Metalloproteases in the pathogenesis of osteoarthritis: Possible targets for treatment?

International Journal of Advances in Rheumatology

Volumn 8, Issue 3, 2010, Pages 103-110

  Monemdjou, Roxana ^a   Fahmi, Hassan ^a   Pelletier, Jean Pierre ^a   Martel Pelletier, Johanne ^a   Kapoor, Mohit ^a  

^a NOTRE DAME HOSPITAL   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

AGGRECANASE; BATIMASTAT; CARBOXY TERMINAL TELOPEPTIDE; COLLAGEN TYPE 2; COLLAGENASE 3; CYCLOOXYGENASE 2 INHIBITOR; DOXYCYCLINE; GELATINASE; GLUCOCORTICOID; INTERLEUKIN 17; INTERSTITIAL COLLAGENASE; MARIMASTAT; MATRILYSIN; MATRIX METALLOPROTEINASE 14; MATRIX METALLOPROTEINASE 15; MATRIX METALLOPROTEINASE 16; MINOCYCLINE; NEUTROPHIL COLLAGENASE; NONSTEROID ANTIINFLAMMATORY AGENT; OPIATE; PARACETAMOL; SCATTER FACTOR; STROMELYSIN; STROMELYSIN 2; TANOMASTAT; TISSUE INHIBITOR OF METALLOPROTEINASE 1; TISSUE INHIBITOR OF METALLOPROTEINASE 2; TISSUE INHIBITOR OF METALLOPROTEINASE 3; TISSUE INHIBITOR OF METALLOPROTEINASE 4;

CRYSTAL STRUCTURE; DISEASE COURSE; DRUG EFFICACY; ENZYME ACTIVE SITE; ENZYME ACTIVITY; GENE EXPRESSION; HUMAN; NONHUMAN; OSTEOARTHRITIS; PATHOGENESIS; PATHOPHYSIOLOGY; PROTEIN BINDING; REVIEW; RHEUMATOID ARTHRITIS; TISSUE DEGENERATION;

EID: 84863817457     PISSN: 1478856X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (97)

1. Lawrence RC, Felson DT, Helmick CG et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58:26-35.
2. Anandacoomarasamy A, March L. Current evidence for osteoarthritis treatments. Ther Adv Musculoskel Dis 2010;2:17-28.
3. Martel-Pelletier J, Lajeunesse D, Pelletier J-P. Etiopathogenesis of osteoarthritis. In: Koopman WJ, Moreland LW. Editors. Arthritis and Allied Conditions. A Textbook of Rheumatology. 15th edition. Baltimore, MD: Lippincott, Williams & Wilkins, 2005:2199-226.
4. Martel-Pelletier J, Boileau C, Pelletier JP et al. Cartilage in normal and osteoarthritis conditions. Best Pract Res Clin Rheumatol 2008;22:351-84. (Pubitemid 351606950)
5. Murphy G, Nagase H. Reappraising metalloproteinases in rheumatoid arthritis and osteoarthritis: destruction or repair? Nat Clin Pract Rheumatol 2008;4:128-35. (Pubitemid 351338627)
6. Karsdal MA, Madsen SH, Christiansen C et al. Cartilage degradation is fully reversible in the presence of aggrecanase but not matrix metalloproteinase activity. Arthritis Res Ther 2008;10:R63.
7. Behrens F, Kraft EL, Oegema TR Jr. Biochemical changes in articular cartilage after joint immobilization by casting or external fixation. J Orthop Res 1989;7:335-43. (Pubitemid 19132851)
8. Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol 2007;213:626-34. (Pubitemid 350058254)
9. Tanaka S, Hamanishi C, Kikuchi H et al. Factors related to degradation of articular cartilage in osteoarthritis: a review. Semin Arthritis Rheum 1998;27:392-9. (Pubitemid 28298352)
10. Gross J, Lapiere CM. Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci U S A 1962;48:1014-22.
11. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006;69:562-73. (Pubitemid 43139720)
12. Benbow U, Brinckerhoff CE. The AP-1 site and MMP gene regulation: what is all the fuss about? Matrix Biol 1997;15:519-26. (Pubitemid 27190026)
13. Davidson RK, Waters JG, Kevorkian L et al. Expression profiling of metalloproteinases and their inhibitors in synovium and cartilage. Arthritis Res Ther 2006;8:R124.
14. Chubinskaya S, Huch K, Mikecz K et al. Chondrocyte matrix metalloproteinase-8: upregulation of neutrophil collagenase by interleukin-1 beta in human cartilage from knee and ankle joints. Lab Invest 1996;74:232-40. (Pubitemid 26041025)
15. Hulejova H, Baresova V, Klezl Z et al. Increased level of cytokines and matrix metalloproteinases in osteoarthritic subchondral bone. Cytokine 2007;38:151-6. (Pubitemid 47248299)
16. Aigner T, Zien A, Gehrsitz A et al. Anabolic and catabolic gene expression pattern analysis in normal versus osteoarthritic cartilage using complementary DNA-array technology. Arthritis Rheum 2001;44:2777-89. (Pubitemid 34016197)
17. Mitsui H, Tsuchiya N, Okinaga S. Expression of membrane-type metalloproteinases in synovial tissue from patients with rheumatoid arthritis or osteoarthritis. Mod Rheumatol 2001;11:34-9. (Pubitemid 32927100)
18. Bauer EA, Eisen AZ, Jeffrey JJ. Immunologic relationship of a purified human skin collagenase to other human and animal collagenases. Biochim Biophys Acta 1970;206:152-60.
19. Balbin M, Fueyo A, Knauper V et al. Identification and enzymatic characterization of two diverging murine counterparts of human interstitial collagenase (MMP-1) expressed at sites of embryo implantation. J Biol Chem 2001;276:10253-62.
20. Nagase H, Suzuki K, Morodomi T et al. Activation mechanisms of the precursors of matrix metalloproteinases 1, 2 and 3. Matrix Suppl 1992;1:237-44.
21. Knauper V, Lopez-Otin C, Smith B et al. Biochemical characterization of human collagenase-3. J Biol Chem 1996;271:1544-50. (Pubitemid 26028643)
22. Welgus HG, Jeffrey JJ, Eisen AZ. The collagen substrate specificity of human skin fibroblast collagenase. J Biol Chem 1981;256:9511-5. (Pubitemid 12234714)
23. Hasty KA, Jeffrey JJ, Hibbs MS et al. The collagen substrate specificity of human neutrophil collagenase. J Biol Chem 1987;262:10048-52. (Pubitemid 17103059)
24. Kobayashi M, Squires GR, Mousa A et al. Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage. Arthritis Rheum 2005;52:128-35. (Pubitemid 40129241)
25. Tardif G, Reboul P, Dupuis M et al. Transforming growth factor-beta induced collagenase-3 production in human osteoarthritic chondrocytes is triggered by Smad proteins: cooperation between activator protein-1 and PEA-3 binding sites. J Rheumatol 2001;28:1631-9. (Pubitemid 32660638)
26. Homandberg GA. Potential regulation of cartilage metabolism in osteoarthritis by fibronectin fragments. Front Biosci 1999;4:D713-30.
27. Roy-Beaudry M, Martel-Pelletier J, Pelletier JP et al. Endothelin 1 promotes osteoarthritic cartilage degradation via matrix metalloprotease 1 and matrix metalloprotease 13 induction. Arthritis Rheum 2003;48:2855-64.
28. Blain EJ, Gilbert SJ, Wardale RJ et al. Up-regulation of matrix metalloproteinase expression and activation following cyclical compressive loading of articular cartilage in vitro. Arch Biochem Biophys 2001;396:49-55.
29. Lee JH, Fitzgerald JB, Dimicco MA et al. Mechanical injury of cartilage explants causes specific time-dependent changes in chondrocyte gene expression. Arthritis Rheum 2005;52:2386-95. (Pubitemid 41117423)
30. Benderdour M, Tardif G, Pelletier JP et al. Interleukin 17 (IL-17) induces collagenase-3 production in human osteoarthritic chondrocytes via AP-1 dependent activation: differential activation of AP-1 members by IL-17 and IL-1beta. J Rheumatol 2002;29:1262-72. (Pubitemid 34601964)
31. Guevremont M, Martel-Pelletier J, Massicotte F et al. Human adult chondrocytes express hepatocyte growth factor (HGF) isoforms but not HgF: potential implication of osteoblasts on the presence of HGF in cartilage. J Bone Miner Res 2003;18:1073-81. (Pubitemid 37294945)
32. 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)
33. Little CB, Barai A, Burkhardt D et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 2009;60:3723-33.
34. Okada Y, Konomi H, Yada T et al. Degradation of type IX collagen by matrix metalloproteinase 3 (stromelysin) from human rheumatoid synovial cells. FEBS Lett 1989;244:473-6. (Pubitemid 19067171)
35. Clements KM, Price JS, Chambers MG et al. Gene deletion of either interleukin-1beta, interleukin-1beta-converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transection of the medial collateral ligament and partial medial meniscectomy. Arthritis Rheum 2003;48:3452-63. (Pubitemid 37531911)
36. Barksby HE, Milner JM, Patterson AM et al. Matrix metalloproteinase 10 promotion of collagenolysis via procollagenase activation: implications for cartilage degradation in arthritis. Arthritis Rheum 2006;54:3244-53. (Pubitemid 44622095)
37. Nakamura H, Fujii Y, Ohuchi E et al. Activation of the precursor of human stromelysin 2 and its interactions with other matrix metalloproteinases. Eur J Biochem 1998;253:67-75. (Pubitemid 28182306)
38. Mohtai M, Smith RL, Schurman DJ et al. Expression of 92-kD type IV collagenase/gelatinase (gelatinase B) in osteoarthritic cartilage and its induction in normal human articular cartilage by interleukin 1. J Clin Invest 1993;92:179-85. (Pubitemid 23208994)
39. Mitsui H, Tsuchiya N, Okinaga S et al. Expression of membrane-type metalloproteinases in synovial tissue from patients with rheumatoid arthritis or osteoarthritis. Mod Rheumatol 2001;11:34-9. (Pubitemid 32927100)
40. Honda S, Migita K, Hirai Y et al. Expression of membrane-type 1 matrix metalloproteinase in rheumatoid synovial cells. Clin Exp Immunol 2001;126:131-6. (Pubitemid 32989502)
41. Knauper V, Will H, Lopez-Otin C et al. Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme. J Biol Chem 1996;271:17124-31. (Pubitemid 26244262)
42. Ohta S, Imai K, Yamashita K et al. Expression of matrix metalloproteinase 7 (matrilysin) in human osteoarthritic cartilage. Lab Invest 1998;78:79-87. (Pubitemid 28074311)
43. 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.
44. 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)
45. -/- mice have less subchondral bone changes after induction of osteoarthritis through surgical instability: implications for a link between cartilage and subchondral bone changes. Osteoarthritis Cartilage 2009;17:636-45.
46. 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)
47. Echtermeyer F, Bertrand J, Dreier R et al. Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nat Med 2009;15:1072-6.
48. Gao G, Plaas A, Thompson VP et al. ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1. J Biol Chem 2004;279:10042-51. (Pubitemid 38372607)
49. Williamson RA, Smith BJ, Angal S et al, Freedman RB. Structural analysis of tissue inhibitor of metalloproteinases-1 (TIMP-1) by tryptic peptide mapping. Biochim Biophys Acta 1993;1164:8-16. (Pubitemid 23186283)
50. Su S, Grover J, Roughley PJ et al. Expression of the tissue inhibitor of metalloproteinases (TIMP) gene family in normal and osteoarthritic joints. Rheumatol Int 1999;18:183-91. (Pubitemid 29294981)
51. Martel-Pelletier J, McCollum R, Fujimoto N et al. Excess of metalloproteases over tissue inhibitor of metalloprotease may contribute to cartilage degradation in osteoarthritis and rheumatoid arthritis. Lab Invest 1994;70:807-15.
52. Zafarullah M, Su S, Martel-Pelletier J et al. Tissue inhibitor of metalloproteinase-2 (TIMP-2) mRNA is constitutively expressed in bovine, human normal, and osteoarthritic articular chondrocytes. J Cell Biochem 1996;60:211-7. (Pubitemid 26069216)
53. Huang W, Li WQ, Dehnade F et al. Tissue inhibitor of metalloproteinases-4 (TIMP-4) gene expression is increased in human osteoarthritic femoral head cartilage. J Cell Biochem 2002;85:295-303. (Pubitemid 34274897)
54. Dean DD, Martel-Pelletier J, Pelletier JP et al. Evidence for metalloproteinase and metalloproteinase inhibitor imbalance in human osteoarthritic cartilage. J Clin Invest 1989;84:678-85. (Pubitemid 19197004)
55. Leco KJ, Khokha R, Pavloff N et al. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem 1994;269:9352-60. (Pubitemid 24209266)
56. 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)
57. Zhao H, Bernardo MM, Osenkowski P et al. Differential inhibition of membrane type 3 (MT3)-matrix metalloproteinase (MMP) and MT1-MMP by tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3 rgulates pro-MMP-2 activation. J Biol Chem 2004;279:8592-601. (Pubitemid 38295913)
58. Amour A, Slocombe PM, Webster A et al. TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett 1998;435:39-44. (Pubitemid 28432011)
59. Kashiwagi M, Tortorella M, Nagase H et al. TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem 2001;276:12501-4.
60. Apte SS, Mattei MG, Olsen BR. Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Genomics 1994;19:86-90. (Pubitemid 24034370)
61. Hashimoto G, Aoki T, Nakamura H et al. Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1, 2, 3 and 4). FEBS Lett 2001;494:192-5. (Pubitemid 32322681)
62. Gomis-Ruth FX, Maskos K, Betz M et al. Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature 1997;389:77-81. (Pubitemid 27387694)
63. Fernandez-Catalan C, Bode W, Huber R et al. Crystal structure of the complex formed by the membrane type 1-matrix metalloproteinase with the tissue inhibitor of metalloproteinases-2, the soluble progelatinase A receptor. EMBO J 1998;17:5238-48. (Pubitemid 28408489)
64. Murphy G, Houbrechts A, Cockett MI et al. The N-terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity. Biochemistry 1991;30:8097-102.
65. Meng Q, Malinovskii V, Huang W et al. Residue 2 of TIMP-1 is a major determinant of affinity and specificity for matrix metalloproteinases but effects of substitutions do not correlate with those of the corresponding P1′ residue of substrate. J Biol Chem 1999;274:10184-9.
66. Wei S, Chen Y, Chung L et al. Protein engineering of the tissue inhibitor of metalloproteinase 1 (TIMP-1) inhibitory domain. In search of selective matrix metalloproteinase inhibitors. J Biol Chem 2003;278:9831-4. (Pubitemid 36800485)
67. Greenwald RA. Thirty-six years in the clinic without an MMP inhibitor. What hath collagenase wrought? Ann N Y Acad Sci 1999;878:413-9. (Pubitemid 29353585)
68. Moore WM, Spilburg CA. Purification of human collagenases with a hydroxamic acid affinity column. Biochemistry 1986;25:5189-95. (Pubitemid 17016532)
69. Clark IM, Parker AE. Metalloproteinases: their role in arthritis and potential as therapeutic targets. Expert Opin Ther Targets 2003;7:19-34. (Pubitemid 36204586)
70. Wojtowicz-Praga S, Torri J, Johnson M et al. Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. J Clin Oncol 1998;16:2150-6. (Pubitemid 28265052)
71. Macaulay VM, O'Byrne KJ, Saunders MP et al. Phase I study of intrapleural batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusions. Clin Cancer Res 1999;5:513-20. (Pubitemid 29131959)
72. Chu QS, Forouzesh B, Syed S et al. A Phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas. Invest New Drugs 2007;25:359-67. (Pubitemid 46944843)
73. Pavlaki M, Zucker S. Matrix metalloproteinase inhibitors (MMPIs): the beginning of Phase I or the termination of Phase III clinical trials. Cancer Metastasis Rev 2003;22:177-203. (Pubitemid 36561057)
74. Brown PD. Ongoing trials with matrix metalloproteinase inhibitors. Expert Opin Investig Drugs 2000;9:2167-77.
75. Lewis EJ, Bishop J, Bottomley KM et al. Ro 32-3555, an orally active collagenase inhibitor, prevents cartilage breakdown in vitro and in vivo. Br J Pharmacol 1997;121:540-6. (Pubitemid 27226308)
76. Y u LP Jr, Smith GN Jr, Brandt KD et al. Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline. Arthritis Rheum 1992;35:1150-9.
77. 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)
78. Skiles JW, Gonnella NC, Jeng AY. The design, structure, and clinical update of small molecular weight matrix metalloproteinase inhibitors. Curr Med Chem 2004;11:2911-77. (Pubitemid 39377700)
79. Krzeski P, Buckland-Wright C, Balint G et al. Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study. Arthritis Res Ther 2007;9:R109.
80. Bohm BB, Aigner T, Roy B et al. Homeostatic effects of the metalloproteinase disintegrin ADAM15 in degenerative cartilage remodeling. Arthritis Rheum 2005;52:1100-9. (Pubitemid 40530117)
81. Johnson AR, Pavlovsky AG, Ortwine DF et al. Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects. J Biol Chem 2007;282:27781-91. (Pubitemid 47529503)
82. Renkiewicz R, Qiu L, Lesch C et al. Broad-spectrum matrix metalloproteinase inhibitor marimastat-induced musculoskeletal side effects in rats. Arthritis Rheum 2003;48:1742-9. (Pubitemid 36682383)
83. Gooljarsingh LT, Lakdawala A, Coppo F et al. Characterization of an exosite binding inhibitor of matrix metalloproteinase 13. Protein Sci 2008;17:66-71.
84. Monovich LG, Tommasi RA, Fujimoto RA et al. Discovery of potent, selective, and orally active carboxylic acid based inhibitors of matrix metalloproteinase-13. J Med Chem 2009;52:3523-38.
85. 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.
86. Schroen DJ, Brinckerhoff CE. Nuclear hormone receptors inhibit matrix metalloproteinase (MMP) gene expression through diverse mechanisms. Gene Expr 1996;6:197-207.
87. Jones A, Doherty M. Intra-articular corticosteroids are effective in osteoarthritis but there are no clinical predictors of response. Ann Rheum Dis 1996;55:829-32. (Pubitemid 26392283)
88. Tardif G, Hum D, Pelletier JP et al. Regulation of the IGFBP-5 and MMP-13 genes by the microRNAs miR-140 and miR-27a in human osteoarthritic chondrocytes. BMC Musculoskelet Disord 2009;10:148.
89. Akhtar N, Rasheed Z, Ramamurthy S et al. MicroRNA-27b regulates the expression of matrix metalloproteinase 13 in human osteoarthritis chondrocytes. Arthritis Rheum 2010;62:1361-71.
90. Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci 2006;11:1696-701.
91. Malemud CJ. Protein kinases in chondrocyte signaling and osteoarthritis. Clin Orthop Relat Res 2004;(427 Suppl):S145-51. (Pubitemid 39362815)
92. Mengshol JA, Mix KS, Brinckerhoff CE. Matrix metalloproteinases as therapeutic targets in arthritic diseases: bull's-eye or missing the mark? Arthritis Rheum 2002;46:13-20. (Pubitemid 34121646)
93. Vincenti MP, Brinckerhoff CE. Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res 2002;4:157-64. (Pubitemid 34460754)
94. Brennan FM, Browne KA, Green PA et al. Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-alpha (cA2) therapy. Br J Rheumatol 1997;36:643-50.
95. Han Z, Boyle DL, Chang L et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 2001;108:73-81. (Pubitemid 32634924)
96. Kwan Tat S, Amiable N, Pelletier JP et al. Modulation of OPG, RANK and RANKL by human chondrocytes and their implication during osteoarthritis. Rheumatology (Oxford) 2009;48:1482-90.
97. Study evaluating AGG-523 in subjects with osteoarthritis. In: ClinicalTrials.gov, Editor: National Library of Medicine (US), Bethesda, MD: 2008. Available from: http://clinicaltrials.gov/ct2/show/NCT00427687.