Anticytokine Therapy for Osteoarthritis

Springer Science and Business Media LLC - Tập 27 - Trang 95-115 - 2012
Charles J. Malemud1
1Department of Medicine, Division of Rheumatic Diseases, Department of Anatomy, Case Western Reserve University, School of Medicine & University Hospitals Case Medical Center, Cleveland, USA

Tóm tắt

Several recent in vitro investigations and experimental studies performed in animal models of osteoarthritis (OA) sustained the previously held view that interleukin (IL)-1 or tumour necrosis factor-α (TNFα) disrupt the metabolism of synovial joint tissues. The evidence to date indicates that, in addition to IL-1 and TNFα, other pro-inflammatory cytokines, including IL-6, members of the IL-6 protein superfamily, IL-7, IL-17 and IL-18, can also promote articular cartilage extracellular matrix protein degradation or synergize with other cytokines to amplify and accelerate cartilage destruction. Most importantly, many of these cytokines have been implicated in causing synovial tissue activation and damage to subchondral bone as well as altering cartilage homeostasis in spontaneously occurring or surgically induced animal models of OA and in transgenic mice genetically primed to develop OA. In this regard, these pro-inflammatory cytokines may also play a significant role in the pathogenesis of human OA. However, attempts to modify the progression of human OA in well designed, controlled clinical trials with an IL-1 receptor antagonist protein (IRAP) have not been successful. Several anabolic cytokines (also termed growth factors), including transforming growth factor-β (TGF-β), insulin-like growth factor-1 (IGF-1), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor (PDGF) and connective tissue growth factor (CTGF), have also been proposed as regulators of skeletal long bone growth and development as well as cartilage and bone homeostasis. TGF-β, IGF-1 and FGF-2, in particular, have been characterized as potential chondroprotective agents. Thus, enzymatic disruption and removal of these growth factors from cartilage extracellular matrix proteins, as in the case of TGF-β and FGF-2, or disruption of their function, as in the case of the enhanced binding of free IGF-1 with IGF binding proteins in OA joint synovial fluid, may compromise and ultimately be responsible for the inadequate repair of articular cartilage in OA. An improved understanding of the cellular and molecular mechanisms by which pro-inflammatory and/or anabolic cytokines alter both the structure and function of synovial joints may eventually result in the commercial development of disease-modifying OA drugs (DMOADs). Since the prevalence of OA is high in the elderly population, future development of DMOADs must also take into account potential differences in the way DMOADs would be metabolized in the older individual compared with younger people.

Tài liệu tham khảo

Goldring MB. Anticytokine therapy for osteoarthritis. Expert Opin Biol Ther 2001; 1(5): 817–29 Fernandes JC, Martel-Pelletier J, Pelletier J-P. The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002; 39(1–2): 237–46 Malemud CJ. Cytokines as therapeutic targets for osteoarthritis. Biodrugs 2004; 18(1): 23–35 Blom AB, van der Kraan PM, van den Berg WB. Cytokine targeting in osteoarthritis. Curr Drug Targets 2007; 8(2): 283–92 Martel-Pelletier J, Pelletier J-P. Inflammatory factors involved in osteoarthritis. In: Buckwalter JA, Lotz M, Stoltz J-F, editors. Osteoarthritis, inflammation and degradation: a continuum. Amsterdam: IOS Press, 2007: 3–13 Otero M, Lago R, Gómez R, et al. Leptin, a metabolic hormone that functions as a proinflammatory adipokine. Drug New Prospect 2006; 19(1): 21–6 Saklatvala J. Inflammatory signalling in cartilage: MAPK and NF-κB pathways in chondrocytes and the use of inhibitors for research into the pathogenesis and therapy of osteoarthritis. Curr Drug Targets 2007; 8(2): 305–13 Fan Z, Söder S, Oehler S, et al. Activation of interleukin-1 signaling cascades and osteoarthritic cartilage. Am J Pathol 2007; 171(3): 938–46 Pujol J-P, Chadjichristos C, Legendre F, et al. Interleukin-1 and transforming growth factor-β1 as crucial factors in osteoarthritic cartilage metabolism. Connect Tissue Res 2008; 49(3): 293–7 Corr M. Wnt-beta-catenin signaling in the pathogenesis of osteoarthritis. Nat Clin Pract Rheumatol 2008; 4(10): 550–6 Morales TI. The quantitative and functional relation between insulin-like growth factor-1 (IGF) and IGF-binding proteins during human osteoarthritis. J Orthop Res 2008; 26(4): 465–74 Goldring MB, Otero M, Tsuchimochi K, et al. Defining the roles of inflammatory and anabolic cytokines in cartilage metabolism. Ann Rheum Dis 2008; 67Suppl. 3: iii75-82 Verbruggen G. Chondroprotective drugs in degenerative joint diseases. Rheumatology (Oxford) 2006; 45(2): 129–38 Tincani A, Andreoli L, Bazzani C, et al. Inflammatory molecules: a target for treatment in systemic autoimmune diseases. Autoimmun Rev 2007; 7(1): 1–7 Sizova L. Approaches to the treatment of early rheumatoid arthritis with disease-modifying antirheumatic drugs. Br J Clin Pharmacol 2008; 66(2): 173–8 Alonso-Ruiz A, Pijoan JI, Ansuategui E, et al. Tumor necrosis factor alpha drugs in rheumatoid arthritis: systemic review and metaanalysis of efficacy and safety. BMC Musculoskel Disord 2008; 9: 52 Tayal V, Kaira BS. Cytokines and anti-cytokines as therapeutics: an update. Eur J Pharmacol 2008; 579(1–3): 1–12 Daheshia M, Yao JQ. The interleukin 1b pathway in the pathogenesis of osteoarthritis. J Rheumatol 2008; 35(12): 2306–12 Glasson SS. In vivo osteoarthritis target validation using genetically-modified mice. Curr Drug Targets 2007; 8(2): 367–76 Chen LX, Lin X, Wang HJ, et al. Suppression of early experimental osteoarthritis by in vivo delivery of the adenoviral vector-mediated NF-κB65-specific siRNA. Osteoarthritis Cartilage 2008; 16(2): 174–84 Huebner JL, Selfer DR, Kraus VB. A longitudinal analysis of serum cytokines in the Hartley guinea pig model of osteoarthritis. Osteoarthritis Cartilage 2007; 15(3): 354–6 Ley C, Ekman S, Elmén A, et al. Interleukin-6 and tumour necrosis factor in synovial fluid from horses with carpal joint pathology. J Vet Med A Physiol Pathol Clin Med 2007; 54(7): 346–51 Maccoux LJ, Salway F, Day PJ, et al. Expression profiling of select cytokines in canine osteoarthritis tissues. Vet Immunol Immunopathol 2007; 118(1–2): 59–67 Bondeson J, Wainwright SD, Lauder S, et al. The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis. Arthritis Res Ther 2006; 8(6): R187 Doss F, Menard J, Hauschild N, et al. Elevated IL-6 levels in the synovial fluid of osteoarthritis patients stem from plasma cells. Scand J Rheumatol 2007; 36(2): 136–9 Kobayashi M, Squires GR, Mousa A, et al. Role of interleukin-1 and tumor necrosis factor α in matrix degradation of human osteoarthritic cartilage. Arthritis Rheum 2005; 52(1): 128–35 Burger D, Dayer J-M, Palmer G, et al. Is IL-1 a good therapeutic target in the treatment of arthritis? Best Pract Res Clin Rheumatol 2006; 20(5): 879–96 Goupille P, Mulleman D, Chevalier X. Is interleukin 1 a good target for therapeutic intervention in intervertebral disc degeneration: lessons for the osteoarthritic experience. Arthritis Res Ther 2007; 9(6): 110 Iqbal I, Fleischmann R. Treatment of osteoarthritis with anakinra. Curr Rheumatol Rep 2007; 9(1): 31–5 Chevalier X, Giraudeau B, Conrozier T, et al. Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: a multicenter study. J Rheumatol 2005; 32(7): 1317–23 Chevalier X, Goupille P, Beaulieu AD, et al. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind placebo-controlled trial. Arthritis Rheum 2009; 61(3): 344–52 Yang KG, Raijmakers NJ, van Arkel ER, et al. Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial. Osteoarthritis Cartilage 2008; 16(4): 498–505 Richette P, François M, Vicaut E, et al. A high interleukin 1 receptor anatagonist/IL-1b ratio occurs naturally in knee osteoarthritis. J Rheumatol 2008; 35(8): 1650–4 Lequesne MG. The algofunctional indices for hip and knee osteoarthritis. J Rheumatol 1997; 24(4): 779–81 Miyaki S, Nakasa T, Otsuki S, et al. MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum 2009; 60(9): 2723–30 Tetlow LC, Adlam DJ, Woolley DE. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritis cartilage: associations with degenerative changes. Arthritis Rheum 2001; 44(3): 585–94 Wu W, Billinghurst RC, Pidoux I, et al. Sites of collagenase cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13. Arthritis Rheum 2002; 46(8): 2087–94 Brandt KD, Dieppe P, Radin E. Etiopathogenesis of osteoarthritis. Med Clin North Am 2009; 93(1): 1–24, xv Denko CW, Malemud CJ. Metabolic disturbances and synovial membrane responses in osteoarthritis. Front Biosci 1999; 4: D686–93 Denko CW, Malemud CJ. Role of the growth hormone/insulin-like growth factor-1 paracrine axis in rheumatic diseases. Semin Arthritis Rheum 2005; 35(1): 24–34 Patel IR, Attur MG, Patel RN, et al. TNF-α convertase enzyme from human arthritis-affected cartilage: isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-α. J Immunol 1998; 160(9): 4570–9 Skotnicki JS, DiGrandi MJ, Levin JI. Design strategies for the identification of MMP-13 and TACE inhibitors. Curr Opin Drug Discov Devel 2003; 6(5): 742–59 Levin JI. The design and synthesis of aryl hydroxamic acid inhibitors of MMPs and TACE. Curr Top Med Chem 2004; 4(12): 1289–310 Pelletier J-P, Martel-Pelletier J, Malemud CJ. Effects of non-steroidal anti-inflammatory drugs and corticosteroids on cartilage metabolism in rheumatoid arthritis and osteoarthritis. In: Lewis AJ, Furst DE, editors. Non-steroidal anti-inflammatory drugs: mechanisms and clinical uses. 2nd ed. New York: Marcel Dekker, 1994: 5–25 Hochberg MC, Dougados M. Pharmacological therapy of osteoarthritis. Best Pract Res Clin Rheumatol 2001; 15(4) 583–93 Petrella RJ, Petrella M. A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. J Rheumatol 2006; 33(5): 951–6 Brzusek D, Petron D. Treating knee osteoarthritis with intra-articular hyaluronans. Curr Med Res Opin 2008; 24(12): 3307–22 Schnitzer TJ, Weaver AL, Polis AB, et al. Efficacy of rofecoxib, celecoxib, and acetaminophen in patients with osteoarthritis of the knee: a combined analysis of the VACT studies. J Rheumatol 2005; 32(6): 1093–105 Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I study. Am J Med 2006; 1993(3): 255–66 Becker MC, Wang TH, Wisniewski L, et al. Rationale, design and governance of Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION), a cardiovascular end point trial of nonsteroidal anti-inflammatory agents in patients with arthritis. Am Heart J 2009; 157(4): 606–12 Curtis SP, Bockow B, Fisher C, et al. Etoricoxib in the treatment of osteoarthritis over 52-weeks: a double blind, active comparator controlled trial [NCT00242489]. BMC Musculoskelet Disord 2005; 6: 58 Reginster JY, Malmstrom K, Mehta A, et al. Evaluation of the efficacy and safety of etoricoxib compared with naproxen in 2, 138-week randomised studies of patients with osteoarthritis. Ann Rheum Dis 2007; 66(7): 945–51 Dahlberg LE, Holme I, Høye K, et al. A randomised, multicentre, double-blind, parallel-group study to assess adverse event-related discontinuation rate with celecoxib and diclofenac in elderly patients with osteoarthritis. Scand J Rheumatol 2009; 38(2): 133–43 Mastbergen SC, Bijlsma JW, Lafeber FP. Selective COX-2 inhibition is favorable to human early and late-stage osteoarthritic cartilage: a human in vitro study. Osteoarthritis Cartilage 2005; 13(6): 519–26 Mastbergen SC, Marijnissen AC, Vianen ME, et al. Inhibition by celecoxib in the canine groove model of osteoarthritis. Rheumatology (Oxford) 2006; 45(4): 405–13 Bottone FG, Barry WT. Postmarketing surveillance of serious adverse events associated with the use of rofecoxib from 1999–2002. Curr Med Res Opin 2009; 25(6): 1535–50 Jeffrey JE, Aspden RM. Cyclooxygenase inhibition lowers prostaglandin E2 release from articular cartilage and reduces apoptosis but not proteoglycan degradation following an impact load in vitro. Arthritis Res Ther 2007; 9(6): R129 Malemud CJ, Gillespie HJ. The role of apoptosis in arthritis. Curr Rheum Rev 2005; 1(2): 131–42 Del Carlo Jr M, Loeser RF. Cell death in osteoarthritis. Curr Rheumatol Rep 2008; 10(1): 37–42 Weng LH, Wang CJ, Ko JY, et al. Inflammation induction of Dickkopf-1 mediates chondrocyte apoptosis in osteoarthritic joint. Osteoarthritis Cartilage 2009; 17(7): 919–29 Burrage PS, Mix KS, Brinckerhoff CE. Matrix metalloproteinases: role in arthritis. Front Biosci 2006; 11: 529–43 Gupta K, Shukla M, Cowland JB, et al. Neutrophil-gela-tinase-associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase-9. Arthritis Rheum 2007; 56(10): 3326–35 Jackson MT, Smith MM, Smith SM, et al. Activation of cartilage matrix metalloproteinases by activated protein C. Arthritis Rheum 2009; 60(3): 780–91 Fosang AJ, Little CB. Drug insight: aggrecanases as therapeutic targets for osteoarthritis. Nat Clin Pract Rheumatol 2008; 4(8): 420–7 Bondeson J, Wainwright S, Hughes C, et al. The regulation of ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review. Clin Exp Rheumatol 2008; 26(1): 139–45 Malemud CJ, Islam N, Haqqi TM. Pathophysiological mechanisms in osteoarthritis lead to novel therapeutic strategies. Cells Tissues Organs 2003; 174(1–2): 34–48 Aigner T, Sachse A, Gebhard A, et al. Osteoarthritis: pathobiology-targets and ways for therapeutic intervention. Adv Drug Deliv Rev 2006; 58(2): 128–49 Malemud CJ, Schulte ME. Is there a final common pathway for arthritis? Future Rheumatol 2008; 3(3): 253–68 Chen FH, Tuan RS. Mesenchymal stem cells in arthritic diseases. Arthritis Res Ther 2008; 10(5): 223 Abramson SB, Attur M. Developments in the scientific understanding of osteoarthritis. Arthritis Res Ther 2009; 11(3): 227 Koelling S, Kruegel J, Irmer M, et al. Migratory chondrogenic progenitor cells from repair tissue during the later stages of human osteoarthritis. Cell Stem Cell 2009; 4(4): 324–35 Zaslav K, Cole B, Brewster R, et al. A prospective study of autologous chondrocyte implantation in patients with failed prior treatment for articular cartilage defect of the knee: results of the Study of the Treatment of Articular Repair (STAR) clinical trial. Am J Sports Med 2009; 37(1): 42–55 Goldring SR. Role of bone in osteoarthritis pathogenesis. Med Clin North Am 2009; 93(1): 25–35, xv Sawitzke AD, Shi H, Finco MF, et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the Glucosamine/Chondroitin Arthritis Intervention Trial. Arthritis Rheum 2008; 58(10): 3183–91 Bruyere O, Reginster JY. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis. Drugs Aging 2007; 24(7): 573–80 Huskison EC. Glucosamine and chondroitin for osteoarthritis. J Int Med Res 2008; 36(6): 1161–79 Uebelhart D. Clinical review of chondroitin sulfate in osteoarthritis. Osteoarthritis Cartilage 2008; 16Suppl. 3: S19–21 Martin JA, Buckwalter JA. Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology 2002; 3(5): 257–64 Valdes AM, Spector TD. The contribution of genes to osteoarthritis. Med Clin North Am 2009; 93(1): 45–66, x Yasuda T. Cartilage destruction by matrix degradation products. Mod Rheumatol 2006; 16(4): 197–205 Sakao K, Takahashi KA, Mazda O, et al. Enhanced expression of interleukin-6, matrix metalloproteinase-13, and receptor activator of NF-KB ligand in cells derived from osteoarthritic subchondral bone. J Orthop Sci 2008; 13(3): 202–10 Livshits G, Zhai G, Hart DJ, et al. Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: the Chingford study. Arthritis Rheum 2009; 60(7): 2037–45 Pola E, Papaleo P, Pola R, et al. Interleukin-6 gene polymorphism and risk of osteoarthritis of the hip: a case-control study. Osteoarthritis Cartilage 2005; 13(11): 1025–8 de Hooge AS, van de Loo FA, Bennink MB, et al. Male IL-6 gene knock out mice developed more advanced osteoarthritis upon aging. Osteoarthritis Cartilage 2005; 13(1): 66–73 Nile CJ, Read RC, Akil M, et al. Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum 2008; 58(9): 2686–93 Pretzel D, Pohlers D, Weinert S, et al. In vitro model for the analysis of synovial fibroblast-mediated degradation of intact cartilage. Arthritis Res Ther 2009; 11(1): R25 Pulai JI, Chen H, Im HJ, et al. NF-κB mediates the stimulation of cytokine and chemokine expression by human articular chondrocytes in response to fibronectin fragments. J Immunol 2005; 174(9): 5781–8 Stanton H, Ung L, Fosang AJ. The 45 kDa collagen-binding fragment of fibronectin induces matrix metalloproteinase-13 synthesis by chondrocytes and aggrecan degradation by aggrecanases. Biochem J 2002; 364 (Pt 1): 181–90 Klatt AR, Paul-Klausch B, Klinger G, et al. A critical role for collagen II in cartilage matrix degradation: collagen II induces pro-inflammatory cytokines and MMPs in primary human chondrocytes. J Orthop Res 2009; 27(1): 65–70 Klatt AR, Zech D, Kühn G, et al. Discoidin domain receptor 2 mediates the collagen II-dependent release of interleukin-6 in primary human chondrocytes. J Pathol 2009; 218(2): 241–7 Porée B, Kypriotou M, Chadjichristos C, et al. Interleukin-6 (IL-6) and soluble IL-6 receptor down-regulation of human type II collagen gene expression in articular chondrocytes requires a decrease of Sp1.Sp3 ratio and of the binding activity of both factors to the COL2A1 promoter. J Biol Chem 2008; 283(8): 4850–65 Mathy-Hartert M, Hogge L, Sanchez C, et al. Interleukin-1β and interleukin-6 disturb the anti-oxidant enzyme system in bovine chondrocytes: a possible explanation for oxidative stress generation. Osteoarthritis Cartilage 2008; 16(7): 756–63 Roach HI. The complex pathology of osteoarthritis: even mitochondria are involved. Arthritis Rheum 2008; 58(8): 2217–8 Guillén MI, Megías J, Clérigues V, et al. The CO-releasing molecule CORM-2 is a novel regulator of the inflammatory process in osteoarthritic chondrocytes. Rheumatology (Oxford) 2008; 47(9): 1323–8 Tanaka M, Miyajima A. Oncostatin M, a multifunctional cytokine. Rev Physiol Biochem Pharmacol 2003; 149: 39–52 Hui W, Rowan AD, Richards CD, et al. Oncostatin M in combination with tumor necrosis factor α induces cartilage damage and matrix metalloproteinases expression in vitro and in vivo. Arthritis Rheum 2003; 48(12): 3404–18 Hui W, Barksby HE, Young DA, et al. Oncostatin M in combination with tumour necrosis factor α induces a chondrocyte membrane associated aggrecanase that is distinct from ADAMTS aggrecanase-1 or -2. Ann Rheum Dis 2005; 64(11): 1624–32 El Mabrouk M, Qureshi HY, Li WQ, et al. Interleukin-4 antagonizes oncostatin M and transforming growth β-induced responses in articular chondrocytes. J Cell Biochem 2008; 103(2): 588–97 Durigova M, Roughley PJ, Mort JS. Mechanism of proteoglycan aggregate degradation in cartilage stimulated by oncostatin M. Osteoarthritis Cartilage 2008; 16(1): 98–104 Durigova M, Soucy P, Fushimi K, et al. Characterization of an ADAMTS-5-mediated cleavage site in aggrecan in OSM-stimulated bovine cartilage. Osteoarthritis Cartilage 2008; 16(10): 1245–52 Barksby HE, Hui W, Wappler I, et al. Interleukin-1 in combination with oncostatin M up-regulates multiple genes in chondrocytes: implications for cartilage destruction and repair. Arthritis Rheum 2006; 54(2): 540–50 El Mabrouk M, Sylvester J, Zafarullah M. Signaling pathways in oncostatin M-induced aggrecanase-1 and matrix metalloproteinase-13 expression in human articular chondrocytes. Biochim Biophys Acta 2007; 1773(3): 309–20 Malemud CJ, Pearlman E. Targeting JAK/STAT signaling pathway in inflammatory diseases. Curr Signal Transduct Ther 2009; 4(3): 201–21 Little CB, Flannery CR, Hughes CE, et al. Cytokine induced matrix metalloproteinase expression and activity does not correlate with focal susceptibility of articular cartilage to degeneration. Osteoarthritis Cartilage 2005; 13(2): 162–70 Sanchez C, Deberg MA, Piccardi N, et al. Osteoblasts from the sclerotic subchondral bone downregulate aggrecan but upregulate metalloproteinase expression by chondrocytes. This effect is mimicked by interleukin-6, -1β and oncostatin M pre-treated non-sclerotic osteoblasts. Osteoarthritis Cartilage 2005; 13(11): 979–87 Manicourt DH, Poilvache P, Van Egeren A, et al. Synovial fluid levels of tumor necrosis factor α and oncostatin M correlate with levels of markers of the degradation of crosslinked collagen and cartilage aggrecan in rheumatoid arthritis but not in osteoarthritis. Arthritis Rheum 2000; 43(2): 281–8 Moreau JF, Donaldson DD, Bennett F, et al. Leukaemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cells. Nature 1988; 336(6200): 690–2 Auernhammer CJ, Melmed S. Leukemia-inhibitory factor-neuroendocrine modulator of endocrine function. Endocr Rev 2000; 21(3): 313–45 Linker R, Gold R, Luhder F. Function of neutrotrophic factors beyond the nervous system: inflammation and autoimmune demyelination. Crit Rev Immunol 2009; 29(1): 43–68 Starr R, Novak U, Willson TA, et al. Distinct roles for leukemia inhibitory factor α-chain and gp 130 in cell type-specific signal transduction. J Biol Chem 1997; 272(32): 19982–86 Malemud CJ. Small molecular weight inhibitors of stress-activated and mitogen-activated protein kinases. Mini Rev Med Chem 2006; 6(6): 689–98 Malemud CJ. Inhibitors of stress-activated and mitogen-activated protein kinase pathways. Curr Opin Pharmacol 2007; 7(3): 339–43 Malemud CJ, Miller AH. Pro-inflammatory cytokine-induced SAP/MAPK and JAK/STAT in rheumatoid arthritis and the new anti-depression drugs. Expert Opin Ther Targets 2008; 12(2): 171–83 Lotz M, Moats T, Villiger PM. Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis. J Clin Invest 1992; 90(3): 888–96 Alaaeddine N, Di Battista JA, Pelleter J-P, et al. Differential effects of IL-8, LIF (pro-inflammatory) and IL-11 (anti-inflammatory) on TNF-α-induced PGE2 release and on signalling pathways in human OA synovial fibroblasts. Cytokine 1999; 11(12): 1020–30 Lisignoli G, Piacentini A, Toneguzzi S, et al. Osteoblasts and stromal cells isolated from femora in rheumatoid arthritis (RA) and osteoarthritis (OA) patients express IL-11, leukaemia inhibitory factor and oncostatin M. Clin Exp Immunol 2000; 119(2) 346–53 Fan Z, Bau B, Yang H, et al. IL-1β induction of IL-6 and LIF in normal articular human chondrocytes involves the ERK, p38 and NFκB signaling pathways. Cytokine 2004; 28(1): 17–24 Sandell LJ, Xing X, Franz C, et al. Exuberant expression of chemokine genes by adult human articular chondrocytes in response to IL-1β. Osteoarthritis Cartilage 2008; 16(12): 1560–71 Malemud CJ, Reddy SK. Targeting cytokines, chemokines and adhesion molecules in rheumatoid arthritis. Curr Rheum Rev 2008; 4(4): 219–34 Fry TJ, Mackall CL. Interleukin-7: from bench to clinic. Blood 2002; 99(11): 3892–904 Surh CD, Sprent J. Homeostasis of naïve and memory T cells. Immunity 2008; 29(6): 848–62 Sakkas LI, Scanzello C, Johanson N, et al. T-cells and T-cell transcripts in the synovial membrane in patients with osteoarthritis. Clin Diagn Lab Immunol 1998; 5(4): 430–7 Haynes MK, Hume EL, Smith JB. Phenotypic characterization of inflammatory cells from osteoarthritic synovial fluids. Clin Immunol 2002; 105(3): 315–25 Nakamura H, Tanaka M, Masuko-Hongo K, et al. Enhanced production of MMP-1, MMP-3, MMP-13, and Rantes by interaction of chondrocytes with autologous T cells. Rheumatol Int 2006; 26(11): 984–90 Sakkas LI, Platsoucas CD. The role of T cells in the pathogenesis of osteoarthritis. Arthritis Rheum 2007; 56(2): 409–24 Rollin R, Marco F, Jover JA, et al. Early lymphocyte activation in the synovial microenvironment in patients with osteoarthritis: comparison with rheumatoid arthritis patients and healthy controls. Rheumatol Int 2008; 28(8): 757–64 Van Roon JA, Lafeber FP. Role of interleukin-7 in degenerative and inflammatory joint diseases. Arthritis Res Ther 2008; 10(2): 107 Long D, Blake S, Song XY, et al. Human articular chondrocytes produce IL-7 and respond to IL-7 with increased production of matrix metalloproteinase-13. Arthritis Res Ther 2008; 10(1): R23 Yammani RR, Long DD, Loeser RF. Interleukin-7 stimulates secretion of S100A by activating the JAK/STAT signaling pathway in human articular chondrocytes. Arthritis Rheum 2009; 60(3): 792–800 Geginat J, Campagnaro S, Sallusto F, et al. TCR-in-dependent proliferation and differentiation of human CD4+ cell subsets induced by cytokines. Adv Exp Med Biol 2002; 512: 107–12 van Roon JAG, Hartgring SAY, Wenting-van Wijk M, et al. Persistence of interleukin-7 activity and levels on tumor necrosis factor α blockade in patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66(5): 664–9 Dinarello CA. The IL-1 family and inflammatory diseases. Clin Exp Rheumatol 2002; 20(5 Suppl. 27): S1–13 Nakanishi K, Yoshimoto T, Tsutsui T, et al. Interleukin-18 regulates both TH1 and TH2 responses. Annu Rev Immunol 2001; 19:423–74 Singh R, Ahmed S, Malemud CJ, et al. Epigallocatechin-3-gallate selectively inhibits interleukin-1 b-induced activation of mitogen activated protein kinase subgroup c-Jun-N-terminal kinase in human osteoarthritis chondrocytes. J Orthop Res 2003; 21(1): 102–9 Notoya K, Jovanovic DV, Reboul P, et al. The induction of cell death in human osteoarthritis chondrocytes by nitric oxide is related to the production of prostaglandin E2 via the induction of cyclooxygenase-2. J Immunol 2000; 165(6): 3402–10 Matsui K, Tsutsui H, Nakanishi K. Pathophysiological roles for IL-18 in inflammatory arthritis. Expert Opin Ther Targets 2003; 7(6): 701–24 Lee JK, Kim SH, Lewis EC, et al. Differences in signaling pathways by IL-1β and IL-18. Proc Natl Acad Sci U S A 2004; 101(23): 8815–20 Wannamaker W, Davies R, Namchuk M, et al. (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3, 3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX–765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1β and IL-18. J Pharmacol Exp Ther 2007; 321(2): 509–16 Gracie JA, Forsey RJ, Chan WL, et al. A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest 1999; 104(10): 1393–401 Wei XQ, Leung BP, Arthur HM, et al. Reduced incidence and severity of collagen-induced arthritis in mice lacking IL-18. J Immunol 2001; 166(1): 517–21 Ye XJ, Tang B, Ma Z, et al. The role of interleukin-18 in collagen-induced arthritis in the BB rat. Clin Exp Immunol 2004; 136(3): 440–7 Futani H, Okayama A, Matsui K, et al. Relationship between interleukin-18 and PGE2 in synovial fluid of osteoarthritis: a potential therapeutic target of cartilage degradation. J Immunother 2002; 25Suppl. 1: S61–4 Dai SM, Shan ZZ, Nishioka K, et al. Implication of interleukin 18 in production of matrix metalloproteinases in articular chondrocytes in arthritis: direct effect on chondrocytes may not be pivotal. Ann Rheum Dis 2005; 64(5): 735–42 John T, Kohl B, Mobasheri A, et al. Interleukin-18 induces apoptosis in human articular chondrocytes. Histol Histopathol 2007; 22(5): 469–82 Verri Jr WA, Cunha TM, Parada CA, et al. Antigen-induced inflammatory mechanical hypernocioception in mice is mediated by IL-18. Brain Behav Immun 2007; 21(5): 535–43 Honorati MC, Neri S, Cattini L, et al. Interleukin-17, a regulator of angiogenic factor release by synovial fibroblasts. Osteoarthritis Cartilage 2006; 14(4): 345–52 Van Bezooijen RL, Van Der Wee-Pals L, Papapoulos SE, et al. Interleukin 17 synergizes with tumour necrosis factor alpha to induce cartilage destruction in vitro. Ann Rheum Dis 2002; 61(10): 870–6 Miljkovic D, Trajkovic V. Inducible nitric oxide synthase activation by interleukin-17. Cytokine Growth Factor Rev 2004; 15(1): 21–32 Honorati MC, Bovara M, Cattini L, et al. Contribution of IL-17 to human cartilage degradation and synovial inflammation in osteoarthritis. Osteoarthritis Cartilage 2002; 10(10): 799–807 Honorati MC, Cattini L, Facchini A. VEGF production by osteoarthritic chondrocytes cultured in micromass stimulated by IL-17 and TNF-α. Connect Tissue Res 2007; 48(5): 239–45 Lubberts E, Koenders MI, van den Berg WB. The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res Ther 2005; 7(1): 29–37 Aigner T, Van der Kraan P, Van den Berg WB. Osteoarthritis and inflammation: inflammatory changes in osteoarthritic synoviopathy. In: Buckwalter JA, Lotz M, Stoltz J-F, editors. Osteoarthritis, inflammation and degradation: a continuum. Amsterdam: IOS Press, 2007: 219–35 Wang G, Matsuura I, He D, et al. Transforming growth factor-β-inducible phosphorylation of Smad3. J Biol Chem 2009; 284(15): 9663–73 Scharstuhl A, Vitters EL, van der Kraan PM, et al. Reduction of osteophyte formation and synovial thickening by adenoviral overexpression of transforming growth factor β/bone morphogenetic protein inhibitors during experimental osteoarthritis. Arthritis Rheum 2003; 48(12): 3442–51 Roman-Blas JA, Stokes DG, Jimenez SA. Modulation of TGF-β signaling by proinflammatory cytokines in articular chondrocytes. Osteoarthritis Cartilage 2007; 15(12): 1367–77 Blaney Davidson EN, Vitters EL, van den Berg WB, et al. TGF β-induced cartilage repair is maintained but fibrosis is blocked in the presence of Smad7. Arthritis Res Ther 2006; 8(3): R65 Blaney Davidson EN, Scharstuhl A, Vitters EL, et al. Reduced transforming growth factor-beta signaling in cartilage of old mice: role in impaired repair capacity. Arthritis Res Ther 2005; 7(6): R1338–47 Wu Q, Kim KO, Sampson ER, et al. Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum 2008; 58(10): 3132–44 Nakajima M, Kizawa H, Saitoh M, et al. Mechanisms for asporin function and regulation in articular cartilage. J Biol Chem 2007; 282(44): 32185–92 Kizawa H, Kou I, Iida A, et al. An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat Genet 2005; 37(2): 138–44 Kou I, Nakajima M, Ikegawa S. Expression and regulation of the osteoarthritis-associated protein asporin. J Biol Chem 2007; 282(44): 32193–9 Lires-Deän M, Caramés B, Cillero-Pastor B, et al. Anti-apoptotic effect of transforming growth factor-β1 on human articular chondrocytes: role of protein phosphatase 2A. Osteoarthritis Cartilage 2008; 16(11): 1370–8 Rollín R, Alvarez-Lafuente R, Marco F, et al. Abnormal transforming growth factor-β expression in mesenchymal stem cells from patients with osteoarthritis. J Rheumatol 2008; 35(5): 904–6 Nelson AE, Fang F, Shi XA, et al. Failure of transforming growth factor-beta (TGF-β) as a biomarker of radiographic osteoarthritis of the knee and hip: a cross-sectional analysis in the Johnston County Osteoarthritis Project. Osteoarthritis Cartilage 2009; 17(6): 772–6 Schmidt MB, Chen EH, Lynch SE. A review of the effects of insulin-like growth factor and platelet derived growth factor on in vivo cartilage healing and repair. Osteoarthritis Cartilage 2006; 14(5): 403–12 Loeser RF, Shanker G, Carlson CS, et al. Reduction in the chondrocyte response to insulin-like growth factor 1 in aging and osteoarthritis: studies in a non-human primate model of naturally occurring disease. Arthritis Rheum 2000; 43(9): 2110–20 Okada A, Mochizuki S, Yatabe T, et al. ADAM-12 (meltrin-α) is involved in chondrocyte proliferation via cleavage of insulin-like growth factor binding protein 5 in osteoarthritic cartilage. Arthritis Rheum 2008; 58(3): 778–9 Cravero JD, Carlson CS, Im HJ, et al. Increased expression of the Akt/PKB inhibitor TRB3 in osteoarthritic chondrocytes inhibits insulin-like growth factor 1-mediated cell survival and proteoglycan synthesis. Arthritis Rheum 2009; 60(2): 492–500 Du K, Herzig S, Kulkarni RN, et al. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 2003; 300(5625): 1574–7 Massicotte F, Aubry I, Martel-Pelletier J, et al. Abnormal insulin-like growth factor 1 signaling in human osteoarthritic subchondral bone osteoblasts. Arthritis Res Ther 2006; 8(6): R177 Sawaji Y, Hynes J, Vincent T, et al. Fibroblast growth factor 2 inhibits induction of aggrecanase activity in human articular cartilage. Arthritis Rheum 2008; 58(11): 3498–509 Chia SL, Sawaji Y, Burleigh A, et al. Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMT-5 and delays cartilage degradation in murine osteoarthritis. Arthritis Rheum 2009; 60(7): 2019–27 Vincent TL, McLean CJ, Full LE, et al. FGF-2 is bound to perlecan in the pericellular matrix of articular cartilage where it acts as a chondrocyte mechanotransducer. Osteoarthritis Cartilage 2007; 15(7): 752–63 Huang K, Wu LD. Aggrecanase and aggrecan degradation in osteoarthritis: a review. J Int Med Res 2008; 36(6): 1149–60 Daouti S, Latario B, Nagulapalli S, et al. Development of comprehensive functional genomic screens to identify novel mediators of osteoarthritis. Osteoarthritis Cartilage 2005; 13(6): 508–18 Pohlers D, Huber R, Ukena B, et al. Expression of platelet-derived growth factors C and D in the synovial membrane of patients with rheumatoid arthritis and osteoarthritis. Arthritis Rheum 2006; 54(3): 788–94 Kubota S, Takigawa M. Role of CCN2/CTGF/Hcs24 in bone growth. Int Rev Cytol 2007; 257: 1–41 Tardif G, Reboul P, Pelletier J-P, et al. Ten years in the life of an enzyme: the story of human MMP-13 (collagenase-3). Mod Rheumatol 2004; 14(3): 197–204 Omoto S, Nishida K, Yamaai Y, et al. Expression and localization of connective tissue growth factor (CTGF/Hcs24/CCN2) in osteoarthritic cartilage. Osteoarthritis Cartilage 2004; 12(10): 771–8 Nishida T, Kubota S, Kojima S, et al. Regeneration of defects in articular cartilage in rat knee joints by CCN2 (connective tissue growth factor). J Bone Miner Res 2004; 19(8): 1308–19 Blaney Davidson EN, Vitters EL, Mooren FM, et al. Connective tissue growth factor/CCN2 overexpression in mouse synovial lining results in transient fibrosis and cartilage damage. Arthritis Rheum 2006; 54(5): 1653–61 Woods A, Pala D, Kennedy L, et al. Rac1 signaling regulates CTGF/CCN2 gene expression via TGFβ/Smad signaling in chondrocytes. Osteoarthritis Cartilage 2009; 17(3): 406–13 Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the Tocilizumab in Combination with Traditional Disease-modifying Antirheumatic Drug Therapy Study. Arthritis Rheum 2008; 58(10): 2968–80 Bliddal H, Terslev L, Qvistgaard E, et al. A randomized, controlled study of a single intra-articular injection of etanercept or glucocorticoids in patients with rheumatoid arthritis. Scand J Rheumatol 2006; 35(5): 341–5 van der Bijl AE, Teng YKO, van Oosterhout M, et al. Efficacy of intraarticular infliximab in patients with chronic or recurrent gonarthritis: a clinical randomized trial. Arthritis Care Res 2009; 61(7): 974–8 Kim HA, Cho M-L, Choi HY, et al. The catabolic pathway mediated by Toll-like receptors in human osteoarthritic chondrocytes. Arthritis Rheum 2006; 54(7): 2152–63 Zhang Q, Hui W, Litherland GJ, et al. Differential Toll-like receptor-dependent collagenase expression in chondrocytes. Ann Rheum Dis 2008; 67(11): 1633–41 Scanzello CR, Plaas A, Crow MK. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Curr Opin Rheumatol 2008; 20(5): 565–72 Yudoh K, Nguyen T, Nakamura H, et al. Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function. Arthritis Res Ther 2005; 7(2): R380–91 Vicini P, Incerti M, Cardile V, et al. Benzo[d]isothiazol-3-yl-benzamidines: a class of protective agents on culture of human cartilage and chondrocytes stimulated by IL-1β. ChemMedChem 2007; 2(1): 113–9 Cillero-Pastor B, Caramés B, Lires-Deàn M, et al. Mitochondrial dysfunction activates cyclooxygenase 2 expression in cultured normal human chondrocytes. Arthritis Rheum 2008; 58(8): 2409–19 Kim HA, Blanco FJ. Cell death and apoptosis in osteoarthritic cartilage. Curr Drug Targets 2007; 8(2): 333–45 Lago R, Gomez R, Otero M, et al. A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase II and pro-inflammatory cytokines in chondrocytes. Osteoarthritis Cartilage 2008; 16(9): 1101–9 Giatromanolaki A, Sivridis E, Athanassou N, et al. The angiogenic pathway ‘vascular endothelial growth factor/flk-1 (KDR) receptor’ in rheumatoid arthritis and osteoarthritis. J Pathol 2001; 194(1): 101–8 Giatromanolaki A, Sivridis E, Maltezos E, et al. Upregulated hypoxia-inducible factor-1α and -2α in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 2003; 5(4): R193–201 Valdes AM, Lories RJ, van Meurs JB, et al. Variation at the ANP32a gene is associated with risk of hip osteoarthritis in women. Arthritis Rheum 2009; 60(7): 2046–54 Egli RJ, Southam L, Wilkins JM, et al. Functional analysis of the osteoarthritis susceptibility-associated GDF5 regulatory polymorphism. Arthritis Rheum 2009; 60(7): 2055–64 Nixon AJ, Haupt L, Frisbie DD, et al. Gene-mediated restoration of cartilage matrix by combination insulin-like growth factor-I/interleukin receptor antagonist therapy. Gen Ther 2005; 12(2): 177–86 Malemud CJ. Gene therapy for arthritis: defining novel gene targets. Gen Ther Mol Biol 2007; 11: 27–36