Murphy E. P., van den Berg W. B., FitzGerald O., Bresnihan B. Increased synovial tissue NF–kappa B1 expression at sites adjacent to the cartilage–pannus junction in rheumatoid arthritis. Arthritis Rheum 2004; 50: 1781–1787
  • Aupperle K., Bennett B., Han Z., Boyle D., Manning A., Firestein G. NF-kappaB regulation by IkappaB kinase–2 in rheumatoid artritis synoviocytes. J Immunol 2001; 166: 2705–2711
  • Han Z., Boyle D. L., Manning A. M., Firestein G. S. AP-1 and NF-kappaB regulation in rheumatoid arthritis and murine collagen–induced arthritis. Autoimmunity 1998; 28: 197–208
  • Eguchi J., Koshino T., Takagi T., Hayashi T., Saito T. NF-kappa B I-kappa B overexpression in articular chondrocytes with progression of type II collagen–induced arthritis in DBA/1 mouse knees. Clin Exp Rheumatol 2002; 20: 647–652
  • Tsao P. W., Suzuki T., Totsuka R., Murata T., Takagi T., Ohmachi Y., Fujimura H., Takata I. The effect of dexamethasone on the expression of activated NF-kappa B in adjuvant arthritis. Clin Immunol Immunopathol 1997; 83: 173–178
  • Tak P. P., Gerlag D. M., Aupperle K. R., van de Geest D. A., Overbeek M., Bennett B. L., Boyle D. L., Manning A. M., Firestein G. S. Inhibitor of nuclear factor kappaB kinase beta is a key regulator of synovial inflammation. Arthritis Rheum 2001; 47: 1897–1907
  • Theoleyre S., Wittrant Y., Tat S. K., Fortun Y., Redini F., Heymann D. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev 2004; 15: 457–475
  • Dougall W. C., Glaccum M., Charrier K., Rohrbach K., Brasel K., De Smedt T., Daro E., Smith J., Tometsko M. E., Maliszewski C. R., Armstrong A., Shen V., Bain S., Cosman D., Anderson D., Morrissey P. J., Peschon J. J., Schuh J. RANK is essential for osteoclast and lymph node development. Genes Dev 1999; 13: 2412–2424
  • Kong Y. Y., Yoshida H., Sarosi I., Tan H. L., Timms E., Capparelli C., Morony S., Oliveira-dos-Santos A. J., Van G., Itie A., Khoo W., Wakeham A., Dunstan C. R., Lacey D. L., Mak T. W., Boyle W. J., Penninger J. M. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph–node organogenesis. Nature 1999; 397: 315–323
  • Iotsova V., Caamaño J., Loy J., Yang Y., Lewin A., Bravo R. Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med 1997; 3: 1285–1289
  • Ruocco M. G., Karin M. Control of osteoclast activity and bone loss by IKK subunits: new targets for therapy. Adv Exp Med Biol 2007; 602: 125–134
  • Aya K., Alhawagri M., Hagen-Stapleton A., Kitaura H., Kanagawa O., Novack D. V. NF–[kappa) B–inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis. J Clin Invest 2005; 115: 1848–1854
  • Vaira S., Johnson T., Hirbe A. C., Alhawagri M., Anwisye I., Sammut B., O'Neal J., Zou W., Weilbaecher K. N., Faccio R., Novack D. V. RelB is the NF-kappaB subunit downstream of NIK responsible for osteoclast differentiation. Proc Natl Acad Sci USA 2008; 105: 3897–3902
  • Sioud M., Mellbye O., Førre O. Analysis of the NF–kappa B p65 subunit, Fas antigen, Fas ligand and Bcl-2-related proteins in the synovium of RA and polyarticular JRA. Clin Exp Rheumatol 1998; 16: 125–134
  • Varsani H., Patel A., van Kooyk Y., Woo P., Wedderburn L. R. Synovial dendritic cells in juvenile idiopathic arthritis (JIA) express receptor activator of NF–kappaB [RANK). Rheumatology 2003; 42: 583–590
  • Collantes E., Valle Blázquez M., Mazorra V., Macho A., Aranda E., Muñoz E. Nuclear factor–kappa B activity in T cells from patients with rheumatic diseases: a preliminary report. Ann Rheum Dis 1998; 57: 738–741
  • Eggert M., Seeck U., Semmler M., Maass U., Dietmann S., Schulz M., Dotzlaw H., Neeck G. An evaluation of anti-TNF-alpha-therapy in patients with ankylosing spondylitis: imbalanced activation of NF kappa B subunits in lymphocytes and modulation of serum cortisol concentration. Rheumatol Int 2007; 27: 841–846
  • Danning C. L., Illei G. G., Hitchon C., Greer M. R., Boumpas D. T., McInnes I. B. Macrophage–derived cytokine and nuclear factor kappaB p65 expression in synovial membrane and skin of patients with psoriatic arthritis. Arthritis Rheum 2000; 43: 1244–1256
  • Lories R. J., Derese I., Luyten F. P., de Vlam K. Activation of nuclear factor kappa B and mitogen activated protein kinases in psoriatic arthritis before and after etanercept treatment. Clin Exp Rheumatol 2008; 26: 96–102
  • Liu R., O'Connell M., Johnson K., Pritzker K., Mackman N., Terkeltaub R. Extracellular signal–regulated kinase 1/extracellular signal–regulated kinase 2 mitogen–activated protein kinase signaling and activation of activator protein 1 and nuclear factor kappaB transcription factors play central roles in interleukin–8 expression stimulated by monosodium urate monohydrate and calcium pyrophosphate crystals in monocytic cells. Arthritis Rheum 2000; 43: 1145–1155
  • Jaramillo M., Godbout M., Naccache P. H., Olivier M. Signaling events involved in macrophage chemokine expression in response to monosodium urate crystals. J Biol Chem 2004; 279: 52797–52805
  • Jaramillo M., Naccache P. H., Olivier M. Monosodium urate crystals synergize with IFN–gamma to generate macrophage nitric oxide: involvement of extracellular signal–regulated kinase 1/2 and NF–kappa B. J Immunol 2004; 172: 5734–5742
  • McCarthy G. M., Augustine J. A., Baldwin A. S., Christopherson P. A., Cheung H. S., Westfall P. R., Scheinman R. I. Molecular mechanism of basic calcium phosphate crystal–induced activation of human fibroblasts. Role of nuclear factor kappab, activator protein 1, and protein kinase c. J Biol Chem 1998; 273: 35161–35169
  • Gjertsson I., Hultgren O. H., Collins L. V., Pettersson S., Tarkowski A. Impact of transcription factors AP-1 and NF-kappaB on the outcome of experimental Staphylococcus aureus arthritis and sepsis. Microbes Infect 2001; 3: 527–534
  • Yip K. H., Zheng M. H., Feng H. T., Steer J. H., Joyce D. A., Xu J. Sesquiterpene lactone parthenolide blocks lipopolysaccharide–induced osteolysis through the suppression of NF-kappaB activity. J Bone Miner Res 2004; 19: 1905–1916
  • Wong H. K., Kammer G. M., Dennis G., Tsokos G. C. Abnormal NF-kappa B activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65–RelA protein expression. J Immunol 1999; 163: 1682–168
  • Herndon T. M., Juang Y. T., Solomou E. E., Rothwell S. W., Gourley M. F., Tsokos G. C. Direct transfer of p65 into T lymphocytes from systemic lupus erythematosus patients leads to increased levels of interleukin–2 promoter activity. Clin Immunol 2002; 103: 145–153
  • Burgos P., Metz C., Bull P., Pincheira R., Massardo L., Errázuriz C., Bono R., Jacobelli S., González A. Increased expression of c-rel, from the NF–kappaB/Rel family, in T cells from patients with systemic lupus erythematosus. J Rheumatol 2000; 27: 116–127
  • Enzler T., Bonizzi G., Silverman G. J., Otero D. C., Widhopf G. F., Anzelon-Mills A., Rickert R. C., Karin M. Alternative and classical NF–kappa B signaling retain autoreactive B cells in the splenic marginal zone and result in lupus–like disease. Immunity 2006; 25: 403–415
  • Choi J. Y., Gao W., Odegard J., Shiah H. S., Kashgarian M., McNiff J. M., Baker D. C., Cheng Y. C., Craft J. Abrogation of skin disease in LUPUS–prone MRL/FASlpr mice by means of a novel tylophorine analog. Arthritis Rheum 2006; 54: 3277–3283
  • Roman-Blas J. A., Stokes D. G., Jimenez S. A. Modulation of TGF–beta signaling by proinflammatory cytokines in articular chondrocytes. Osteoarthritis Cartilage 2007; 15: 1367–1377
  • Seguin C. A., Bernier S. M. TNFalpha suppresses link protein and type II collagen expression in chondrocytes: role of MEK1/2 and NF–kappaB signaling pathways. J Cell Physiol 2003; 197: 356–369
  • Liacini A., Sylvester J., Li W. Q., 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: 251–262
  • Liacini A., Sylvester J., Li W. Q., Huang W., Dehnade F., Ahmad M., Zafarullah M. 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: 208–217
  • Pulai J. I., Chen H., Im H. J., Kumar S., Hanning C., Hegde P. S., Loeser R. F. NF-kappa B mediates the stimulation of cytokine and chemokine expression by human articular chondrocytes in response to fibronectin fragments. J Immunol 2005; 174: 5781–5788
  • Forsyth C. B., Cole A., Murphy G., Bienias J. L., Im H. J., Loeser R. F., Jr. Increased matrix metalloproteinase–13 production with aging by human articular chondrocytes in response to catabolic stimuli. J Gerontol A Biol Sci Med Sci 2005; 60: 1118–1124
  • Martin G., Andriamanalijaona R., Grassel S., Dreier R., Mathy-Hartert M., Bogdanowicz P., Boumediene K., Henrotin Y., Bruckner P., Pujol J. P. Effect of hypoxia and reoxygenation on gene expression and response to interleukin–1 in cultured articular chondrocytes. Arthritis Rheum 2004; 50: 3549–3560
  • Agarwal S., Deschner J., Long P., Verma A., Hofman C., Evans C. H., Piesco N. Role of NF–kappaB transcription factors in antiinflammatory and proinflammatory actions of mechanical signals. Arthritis Rheum 2004; 50: 3541–3548
  • Dossumbekova A., Anghelina M., Madhavan S., He L., Quan N., Knobloch T., Agarwal S. Biomechanical signals inhibit IKK activity to attenuate NF–kappaB transcription activity in inflamed chondrocytes. Arthritis Rheum 2007; 56: 3284–3296
  • Kuhn K., Hashimoto S., Lotz M. IL–1 beta protects human chondrocytes from CD95–induced apoptosis. J Immunol 2000; 164: 2233–2239
  • Kim S. J., Hwang S. G., Shin D. Y., Kang S. S., Chun J. S. p38 kinase regulates nitric oxide–induced apoptosis of articular chondrocytes by accumulating p53 via NFkappa B–dependent transcription and stabilization by serine 15 phosphorylation. J Biol Chem 2002; 277: 33501–33508
  • Kim S. J., Chun J. S. Protein kinase C alpha and zeta regulate nitric oxide–induced NF–kappa B activation that mediates cyclooxygenase–2 expression and apoptosis but not dedifferentiation in articular chondrocytes. Biochem Biophys Res Commun 2003; 303: 206–211
  • Yamamoto Y., Gaynor R. Therapeutic potential of inhibition of the NF-κ B pathway in the treatment of inflammation and cancer. J Clin Invest 2001; 107: 135–142
  • De Bosscher K., Vanden Berghe W., Haegeman G. Mechanisms of anti–inflammatory action and of immunosuppression by glucocorticoids: negative interference of activated glucocorticoid receptor with transcription factors. J Neuroimmunol 2000; 109: 16–22
  • Auphan N., DiDonato J. A., Rosette C., Helmberg A., Karin M. Immunosuppression by glucocorticoids: inhibition of NF–kappa B activity through induction of I kappa B synthesis. Science 1995; 270: 286–290
  • Scheinman R. I., Cogswell P. C., Lofquist A. K., Baldwin A. S., Jr. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 1995; 270: 283–286
  • De Bosscher K., Vanden Berghe W., Vermeulen L., Plaisance S., Boone E., Haegeman G. Glucocorticoids repress NF-kappaB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell. Proc Natl Acad Sci USA 2000; 97: 3919–3924
  • De Bosscher K., Schmitz M. L., Vanden Berghe W., Plaisance S., Fiers W., Haegeman G. Glucocorticoid–mediated repression of nuclear factor-kappaB-dependent transcription involves direct interference with transactivation. Proc Natl Acad Sci USA 1997; 94: 13504–13509
  • Sheppard K. A., Rose D. W., Haque Z. K., Kurokawa R., McInerney E., Westin S., Thanos D., Rosenfeld M. G., Glass C. K., Collins T. Transcriptional activation by NF–kappaB requires multiple coactivators. Mol Cell Biol 1999; 19: 6367–6378
  • Tegeder I., Pfeilschifter J., Geisslinger G. Cyclooxygenase–independent actions of cyclooxygenase inhibitors. FASEB J 2001; 15: 2057–2072
  • Takada Y., Bhardwaj A., Potdar P., Aggarwal B. B. Nonsteroidal anti–inflammatory agents differ in their ability to suppress NF–kappaB activation, inhibition of expression of cyclooxygenase–2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene 2004; 23: 9247–9258
  • Wahl C., Liptay S., Adler G., Schmid R. M. Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Invest 1998; 101: 1163–1174
  • Meyer Z., Kohler N. G., Joly A. Cyclosporine A is an uncompetitive inhibitor of proteasome activity and prevents NF-kappaB activation. FEBS Lett 1997; 413: 354–358
  • Venkataraman L., Burakoff S. J., Sen R. FK506 inhibits antigen receptor–mediated induction of c-rel in B and T lymphoid cells. J Exp Med 1995; 181: 1091–1099
  • Chadwick C. C., Chippari S., Matelan E., Borges-Marcucci L., Eckert A. M., Keith J. C., Jr., Albert L. M., Leathurby Y., Harris H. A., Bhat R. A., Ashwell M., Trybulski E., Winneker R. C., Adelman S. J., Steffan R. J., Harnish D. C. Identification of pathway–selective estrogen receptor ligands that inhibit NF–kappaB transcriptional activity. Proc Natl Acad Sci USA 2005; 102: 2543–2548
  • Keith J. C., Jr., Albert L. M., Leathurby Y., Follettie M., Wang L., Borges-Marcucci L., Chadwick C. C., Steffan R. J., Harnish D. C. The utility of pathway selective estrogen receptor ligands that inhibit nuclear factor–kappa B transcriptional activity in models of rheumatoid arthritis. Arthritis Res Ther 2005; 7: R427–438
  • Firestein G. S. NF-κ B: Holy Grail for rheumatoid arthritis?. rthritis Rheum 2004; 50: 2381–2386
  • Bacher S., Schmitz M. L. The NF–kappaB pathway as a potential target for autoimmune disease therapy. Curr Pharm Des 2004; 10: 2827–2837
  • Feldmann M., Andreakos E., Smith C., Bondeson J., Yoshimura S., Kiriakidis S., Monaco C., Gasparini C., Sacre S., Lundberg A., Paleolog E., Horwood N. J., Brennan F. M., Foxwell B. M. Is NF–kappaB a useful therapeutic target in rheumatoid arthritis?. Ann Rheum Dis 2002; 61(Suppl 2)ii13–18
  • Smolen J. S., Steiner G. Therapeutic strategies for rheumatoid arthritis. Nature Rev Drug Dis 2003; 2: 473–488
  • Epinat J. C., Gilmore T. D. Diverse agents act at multiple levels to inhibit the Rel/NF–kappaB signal transduction pathway. Oncogene 1999; 18: 6896–6909
  • Elliott P. J., Zollner T. M., Boehncke W. H. Proteasome inhibition: a new anti–inflammatory strategy. J Mol Med 2003; 81: 235–245
  • Kawakami A., Nakashima T., Sakai H., Hida A., Urayama S., Yamasaki S., Nakamura H., Ida H., Ichinose Y., Aoyagi T., Furuichi I., Nakashima M., Migita K., Kawabe Y., Eguchi K. Regulation of synovial cell apoptosis by proteasome inhibitor. Arthritis Rheum 1999; 42: 2440–2448
  • Tomita T., Takeuchi E., Tomita N., Morishita R., Kaneko M., Yamamoto K., Nakase T., Seki H., Kato K., Kaneda Y., Ochi T. Suppressed severity of collagen–induced arthritis by in vivo transfection of nuclear factor kappaB decoy oligodeoxynucleotides as a gene therapy. Arthritis Rheum 1999; 42: 2532–2542
  • Hashimoto H., Tomita T., Kunugiza Y., Nampei A., Morishita R., Kaneda Y., Yoshikawa H. NF-κ B Decoy oligodeoxynucleotides suppressed the progression of osteoarthritis in rat arthritis. Arthritis Rheum 2003; 48: S630
  • Tilstra J., Rehman K. K., Hennon T., Plevy S. E., Clemens P., Robbins P. D. Protein transduction: identification, characterization and optimization. Biochem Soc Trans 2007; 35: 811–815
  • Fujihara S. M., Cleaveland J. S., Grosmaire L. S., Berry K. K., Kennedy K. A., Blake J. J., Loy J., Rankin B. M., Ledbetter J. A., Nadler S. G. A D–amino acid peptide inhibitor of NF–kappa B nuclear localization is efficacious in models of inflammatory disease. J Immunol 2000; 165: 1004–1012
  • Tas S. W., Adriaansen J., Hajji N., Bakker A. C., Firestein G. S., Vervoordeldonk M. J., Tak P. P. Amelioration of arthritis by intraarticular dominant negative Ikk beta gene therapy using adeno–associated virus type 5. Hum Gene Ther 2006; 17: 821–832
  • Blackwell N. M., Sembi P., Newson J. S., Lawrence T., Gilroy D. W., Kabouridis P. S. Reduced infiltration and increased apoptosis of leukocytes at sites of inflammation by systemic administration of a membrane–permeable IkappaBalpha repressor. Arthritis Rheum 2004; 50: 2675–2684
  • Tas S. W., Vervoordeldonk M. J., Hajji N., May M. J., Ghosh S., Tak P. P. Local treatment with the selective IkappaB kinase beta inhibitor NEMO–binding domain peptide ameliorates synovial inflammation. Arthritis Res Ther 2006; 8: R86
  • Amos N., Lauder S., Evans A., Feldmann M., Bondeson J. Adenoviral gene transfer into osteoarthritis synovial cells using the endogenous inhibitor IkappaBalpha reveals that most, but not all, inflammatory and destructive mediators are NFkappaB dependent. Rheumatology 2006; 45: 1201–1209
  • Bondeson J., Lauder S., Wainwright S., Amos N., Evans A., Hughes C., Feldmann M., Caterson B. Adenoviral gene transfer of the endogenous inhibitor IkappaBalpha into human osteoarthritis synovial fibroblasts demonstrates that several matrix metalloproteinases and aggrecanases are nuclear factor–kappaB–dependent. J Rheumatol 2007; 34: 523–533
  • Kishore N. A., Sommers C., Mathialagan S., et al. A selective IKK–2 inhibitor blocks NF–kappa B–dependent gene expression in interleukin–1 beta–stimulated synovial fibroblasts. J Biol Chem 2003; 278: 32861–32871
  • Podolin P. L., Callahan J. F., Bolognese B. J., Li Y. H., Carlson K., Davis T. G., Mellor G. W., Evans C., Roshak A. K. Attenuation of murine collagen–induced arthritis by a novel, potent, selective small molecule inhibitor of IkappaB Kinase 2, TPCA-1 [2-[[aminocarbonyl)amino]-5-[4-fluorophenyl)-3-thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen–induced T cell Proliferation. J Pharmacol Exp Ther 2005; 312: 373–381
  • McIntyre K. W., Shuster D. J., Gillooly K. M., Dambach D. M., Pattoli M. A., Lu P, et al. A highly selective inhibitor of I kappa B kinase, BMS–345541, blocks both joint inflammation and destruction in collagen–induced arthritis in mice. Arthritis Rheum 2003; 48: 2652–2659
  • Schopf L., Savinainen A., Anderson K., Kujawa J., DuPont M., Silva M., Siebert E., Chandra S., Morgan J., Gangurde P., Wen D., Lane J., Xu Y, Hepperle M., Harriman G., Ocain T., Jaffee B. IKKbeta inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis. Arthritis Rheum 2006; 54: 3163–3173
  • Izmailova E. S., Paz N., Alencar H., Chun M., Schopf L., Hepperle M., Lane J. H., Harriman G., Xu Y., Ocain T., Weissleder R., Mahmood U., Healy A. M., Jaffee B. Use of molecular imaging to quantify response to IKK–2 inhibitor treatment in murine arthritis. Arthritis Rheum 2007; 56: 117–128
  • Wakamatsu K., Nanki T., Miyasaka N., Umezawa K., Kubota T. Effect of a small molecule inhibitor of nuclear factor–kappaB nuclear translocation in a murine model of arthritis and cultured human synovial cells. Arthritis Res Ther 2005; 7: R1348–1359
  • Kubota T., Hoshino M., Aoki K., Ohya K., Komano Y., Nanki T., Miyasaka N., Umezawa K. NF-kappaB inhibitor dehydroxymethylepoxyquinomicin suppresses osteoclastogenesis and expression of NFATc1 in mouse arthritis without affecting expression of RANKL, osteoprotegerin or macrophage colony–stimulating factor. Arthritis Res Ther 2007; 9: R97
  • Martin E., Capini C., Duggan E., Lutzky V. P., Stumbles P., Pettit A. R., O'Sullivan B., Thomas R. Antigen–specific suppression of established arthritis in mice by dendritic cells deficient in NF–kappaB. Arthritis Rheum 2007; 56: 2255–2266
  • Millenium. Available at: http://investor.millenium.com/phoenix.zhtml?c=80159&p=irol–newsmediaArticle&ID=900341&highlight=. Press release August 30, 2006
  • VGX Pharmaceutical. Available at: http://www.vgxp.com/PR011408.html. Press release January 14, 2008
  • Jepsen J. S., Wengel J. LNA–antisense rivals siRNA for gene silencing. Curr Opin Drug Discov Devel 2004; 2: 188–194
  • Heasman J. Morpholino oligos: making sense of antisense?. Dev Biol 2002; 243: 209–214
  • McManus M. T., Sharp P. A. Gene silencing in mammals by small interfering RNAs. Nat Rev Genet 2002; 3: 737–747
  • Huppi K., Martin S. E., Caplen N. J. Defining and assaying RNAi in mammalian cells. Molecular Cell 2005; 17: 1–10
  • Lianxu C., Hongti J., Changlong Y. NF–kappaBp65-specific siRNA inhibits expression of genes of COX-2, NOS-2 and MMP-9 in rat IL-1beta-induced and TNF-alpha-induced chondrocytes. Osteoarthritis Cartilage 2006; 14: 367–376
  • Chen L. X., Lin L., Wang H. J., Wei X. L., Fu X., Zhang J. Y., Yu C. L. Suppression of early experimental osteoarthritis by in vivo delivery of the adenoviral vector–mediated NF–kappaBp65–specific siRNA. Osteoarthritis Cartilage 2008; 16: 174–84

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.