Are we moving in the right direction with osteoarthritis drug discovery?

Expert Opinion on Therapeutic Targets

Volumn 15, Issue 12, 2011, Pages 1355-1368

  Bondeson, Jan ^a  

^a CARDIFF UNIVERSITY   (United Kingdom)

Author keywords

disease modifying drug; interleukin 1; macrophage; osteoarthritis; tumour necrosis factor alpha

Indexed keywords

AGGRECANASE; CYTOKINE; DISEASE MODIFYING ANTIRHEUMATIC DRUG; ETANERCEPT; INDUCIBLE NITRIC OXIDE SYNTHASE; INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITOR; INTERLEUKIN 1 ANTIBODY; MATRIX METALLOPROTEINASE; MATRIX METALLOPROTEINASE INHIBITOR; NITRIC OXIDE SYNTHASE INHIBITOR; UNCLASSIFIED DRUG; WNT PROTEIN;

BONE INJURY; CARTILAGE DEGENERATION; DRUG RESEARCH; DRUG TARGETING; HUMAN; MACROPHAGE; NONHUMAN; OSTEOARTHRITIS; OSTEOPHYTE; REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; SYNOVIUM;

ANIMALS; CYTOKINES; DRUG DISCOVERY; HUMANS; MACROPHAGES; MATRIX METALLOPROTEINASES; NITRIC OXIDE SYNTHASE TYPE II; OSTEOARTHRITIS; SYNOVIAL MEMBRANE; WNT SIGNALING PATHWAY;

EID: 83655193181     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2011.636740     Document Type: Review

References (86)

1. Qvist P, Bay-Jensen AC, Christiansen C, et al. The disease modifying osteoarthritis drug (DMOAD): is it in the horizon? Pharmacol Res 2008;58:1-7
2. Hellio Le Graverand-Gastineau MP. OA clinical trials: current targets and trials for OA. Choosing molecular targets: what have we learned and where we are headed? Osteoarthritis Cartilage 2009;17:1393-401
3. Bondeson J. Activated synovial macrophages as targets for osteoarthritis drug therapy. Curr Drug Targets 2010;11:576-85
4. van den Berg WB. Osteoarthritis year 2010 in review: pathomechanisms. Osteoarthritis Cartilage 2011;19:338-241
5. Flannery CR. Novel therapies in OA. Curr Drug Targets 2010;11:614-19
6. Hunter DJ. Pharmacologic therapy for osteoarthritis - the era of disease modulation. Nat Rev Rheumatol 2011;7:13-22
7. Bingham CO III, Buckland-Wright JC, Garnero P, et al. Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study. Arthritis Rheum 2006;54:3494-507 (Pubitemid 44737161)
8. Brandt KD, Mazzuca SA, Katz BP, et al. Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum 2005;52:2015-25 (Pubitemid 40994324)
9. Hunter DJ, Li J, LaValley M, et al. Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study. Arthritis Res Ther 2007;9:R108
10. Williams FM, Spector TD. Biomarkers in osteoarthritis. Arthritis Res Ther 2008;10:101
11. Hunter DJ, Losina E, Guermazi A, et al. A pathway and approach to biomarker validation and qualification for osteoarthritis clinical trials. Curr Drug Targets 2010;11:536-45
12. Nüesch E, Rutjes AW, Trelle S, et al. Doxycycline for osteoarthritis of the knee or hip. Cochrane Database Syst Rev 2009;4:CD007323
13. Mazzuca SA, Brandt KD, Chakr R, Lane KA. Varus malalignment negates the structure-modifying benefits of doxycycline in obese women with knee osteoarthritis. Osteoarthritis Cartilage 2010;18:1008-11
14. Rintelen B, Neumann K, Leeb BF. A meta-analysis of controlled clinical studies with diacerein in the treatment of osteoarthritis. Arch Intern Med 2006;166:1899-906 (Pubitemid 44455174)
15. Dougados M, Nguyen M, Berdah L, et al. Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip. Arthritis Rheum 2001;44:2539-47 (Pubitemid 33049332)
16. Pham T, Le Henanff A, Ravaud P, et al. Evaluation of the symptomatic and structural efficacy of a new hyaluronic acid compound, NRD101, in comparison with diacerein and placebo in a 1 year randomised controlled study in symptomatic knee osteoarthritis. Ann Rheum Dis 2004;63:1611-17 (Pubitemid 39573690)
17. Raynauld JP, Martel-Pelletier J, Bias P, et al. Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis: a first multicentre clinical trial using quantitative MRI. Ann Rheum Dis 2009;68:938-47
18. Wildi LM, Paynauld J-P, Martel-Pelletier J, et al. Chondroitin sulphate reduces both cartilage volume loss and bone marrow lesions in knee osteoarthritis patients starting as early as 6 months after initiation of therapy: a randomised, double-blind, placebo-controlled pilot study using MRI. Ann Rheum Dis 2011;70:982-9
19. Wandel S, Jüni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ 2010;341:c4675
20. Pelletier J-P, Roughley PJ, DiBattista JA, et al. Are cytokines involved in osteoarthritic pathophysiology? Semin Arthritis Rheum 1991;20(Suppl 2):12-25
21. Blom AB, van den Berg WB. The synovium and its role in osteoarthritis. In: Bronner F, Farach-Carson MC, editors. Bone and Osteoarthritis. Volume 4 Springer Verlag; Berlin: 2007. p. 65-79
22. Bondeson J, Blom AB, Wainwright SD, et al. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum 2010;62:647-57
23. Clark AG, Jordan JM, Vilim V, et al. Serum cartilage oligomeric protein reflects osteoarthritis presence and severity. Arthritis Rheum 1999;42:2356-64
24. Sowers M, Jannausch M, Stein E, et al. C-reactive protein as a biomarker of emergent osteoarthritis. Osteoarthritis Cartilage 2002;10:595-601 (Pubitemid 34993944)
25. Benito MJ, Veale DJ, FitzGerald O, et al. Synovial tissue inflammation in early and late osteoarthritis. Ann Rheum Dis 2005;64:1263-7 (Pubitemid 41206240)
26. Foxwell BMJ, Browne KA, Bondeson J, et al. Efficient adenoviral infection with IkappaBalpha reveals that macrophage TNFalpha production in rheumatoid arthritis is NF-kappaB dependent. Proc Natl Acad Sci USA 1998;95:8211-15 (Pubitemid 28326092)
27. Bondeson J, Foxwell BMJ, Brennan FM, Feldmann M. A new approach to defining therapeutic targets: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium, but spares anti-inflammatory mediators. Proc Natl Acad Sci USA 1999;96:5668-73 (Pubitemid 29234676)
28. Amos N, Lauder S, Evans A, et al. Adenoviral gene transfer into osteoarthritis synovial cells using the endogenous inhibitor IkappaBalpha reveals that most, but not all, inhibitory and destructive mediators, are NFkappaB dependent. Rheumatology 2006;45:1201-9 (Pubitemid 44542060)
29. Bondeson J, Browne KA, Brennan FM, et al. Selective regulation of cytokine induction by adenoviral gene transfer of IkappaBalpha into human macrophages: lipopolysaccharide-induced, but not zymosan-induced, proinflammatory cytokines are inhibited, but IL-10 is NFkappaB independent. J Immunol 1999;162:2939-45 (Pubitemid 29309322)
30. 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:R187
31. Blom AB, van Lent PLEM, Holthuysen AEM, et al. Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartilage 2004;12:627-35 (Pubitemid 39022781)
32. Van Lent PLEM, Blom AB, van der Kraan P, et al. Cricial role of synovial lining macrophages in the promotion of transforming growth factor beta-mediated osteophyte formation. Arthritis Rheum 2004;50:103-11 (Pubitemid 38084294)
33. Blom AB, van Lent PL, Libregts S, et al. Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis. Arthritis Rheum 2007;56:147-57 (Pubitemid 46106187)
34. Brennan FM, Chantry D, Jackson A, et al. Inhibitory effect of TNFalpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 1989;334:244-7 (Pubitemid 19180612)
35. Bondeson J, Wainwright S, Hughes C, Caterson B. The regulation of ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review. Clin Exp Rheumatol 2008;26:139-45 (Pubitemid 351385270)
36. Burger D, Dayer J-M, Palmer G, Gabay C. Is IL-1 a good therapeutic target in the treatment of arthritis? Best Pract Res Clin Rheumatol 2006;20:879-96
37. Kalliolias GD, Liossis SNC. The future of the IL-1 receptor antagonist anakinra: from rheumatoid arthritis to adult-onset Still's disease and systemic-onset juvenile idiopathic arthritis. Expert Opin Investig Drugs 2008;17:349-59 (Pubitemid 351578187)
38. Rudolphi K, Gerwin N, Verzijl N, et al. Pralnacasan, an inhibitor of interleukin-1 converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoarthritis Cartilage 2003;11:738-46 (Pubitemid 37184492)
39. Grunke M, Schulze-Koops H. Successful treatment of inflammatory knee osteoarthritis with tumour necrosis factor blockade. Ann Rheum Dis 2006;65:555-6
40. Magnano MD, Chakravarty EF, Broudy C, et al. A pilot study of tumor necrosis factor inhibition in erosive/ inflammatory osteoarthritis of the hands. J Rheumatol 2007;34:1323-7 (Pubitemid 46898115)
41. Fioravanti A, Fabbroni M, Cerase A, Galeazzi M. Treatment of erosive osteoarthritis of the hands by intra-articular inflizimab injections: a pilot study. Rheumatol Int 2009;29:961-5
42. Güler-Yüksel M, Kloppenburg M, Allaart CF, et al. Infliximab might be protective against progressive radiographic interphalangeal osteoarthritis. Osteoarthritis Cartilage 2008;16(Suppl 4):S228
43. Güler-Yüksel M, Allaart CF, Watt I, et al. Treatment with TNF-alpha inhibitor infliximab might reduce hand osteoarthritis in patients with rheumatoid arthritis. Osteoarthritis Cartilage 2010;18:1256-62
44. Chevalier X, Girardeau B, Conzorier 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;32:1317-23 (Pubitemid 40995389)
45. Goupille P, Mulleman D, Chevalier X. Is interleukin-1 a good target for therapeutic intervention in intervertebral disc degeneration: lessons from the osteoarthritic experience. Arthritis Res Ther 2007;9:110
46. Chevalier X, Goupille P, Beaulieu AD, et al. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, double-blind, placebo-controlled study. Arthritis Care Res 2009;61:344-52
47. Saklatvala J. Inflammatory signaling in cartilage: MAPK and NF-kappa B pathways in chondrocytes and the use of inhibitors for research into pathogenesis and therapy of osteoarthritis. Curr Drug Targets 2007;7:305-13
48. Frisbie DD, Ghivizzani SC, Robbins PD, et al. Treatment of equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther 2002;9:12-20 (Pubitemid 34145163)
49. Chen LX, Lin L, Wang HJ, et al. Suppression of early experimental osteoartritis by in vivo delivery of the adenoviral vector-mediated NFkappaBspecific siRNA. Osteoarthritis Cartilage 2008;16:174-84 (Pubitemid 351218179)
50. Hashimoto S, Takahashi K, Amiel D, et al. Chondrocyte apoptosis and nitric oxide production during experimentally induced osteoarthritis. Arthritis Rheum 1998;41:1266-74 (Pubitemid 28313430)
51. Hellio le Graverand MP, Vignon E, Otterness IG, et al. Early changes in lapine menisci during osteoarthritis development Part II: molecular alterations. Osteoarthritis Cartilage 2000;9:65-72 (Pubitemid 32154919)
52. Van Den Berg WB, van de Loo F, Joosten LA, Arntz OJ. Animal models of arthritis in NOS2-deficient mice. Osteoarthritis Cartilage 1999;7:413-15 (Pubitemid 29331565)
53. Hellio Le Graverand-Gastineau M-P. Disease modifying osteoarthritis drugs: Facing development challenges and choosing molecular targets. Curr Drug Targets 2010;11:528-35
54. Hutchinson JW, Tierney GM, Parsons SL, Davis TR. Dupuytren's disease and frozen shoulder induced by treatment with a matrix metalloproteinase inhibitor. J Bone Joint Surg Br 1998;80:907-8 (Pubitemid 28457089)
55. Neuhold LA, Killar L, Zhao W, et al. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest 2001;107:35-44 (Pubitemid 32047412)
56. Baragi VM, Becher G, Bendele AM, et al. A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models. Arthritis Rheum 2009;60:2008-18
57. Glasson SS, Askew R, Sheppard B, et al. Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum 2004;50:2547-58 (Pubitemid 39062716)
58. Glasson SS, Askew R, Sheppard B, et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 2005;434:644-8 (Pubitemid 40488556)
59. Stanton H, Rogerson FM, East CJ, et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 2005;434:648-52 (Pubitemid 40488557)
60. Song RH, Tortorella MD, Malfait AM, et al. Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum 2007;56:575-85
61. Gendron C, Kashiwagi M, Lim NH, et al. Proteolytic activities of human ADAMTS-5. Comparative studies with ADAMTS-4. J Biol Chem 2007;282:18294-306 (Pubitemid 47100219)
62. Fosang AJ, Rogerson FM, East CJ, Stanton H. ADAMTS-5: the story so far. Eur Cell Mater 2008;15:11-26 (Pubitemid 351955729)
63. Wittwer AJ, Hills RL, Keith RH, et al. Substrate-dependent inhibition kinetics of an active site-directed inhibitor of ADAMTS-4 (Aggrecanase 1). Biochemistry 2007;46:6393-401 (Pubitemid 46842882)
64. Tortorella MD, Tomasselli AG, Mathis KJ, et al. Structural and inhibition analysis reveals the mechanism of selectivity of a series of aggrecanase inhibitors. J Biol Chem 2009;284:24185-91
65. Gilbert AM, Bikker JA, O'Neil SV. Advances in the development of novel aggrecanase inhibitors. Expert Opin Ther Patents 2011;21:1-12
66. Kashiwagi M, Tortorella M, Nagase H, Brew K. TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem 2001;276:12501-4
67. Wayne GJ, Deng SJ, Amour A, et al. TIMP-3 inhibition of ADAMTS-4 (Aggrecanase-1) is modulated by interactions between aggrecan and the C-terminal domain of ADAMTS-4. J Biol Chem 2007;282:20991-8 (Pubitemid 47099922)
68. Lim NH, Kashiwagi M, Visse R, et al. Reactive-site mutants of N-TIMP-3 that selectively inhibit ADAMTS-4 and ADAMTS-5: biological and structural implications Biochem J. 2010;431:113-22
69. Sahebjam S, Khokha R, Mort JS. Increased collagen and aggrecan degradation with age in the joints of Timp3-/- mice. Arthritis Rheum 2007;56:905-9 (Pubitemid 46399438)
70. Blom AB, van Lent PL, van der Kraan PM, van den Berg WB. To seek shelter from the WNT in osteoarthritis? WNT-signaling as a target for osteoarthritis therapy. Curr Drug Targets 2010;11:620-9
71. Blom AB, Brockbank SM, van Lent PL, et al. Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1. Arthritis Rheum 2009;60:501-12
72. Urano T, Narusawa K, Shiraki M, et al. Association of a single nucleotide polymorphism in the WISP1 gene with spinal osteoarthritis in postmenopausal Japanese women. J Bone Miner Metab 2007;25:253-8 (Pubitemid 47012483)
73. Manicourt DH, Devogelaer JP, Azria M, Silverman S. Rationale for the potential use of calcitonin in osteoarthritis. J Musculoskelet Neuronal Interact 2005;5:285-93 (Pubitemid 41684177)
74. Karsdal MA, Sondergaard BC, Arnold M, Christiansen C. Calcitonin affects both bone and cartilage: a dual action treatment for osteoarthritis? Ann NY Acad Sci 2007;1117:181-95
75. Jubb RW, Piva S, Beinat L, et al. A one-year, randomised, placebo (saline) controlled clinical trial of 500 - 730 kDa sodium hyaluronate (Hyalgan) on the radiological change in osteoarthritis of the knee. Int J Clin Pract 2003;57:467-74 (Pubitemid 36974884)
76. Chevalier X. Intraarticular treatments for osteoarthritis: new perspectives. Curr Drug Targets 2010;11:546-60
77. Elsaid KA, Fleming BC, Oksendahl HL, et al. Decreased lubricin concentrations and markers of joint inflammation in the synovial fluid of patients with anterior cruciate ligament injury. Arthritis Rheum 2008;58:1707-15 (Pubitemid 351847524)
78. Flannery CR, Zollner R, Corcoran C, et al. Prevention of cartilage degeneration in a rat model of osteoarthritis by intraarticular treatment with recombinant lubricin. Arthritis Rheum 2009;60:840-7
79. Badlani N, Inoue A, Healey R, et al. The protective effect of OP-1 on articular cartilage in the development of osteoarthritis. Osteoarthritis Cartilage 2008;16:600-6 (Pubitemid 351524695)
80. Sekiya I, Tang T, Hayashi M, et al. Periodic knee injections of BMP-7 delay cartilage degeneration induced by excessive running in rats. J Orthop Res 2009;27:1088-92
81. Moore EE, Bendele AM, Thompson DL, et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model ofinjury-induced osteoarthritis. Osteoarthritis Cartilage 2005;13:623-31 (Pubitemid 40867862)
82. Maini RN, Feldmann M. The pitfalls in the development of biologic therapy. Nat Clin Pract Rheumatol 2007;3:1
83. Feldmann M. Translating molecular insights in autoimmunity into effective therapy. Annu Rev Immunol 2009;27:1-27
84. Blom AB, van den Berg WB. The synovium and its role in osteoarthritis. In: Bronner F, Farach-Carson MC, editors. Bone and Osteoarthritis. Volume 4 Springer Verlag; Berlin: 2007. p. 65-79
85. Shahrara S, Castro-Rueda HP, Haines GK, Koch AE. Differential expression of the FAK family kinases in rheumatoid arthritis and osteoarthritis synovial tissue. Arthritis Res Ther 2007;9:R112
86. McCulloch DR, Nelson CM, Dixon LJ, et al. ADAMTS metalloproteases generate active versican fragments that regulate interdigital web regression. Dev Cell 2009;17:687-98