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05-04-2018 | Osteoarthritis | Article

CCL17 blockade as a therapy for osteoarthritis pain and disease

Journal: Arthritis Research & Therapy

Authors: Ming-Chin Lee, Reem Saleh, Adrian Achuthan, Andrew J. Fleetwood, Irmgard Förster, John A. Hamilton, Andrew D. Cook

Publisher: BioMed Central

Abstract

Background

Granulocyte macrophage-colony stimulating factor (GM-CSF) has been implicated in the pathogenesis of a number of inflammatory diseases and in osteoarthritis (OA). We identified previously a new GM-CSF→Jmjd3→interferon regulatory factor 4 (IRF4)→chemokine (c-c motif) ligand 17 (CCL17) pathway, which is important for the development of inflammatory arthritis pain and disease. Tumour necrosis factor (TNF) can also be linked with this pathway. Here we investigated the involvement of the pathway in OA pain and disease development using the GM-CSF-dependent collagenase-induced OA (CiOA) model.

Methods

CiOA was induced in C57BL/6 wild-type (WT), Irf4^−/−, Ccl17^E/E, Ccr4^−/−, Tnf^−/− and GM-CSF^−/− mice. Additionally, therapeutic targeting of CCL17, Jmjd3 and cyclooxygenase 2 (COX-2) was evaluated. Development of pain (assessment of weight distribution) and OA disease (histologic scoring of synovitis, cartilage destruction and osteophyte size) were assessed. Synovial joint cells, including neutrophils, macrophages, fibroblasts and endothelial cells, were isolated (cell sorting) and gene expression analyzed (quantitative PCR).

Results

Studies in the gene-deficient mice indicated that IRF4, CCL17 and the CCL17 receptor, CCR4, but not TNF, were required for CiOA pain and optimal cartilage destruction and osteophyte size. Therapeutic neutralization of CCL17 and Jmjd3 ameliorated both pain and disease, whereas the COX-2 inhibitor only ameliorated pain. In the synovium Ccl17 mRNA was expressed only in the macrophages in a GM-CSF-dependent and IRF4-dependent manner.

Conclusions

The GM-CSF→Jmjd3→IRF4→CCL17 pathway is important for the development of CiOA, with CCL17 thus being a potential therapeutic target for the treatment of both OA pain and disease.

Chen D, Shen J, Zhao W, Wang T, Han L, Hamilton JL, Im HJ. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res. 2017;5:16044.CrossRefPubMedPubMedCentral

Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B. Synovial tissue inflammation in early and late osteoarthritis. Ann Rheum Dis. 2005;64:1263–7.CrossRefPubMedPubMedCentral

Liu-Bryan R, Terkeltaub R. Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol. 2015;11:35–44.CrossRefPubMed

Wenham CY, McDermott M, Conaghan PG. Biological therapies in osteoarthritis. Curr Pharm Des. 2015;21:2206–15.CrossRefPubMed

Mathiessen A, Conaghan PG. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Res Ther. 2017;19:18.CrossRefPubMedPubMedCentral

Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, Sokolove J. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12:580–92.CrossRefPubMedPubMedCentral

Kamekura S, Hoshi K, Shimoaka T, Chung U, Chikuda H, Yamada T, Uchida M, Ogata N, Seichi A, Nakamura K, Kawaguchi H. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthr Cartil. 2005;13:632–41.CrossRefPubMed

Cook AD, Pobjoy J, Steidl S, Durr M, Braine EL, Turner AL, Lacey DC, Hamilton JA. Granulocyte-macrophage colony-stimulating factor is a key mediator in experimental osteoarthritis pain and disease development. Arthritis Res Ther. 2012;14:R199.CrossRefPubMedPubMedCentral

Blom AB, van Lent PL, Libregts S, Holthuysen AE, van der Kraan PM, van Rooijen N, van den Berg WB. Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3. Arthritis Rheum. 2007;56:147–57.CrossRefPubMed

10.

Botter SM, van Osch GJ, Waarsing JH, van der Linden JC, Verhaar JA, Pols HA, van Leeuwen JP, Weinans H. Cartilage damage pattern in relation to subchondral plate thickness in a collagenase-induced model of osteoarthritis. Osteoarthr Cartil. 2008;16:506–14.CrossRefPubMed

11.

Blom AB, van Lent PL, Holthuysen AE, van der Kraan PM, Roth J, van Rooijen N, van den Berg WB. Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis. Osteoarthr Cartil. 2004;12:627–35.CrossRefPubMed

12.

van Lent PL, Blom AB, van der Kraan P, Holthuysen AE, Vitters E, van Rooijen N, Smeets RL, Nabbe KC, van den Berg WB. Crucial role of synovial lining macrophages in the promotion of transforming growth factor beta-mediated osteophyte formation. Arthritis Rheum. 2004;50:103–11.CrossRefPubMed

13.

Adaes S, Mendonca M, Santos TN, Castro-Lopes JM, Ferreira-Gomes J, Neto FL. Intra-articular injection of collagenase in the knee of rats as an alternative model to study nociception associated with osteoarthritis. Arthritis Res Ther. 2014;16:R10.CrossRefPubMedPubMedCentral

14.

McGonagle D, Hermann KG, Tan AL. Differentiation between osteoarthritis and psoriatic arthritis: implications for pathogenesis and treatment in the biologic therapy era. Rheumatology. 2015;54:29–38.CrossRefPubMed

15.

Hamilton JA, Cook AD, Tak PP. Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases. Nat Rev Drug Discov. 2017;16:53–70.CrossRef

16.

Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol. 2008;8:533–44.CrossRefPubMed

17.

Cook AD, Pobjoy J, Sarros S, Steidl S, Durr M, Lacey DC, Hamilton JA. Granulocyte-macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain. Ann Rheum Dis. 2013;72:265–70.CrossRefPubMed

18.

Achuthan A, Cook AD, Lee MC, Saleh R, Khiew HW, Chang MW, Louis C, Fleetwood AJ, Lacey DC, Christensen AD, Frye AT, Lam PY, Kusano H, Nomura K, Steiner N, Forster I, Nutt SL, Olshansky M, Turner SJ, Hamilton JA. Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. J Clin Invest. 2016;126:3453–66.CrossRefPubMedPubMedCentral

19.

Cook AD, Braine EL, Campbell IK, Rich MJ, Hamilton JA. Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res. 2001;3:293–8.

20.

Cook AD, Lee MC, Saleh R, Khiew HW, Christensen AD, Achuthan A, Fleetwood AJ, Lacey DC, Smith JE, Förster I, Hamilton JA. TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17. JCI Insight 2018;3:e99249.

21.

Korner H, Cook M, Riminton DS, Lemckert FA, Hoek RM, Ledermann B, Kontgen F, Fazekas de St Groth B, Sedgwick JD. Distinct roles for lymphotoxin-alpha and tumor necrosis factor in organogenesis and spatial organization of lymphoid tissue. Eur J Immunol. 1997;27:2600–9.CrossRefPubMed

22.

Chvatchko Y, Hoogewerf AJ, Meyer A, Alouani S, Juillard P, Buser R, Conquet F, Proudfoot AE, Wells TN, Power CA. A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock. J Exp Med. 2000;191:1755–64.CrossRefPubMedPubMedCentral

23.

Stanley E, Lieschke GJ, Grail D, Metcalf D, Hodgson G, Gall JA, Maher DW, Cebon J, Sinickas V, Dunn AR. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci USA. 1994;91:5592–6.CrossRefPubMedPubMedCentral

24.

Mittrucker HW, Matsuyama T, Grossman A, Kundig TM, Potter J, Shahinian A, Wakeham A, Patterson B, Ohashi PS, Mak TW. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science. 1997;275:540–3.CrossRefPubMed

25.

Alferink J, Lieberam I, Reindl W, Behrens A, Weiss S, Huser N, Gerauer K, Ross R, Reske-Kunz AB, Ahmad-Nejad P, Wagner H, Forster I. Compartmentalized production of CCL17 in vivo: strong inducibility in peripheral dendritic cells contrasts selective absence from the spleen. J Exp Med. 2003;197:585–99.CrossRefPubMedPubMedCentral

26.

van den Bosch MH, Blom AB, Kram V, Maeda A, Sikka S, Gabet Y, Kilts TM, van den Berg WB, van Lent PL, van der Kraan PM, Young MF. WISP1/CCN4 aggravates cartilage degeneration in experimental osteoarthritis. Osteoarthr Cartil. 2017;25:1900–11.CrossRefPubMed

27.

Inglis JJ, McNamee KE, Chia SL, Essex D, Feldmann M, Williams RO, Hunt SP, Vincent T. Regulation of pain sensitivity in experimental osteoarthritis by the endogenous peripheral opioid system. Arthritis Rheum. 2008;58:3110–9.CrossRefPubMed

28.

Lee MC, McCubbin JA, Christensen AD, Poole DP, Rajasekhar P, Lieu T, Bunnett NW, Garcia-Caraballo S, Erickson A, Brierley SM, Saleh R, Achuthan A, Fleetwood AJ, Anderson RL, Hamilton JA, Cook AD. G-CSF Receptor Blockade Ameliorates Arthritic Pain and Disease. The Journal of Immunology 2017;198(9):3565–575.

29.

ter Huurne M, Schelbergen R, Blattes R, Blom A, de Munter W, Grevers LC, Jeanson J, Noel D, Casteilla L, Jorgensen C, van den Berg W, van Lent PL. Antiinflammatory and chondroprotective effects of intraarticular injection of adipose-derived stem cells in experimental osteoarthritis. Arthritis Rheum. 2012;64:3604–13.CrossRefPubMed

30.

Glasson SS, Chambers MG, Van Den Berg WB, Little CB. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthr Cartil. 2010;18(Suppl 3):S17–23.CrossRefPubMed

31.

Santulli-Marotto S, Boakye K, Lacy E, Wu SJ, Luongo J, Kavalkovich K, Coelho A, Hogaboam CM, Ryan M. Engagement of two distinct binding domains on CCL17 is required for signaling through CCR4 and establishment of localized inflammatory conditions in the lung. PLoS One. 2013;8:e81465.CrossRefPubMedPubMedCentral

32.

Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T, Honma K, Matsuyama T, Yui K, Tsujimura T, Standley DM, Nakanishi K, Nakai K, Akira S. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol. 2010;11:936–44.CrossRefPubMed

33.

Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012;51:249–57.CrossRefPubMedPubMedCentral

34.

Cook AD, Louis C, Robinson MJ, Saleh R, Sleeman MA, Hamilton JA. Granulocyte macrophage colony-stimulating factor receptor alpha expression and its targeting in antigen-induced arthritis and inflammation. Arthritis Res Ther. 2016;18:287.CrossRefPubMedPubMedCentral

35.

Anzai A, Choi JL, He S, Fenn AM, Nairz M, Rattik S, McAlpine CS, Mindur JE, Chan CT, Iwamoto Y, Tricot B, Wojtkiewicz GR, Weissleder R, Libby P, Nahrendorf M, Stone JR, Becher B, Swirski FK. The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes. J Exp Med. 2017;214:3293–310.PubMed

36.

Rose BJ, Kooyman DL. A Tale of Two Joints: The role of matrix metalloproteases in cartilage biology. Dis Markers. 2016;2016:4895050.CrossRefPubMedPubMedCentral

37.

van Dalen SC, Blom AB, Sloetjes AW, Helsen MM, Roth J, Vogl T, van de Loo FA, Koenders MI, van der Kraan PM, van den Berg WB, van den Bosch MH, van Lent PL. Interleukin-1 is not involved in synovial inflammation and cartilage destruction in collagenase-induced osteoarthritis. Osteoarthr Cartil. 2017;25:385–96.CrossRefPubMed

38.

van Lent PL, Blom AB, Schelbergen RF, Sloetjes A, Lafeber FP, Lems WF, Cats H, Vogl T, Roth J, van den Berg WB. Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis. Arthritis Rheum. 2012;64:1466–76.CrossRefPubMed

39.

Scanzello CR, Plaas A, Crow MK. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound? Curr Opin Rheumatol. 2008;20:565–72.CrossRefPubMed

40.

Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia F, D'Ambrosio D. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med. 2001;194:847–53.CrossRefPubMedPubMedCentral

41.

Katakura T, Miyazaki M, Kobayashi M, Herndon DN, Suzuki F. CCL17 and IL-10 as effectors that enable alternatively activated macrophages to inhibit the generation of classically activated macrophages. J Immunol. 2004;172:1407–13.CrossRefPubMed

42.

Stutte S, Quast T, Gerbitzki N, Savinko T, Novak N, Reifenberger J, Homey B, Kolanus W, Alenius H, Forster I. Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells. Proc Natl Acad Sci USA. 2010;107:8736–41.CrossRefPubMedPubMedCentral

43.

Heiseke AF, Faul AC, Lehr HA, Forster I, Schmid RM, Krug AB, Reindl W. CCL17 promotes intestinal inflammation in mice and counteracts regulatory T cell-mediated protection from colitis. Gastroenterology. 2012;142:335–45.CrossRefPubMed

44.

Weber C, Meiler S, Doring Y, Koch M, Drechsler M, Megens RT, Rowinska Z, Bidzhekov K, Fecher C, Ribechini E, van Zandvoort MA, Binder CJ, Jelinek I, Hristov M, Boon L, Jung S, Korn T, Lutz MB, Forster I, Zenke M, Hieronymus T, Junt T, Zernecke A. CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J Clin Invest. 2011;121:2898–910.CrossRefPubMedPubMedCentral

45.

Okamoto H, Koizumi K, Yamanaka H, Saito T, Kamatani N. A role for TARC/CCL17, a CC chemokine, in systemic lupus erythematosus. J Rheumatol. 2003;30:2369–73.PubMed

46.

Hillen MR, Moret FM, van der Wurff-Jacobs K, Radstake T, Hack CE, Lafeber F, van Roon J. Targeting CD1c-expressing classical dendritic cells to prevent thymus and activation-regulated chemokine (TARC)-mediated T-cell chemotaxis in rheumatoid arthritis. Scand J Rheumatol. 2017;46:11–6.CrossRefPubMed

47.

Oh SB, Tran PB, Gillard SE, Hurley RW, Hammond DL, Miller RJ. Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci. 2001;21:5027–35.PubMed

48.

Thakur M, Crow M, Richards N, Davey GI, Levine E, Kelleher JH, Agley CC, Denk F, Harridge SD, McMahon SB. Defining the nociceptor transcriptome. Front Mol Neurosci. 2014;7:87.CrossRefPubMedPubMedCentral

49.

Li CL, Li KC, Wu D, Chen Y, Luo H, Zhao JR, Wang SS, Sun MM, Lu YJ, Zhong YQ, Hu XY, Hou R, Zhou BB, Bao L, Xiao HS, Zhang X. Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity. Cell Res. 2016;26:83–102.CrossRefPubMed

50.

Cook AD, Christensen AD, Tewari D, SB MM, Hamilton JA. Immune Cytokines and Their Receptors in Inflammatory Pain. Trends Immunol. 2018;10:29-38.

51.

Etemad S, Zamin RM, Ruitenberg MJ, Filgueira L. A novel in vitro human microglia model: characterization of human monocyte-derived microglia. J Neurosci Methods. 2012;209:79–89.CrossRefPubMed

52.

Neuhold LA, Killar L, Zhao W, Sung ML, Warner L, Kulik J, Turner J, Wu W, Billinghurst C, Meijers T, Poole AR, Babij P, DeGennaro LJ. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest. 2001;107:35–44.CrossRefPubMedPubMedCentral

53.

van den Berg WB. Osteoarthritis year 2010 in review: pathomechanisms. Osteoarthr Cartil. 2011;19:338–41.CrossRefPubMed

54.

Bondeson J, Blom AB, Wainwright S, Hughes C, Caterson B, van den Berg WB. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 2010;62:647–57.CrossRefPubMed

55.

van den Bosch MH, Blom AB, van de Loo FA, Koenders MI, Lafeber FP, van den Berg WB, van der Kraan PM, van Lent PL. Brief report: induction of matrix metalloproteinase expression by synovial wnt signaling and association with disease progression in early symptomatic osteoarthritis. Arthritis Rheumatol. 2017;69:1978–83.CrossRefPubMed

56.

Ou B, Zhao J, Guan S, Feng H, Wangpu X, Zhu C, Zong Y, Ma J, Sun J, Shen X, Zheng M, Lu A. CCR4 promotes metastasis via ERK/NF-kappaB/MMP13 pathway and acts downstream of TNF-alpha in colorectal cancer. Oncotarget. 2016;7:47637–49.PubMedPubMedCentral

57.

Li CM, Hou L, Zhang H, Zhang WY. CCL17 Induces trophoblast migration and invasion by regulating matrix metalloproteinase and integrin expression in human first-trimester placenta. Reprod Sci. 2014; https://doi.org/10.1177/1933719113519170.

58.

Lee AS, Ellman MB, Yan D, Kroin JS, Cole BJ, van Wijnen AJ, Im HJ. A current review of molecular mechanisms regarding osteoarthritis and pain. Gene. 2013;527:440–7.CrossRefPubMedPubMedCentral

59.

Leizer T, Cebon J, Layton JE, Hamilton JA. Cytokine regulation of colony-stimulating factor production in cultured human synovial fibroblasts: I. Induction of GM-CSF and G-CSF production by interleukin-1 and tumor necrosis factor. Blood. 1990;76:1989–96.PubMed

60.

Campbell IK, Novak U, Cebon J, Layton JE, Hamilton JA. Human articular cartilage and chondrocytes produce hemopoietic colony-stimulating factors in culture in response to IL-1. J Immunol. 1991;147:1238–46.PubMed

61.

Lawlor KE, Wong PK, Campbell IK, van Rooijen N, Wicks IP. Acute CD4+ T lymphocyte-dependent interleukin-1-driven arthritis selectively requires interleukin-2 and interleukin-4, joint macrophages, granulocyte-macrophage colony-stimulating factor, interleukin-6, and leukemia inhibitory factor. Arthritis Rheum. 2005;52:3749–54.CrossRefPubMed

62.

Yang YH, Hamilton JA. Dependence of interleukin-1-induced arthritis on granulocyte-macrophage colony-stimulating factor. Arthritis Rheum. 2001;44:111–9.CrossRefPubMed

63.

McNamee KE, Burleigh A, Gompels LL, Feldmann M, Allen SJ, Williams RO, Dawbarn D, Vincent TL, Inglis JJ. Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain. Pain. 2010;149:386–92.CrossRefPubMed

64.

Chevalier X, Eymard F, Richette P. Biologic agents in osteoarthritis: hopes and disappointments. Nat Rev Rheumatol. 2013;9:400–10.CrossRefPubMed

65.

Schaible HG. Mechanisms of chronic pain in osteoarthritis. Curr Rheumatol Rep. 2012;14:549–56.CrossRefPubMed

66.

Rahmati M, Mobasheri A, Mozafari M. Inflammatory mediators in osteoarthritis: a critical review of the state-of-the-art, current prospects, and future challenges. Bone. 2016;85:81–90.CrossRefPubMed

67.

Hamilton JA. GM-CSF as a target in inflammatory/autoimmune disease: current evidence and future therapeutic potential. Expert Rev Clin Immunol. 2015;11:457–65.CrossRefPubMed