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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2019

Open Access 01-12-2019 | Arthritis | Research article

Cytosolic group IVA phospholipase A2 inhibitors, AVX001 and AVX002, ameliorate collagen-induced arthritis

Authors: A. J. Feuerherm, E. A. Dennis, B. Johansen

Published in: Arthritis Research & Therapy | Issue 1/2019

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Abstract

Background

Cytosolic phospholipase A2 group IVA (cPLA2α)-deficient mice are resistant to collagen-induced arthritis, suggesting that cPLA2α is an important therapeutic target. Here, the anti-inflammatory effects of the AVX001 and AVX002 cPLA2α inhibitors were investigated.

Methods

In vitro enzyme activity was assessed by a modified Dole assay. Effects on inhibiting IL-1β-induced release of arachidonic acid (AA) and prostaglandin E2 (PGE2) were measured using SW982 synoviocyte cells. In vivo effects were studied in prophylactic and therapetic murine collagen-induced arthritis models and compared to methotrexate (MTX) and Enbrel, commonly used anti-rheumatic drugs. The in vivo response to treatment was evaluated in terms of the arthritis index (AI), histopathology scores and by plasma levels of PGE2 following 14 and 21 days of treatment.

Results

Both cPLA2α inhibitors are potent inhibitors of cPLA2α in vitro. In synoviocytes, AVX001 and AVX002 reduce, but do not block, release of AA or PGE2 synthesis. In both CIA models, the AI and progression of arthritis were significantly lower in the mice treated with AVX001, AVX002, Enbrel and MTX than in non- treated mice. Several histopathology parameters of joint damage were found to be significantly reduced by AVX001 and AVX002 in both prophylactic and therapeutic study modes; namely articular cavity and peripheral tissue inflammatory cell infiltration; capillary and synovial hyperplasia; articular cartilage surface damage; and periostal and endochondral ossification. In comparison, MTX did not significantly improve any histopathology parameters and Enbrel only improved ossification. Finally, as a biomarker of inflammation and as an indication that AVX001 and AVX002 blocked the cPLA2α target, we determined that plasma levels of PGE2 were significantly reduced in response to the AVX inhibitors and MTX, but not Enbrel.

Conclusions

AVX001 and AVX002 display potent anti-inflammatory activity and disease-modifying properties in cellular and in vivo models. The in vivo effects of AVX001 and AVX002 were comparable to, or superior, to those of MTX and Enbrel. Taken together, this study suggests that cPLA2α inhibitors AVX001 and AVX002 are promising small molecule disease-modifying anti-rheumatic therapies.
Literature
1.
Harris ED, et al. Kelley’s textbook of rheumatology, vol. I. Philadelphia: Elseviers Saunders; 2005.
2.
Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14(1):397–440.PubMedCrossRef
3.
Feldmann M. Anti-TNF therapy: where have we got to in 2005? Autoimmunity. 2005;25:26–8.CrossRef
4.
Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology. 2012;51(suppl 5):v3–v11.PubMedCrossRef
5.
Charles P, et al. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNFa therapy in rheumatoid arthritis. J Immunol. 1999;163(3):1521–8.PubMed
6.
Taylor PC, et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor α blockade in patients with rheumatoid arthritis. Arthritis Rheum. 2000;43(1):38–47.PubMedCrossRef
7.
Brennan FM, et al. Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-alpha (cA2) therapy. Rheumatology. 1997;36(6):643–50.CrossRef
8.
Anthonsen MW, et al. Atypical lambda /iota PKC conveys 5-lipoxygenase/leukotriene B4-mediated cross-talk between phospholipase A2s regulating NF-kappa B activation in response to tumor necrosis factor-alpha and interleukin-1beta. J Biol Chem. 2001;276(38):35344–51.PubMedCrossRef
9.
Anthonsen MW, Solhaug A, Johansen B. Functional coupling between secretory and cytosolic phospholipase a2 modulates tumor necrosis factor-alpha - and interleukin-1beta -induced NF-kappa B activation. J Biol Chem. 2001;276(32):30527–36.PubMedCrossRef
10.
Leistad L, et al. Multiple phospholipase A2 enzymes participate in the inflammatory process in osteoarthritic cartilage. Scand J Rheumatol. 2011;40(4):308–16.PubMedCrossRef
11.
Huwiler A, et al. The ω3-polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A2 and suppress PGE2 formation in mesangial cells. Br J Pharmacol. 2012;167(8):1691–701.PubMedPubMedCentralCrossRef
12.
Sommerfelt RM, et al. Cytosolic phospholipase A2 regulates TNF-induced production of joint destructive effectors in synoviocytes. PLoS One. 2013;8(12):e83555.PubMedPubMedCentralCrossRef
13.
14.
15.
16.
Clark JD, et al. A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+−dependent translocation domain with homology to PKC and GAP. Cell. 1991;65(6):1043–51.PubMedCrossRef
17.
Sapirstein A, Bonventre JV. Specific physiological roles of cytosolic phospholipase A2 as defined by gene knockouts. Biochim Biophys Acta. 2000;1488(1–2):139–48.PubMedCrossRef
18.
Akaogi J, et al. Role of PGE2 and EP receptors in the pathogenesis of rheumatoid arthritis and as a novel therapeutic strategy. Endocr Metab Immune Disord Drug Targets. 2006;6(4):383–94.PubMedCrossRef
19.
Martel-Pelletier J, Pelletier JP, Fahmi H. Cyclooxygenase-2 and prostaglandins in articular tissues. Semin Arthritis Rheum. 2003;33(3):155–67.PubMedCrossRef
20.
Sakata D, Yao C, Narumiya S. Prostaglandin E2, an immunoactivator. J Pharmacol Sci. 2010;112(1):1–5.PubMedCrossRef
21.
Samuelsson B. Arachidonic acid metabolism: role in inflammation. Z Rheumatol. 1991;50(Suppl 1):3–6.PubMed
22.
Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286(8):954–9.PubMedCrossRef
23.
Laine L, et al. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis. Gastroenterol. 2002;123(4):1006–12.CrossRef
24.
Vuolteenaho K, Moilanen T, Moilanen E. Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process. Basic Clin Pharmacol Toxicol. 2008;102(1):10–4.PubMed
25.
26.
Farkouh ME, Greenberg BP. An evidence-based review of the cardiovascular risks of nonsteroidal anti-inflammatory drugs. Am J Cardiol. 2009;103(9):1227–37.PubMedCrossRef
27.
Vane J. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231(25):232–5.PubMedCrossRef
28.
Conaghan P. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatol Int. 2012;32(6):1491–502.PubMedCrossRef
29.
Agca R, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2017;76(1):17–28.PubMedCrossRef
30.
Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960–77.PubMedCrossRef
31.
Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis. 2009;68(7):1094-9.
32.
Emery P, Sebba A, Huizinga TWJ. Biologic and oral disease-modifying antirheumatic drug monotherapy in rheumatoid arthritis. Ann Rheum Dis. 2013;72(12):1897–904.PubMedCrossRef
33.
Scher JU. Monotherapy in rheumatoid arthritis. Bull Hosp Jt Dis. 2013;71(3):204–7.
34.
35.
Vincent FB, et al. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis. 2013;72(2):165–78.PubMedCrossRef
36.
Bongartz TA, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295:2275–85.PubMedCrossRef
37.
Courties G, et al. Cytosolic phospholipase A2alpha gene silencing in the myeloid lineage alters development of Th1 responses and reduces disease severity in collagen-induced arthritis. Arthritis Rheum. 2011;63(3):681–90.PubMedCrossRef
38.
39.
Raichel L, et al. Reduction of cPLA2alpha overexpression: an efficient anti-inflammatory therapy for collagen-induced arthritis. Eur J Immunol. 2008;38:1–11.CrossRef
40.
Tai N, et al. Cytosolic phospholipase A2 alpha inhibitor, pyrroxyphene, displays anti-arthritic and anti-bone destructive action in a murine arthritis model. Inflamm Res. 2010;59(1):53–62.PubMedCrossRef
41.
Street IP, et al. Slow- and tight-binding inhibitors of the 85-kDa human phospholipase A2. Biochemistry. 1993;32(23):5935–40.PubMedCrossRef
42.
Dennis EA, et al. Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev. 2011;111(10):6130–85.PubMedPubMedCentralCrossRef
43.
Magrioti V, Kokotos G. Phospholipase A2 inhibitors as potential therapeutic agents for the treatment of inflammatory diseases. Expert Opin Ther Pat. 2010;20(1):1–18.PubMedCrossRef
44.
Magrioti V, Kokotos G. Phospholipase A2 inhibitors for the treatment of inflammatory diseases: a patent review (2010--present). Expert Opin Ther Pat. 2013;23(3):333–44.PubMedCrossRef
45.
Kokotou MG, et al. Inhibitors of phospholipase A2 and their therapeutic potential: an update on patents (2012-2016). Expert Opin Ther Pat. 2017;27(2):217–25.PubMedCrossRef
46.
Cross M, et al. The global burden of rheumatoid arthritis: estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis. 2014;73(7):1316–22.PubMedCrossRef
47.
Gaujoux-Viala C, et al. Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2014;73(3):510–5.PubMedCrossRef
48.
Smolen JS, et al. New therapies for treatment of rheumatoid arthritis. Lancet. 2007;370(9602):1861–74.PubMedCrossRef
49.
50.
Kokotos G, et al. Inhibition of group IVA cytosolic phospholipase A2 by thiazolyl ketones in vitro, ex vivo, and in vivo. J Med Chem. 2014;57(18):7523–35.PubMedCrossRef
51.
Kim E, et al. Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model. BMC Cancer. 2016;16(1):1–11.CrossRef
52.
Trentham DE, Townes AS, Kang AH. Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med. 1997;146:857–68.CrossRef
53.
Hegen M, et al. Utility of animal models for identification of potential therapeutics for rheumatoid arthritis. Ann Rheum Dis. 2008;67(11):1505–15.PubMedCrossRef
54.
Rosloniec EF, et al. Collagen-induced arthritis. Curr Protoc Immunol. 2010;15(5):1–25.
55.
Holmeide AK, Skattebol L. Syntheses of some polyunsaturated trifluoromethyl ketones as potential phospholipase A(2) inhibitors. J Chem Soc Perkin Trans. 2000;1(14):2271–6.CrossRef
56.
Yang H-C, et al. Group-specific assays that distinguish between the four major types of mammalian phospholipase A2. Anal Biochem. 1999;269(2):278–88.PubMedCrossRef
57.
Kokotos G, et al. Inhibition of group IVA Cytosolic phospholipase A2 by novel 2-oxoamides in vitro, in cells, and in vivo. J Med Chem. 2004;47(14):3615–28.PubMedCrossRef
58.
Lucas KK, Dennis EA. Distinguishing phospholipase A2 types in biological samples by employing group-specific assays in the presence of inhibitors. Prostaglandins Other Lipid Mediat. 2005;77(1–4):235–48.PubMedCrossRef
59.
60.
Malaviya R, et al. Targeting cytosolic phospholipase A2 by arachidonyl trifluoromethyl ketone prevents chronic inflammation in mice. Eur J Pharmacol. 2006;539(3):195–204.PubMedCrossRef
61.
Wooley PH, et al. Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates. J Exp Med. 1981;154(3):688–700.PubMedCrossRef
62.
Thommesen L, et al. Selective inhibitors of cytosolic or secretory phospholipase A2 block TNF-induced activation of transcription factor nuclear factor-{kappa}B and expression of ICAM-1. J Immunol. 1998;161(7):3421–30.PubMed
63.
64.
Sheibanie AF, et al. Prostaglandin E2 exacerbates collagen-induced arthritis in mice through the inflammatory interleukin-23/interleukin-17 axis. Arthritis Rheum. 2007;56(8):2608–19.PubMedCrossRef
65.
Williams RO, Feldmann M, Maini RN. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 1992;89(20):9784–8.PubMedPubMedCentralCrossRef
66.
Novaes GS, et al. Low dose methotrexate decreases intraarticular prostaglandin and interleukin 1 levels in antigen induced arthritis in rabbits. J Rheumatol. 1996;23(12):2092–7.PubMed
67.
Segawa Y, et al. Methotrexate maintains bone mass by preventing both a decrease in bone formation and an increase in bone resorption in adjuvant-induced arthritic rats. Bone. 1997;20(5):457–64.PubMedCrossRef
68.
Vergne P, et al. Methotrexate and cyclooxygenase metabolism in cultured human rheumatoid synoviocytes. J Rheumatol. 1998;25(3):433–40.PubMed
69.
Williams AS, et al. Amelioration of rat antigen-induced arthritis by liposomally conjugated methotrexate is accompanied by down-regulation of cytokine mRNA expression. Rheumatology (Oxford). 2001;40(4):375–83.CrossRef
70.
van den Berg WB. Uncoupling of inflammatory and destructive mechanisms in arthritis. Semin Arthritis Rheum. 2001;30(5 Suppl 2):7–16.PubMedCrossRef
71.
Joosten LA, et al. IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. J Immunol. 1999;163(9):5049–55.PubMed
72.
Williams RO, et al. Evaluation of TNF-alpha and IL-1 blockade in collagen-induced arthritis and comparison with combined anti-TNF-alpha/anti-CD4 therapy. J Immunol. 2000;165(12):7240–5.PubMedCrossRef
73.
Mello SBV, et al. Methotrexate as a preferential cyclooxygenase 2 inhibitor in whole blood of patients with rheumatoid arthritis. Rheumatology. 2000;39(5):533–6.PubMedCrossRef
74.
Mancini AD, Di Battista JA. The cardinal role of the phospholipase A(2)/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E(2) (PCPP) axis in inflammostasis. Inflamm Res. 2011;60(12):1083–92.PubMedCrossRef
75.
76.
Hoxha M. A systematic review on the role of eicosanoid pathways in rheumatoid arthritis. Adv Med Sci. 2018;63(1):22–9.PubMedCrossRef
77.
Edwards SW, Hallett MB. Seeing the wood for the trees: the forgotten role of neutrophils in rheumatoid arthritis. Immunol Today. 1997;18(7):320–4.PubMedCrossRef
78.
Wright HL, Moots RJ, Edwards SW. The multifactorial role of neutrophils in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10(10):593–601.PubMedCrossRef
79.
Yang L, et al. ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-α-activated vascular endothelium under flow. Blood. 2005;106:584–92.PubMedPubMedCentralCrossRef
80.
Miwa M, et al. Induction of apoptosis in bovine articular chondrocyte by prostaglandin E2 through cAMP-dependent pathway. Osteoarthr Cartil. 2000;8(1):17–24.CrossRef
81.
Miyaura C, et al. An essential role of cytosolic phospholipase A2-alpha in prostaglandin E2-mediated bone resorption associated with inflammation. J Exp Med. 2003;197(10):1303–10.PubMedPubMedCentralCrossRef
82.
83.
Naini SM, et al. Cytosolic phospholipase A2alpha regulates G1 progression through modulating FOXO1 activity. FASEB J. 2016;30(3):1155–70.PubMedCrossRef
84.
Naini SM, et al. Group IVA cytosolic phospholipase A2 regulates the G2-to-M transition by modulating the activity of tumor suppressor SIRT2. Mol Cell Biol. 2015;35(21):3768–84.CrossRef
Metadata
Title
Cytosolic group IVA phospholipase A2 inhibitors, AVX001 and AVX002, ameliorate collagen-induced arthritis
Authors
A. J. Feuerherm
E. A. Dennis
B. Johansen
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2019
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-018-1794-6

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