Presence of IL-17 in synovial fluid identifies a potential inflammatory osteoarthritic phenotype

Sarah J B Snelling, Sylvette Bas, Gabor J Puskas, Stephanie G Dakin, Domizio Suva, Axel Finckh, Cem Gabay, Pierre Hoffmeyer, Andrew J Carr, Anne Lübbeke, Sarah J B Snelling, Sylvette Bas, Gabor J Puskas, Stephanie G Dakin, Domizio Suva, Axel Finckh, Cem Gabay, Pierre Hoffmeyer, Andrew J Carr, Anne Lübbeke

Abstract

Purpose: Osteoarthritis (OA) is a common and heterogeneous arthritic disorder. Patients suffer pain and their joints are characterized by articular cartilage loss and osteophyte formation. Risk factors for OA include age and obesity with inflammation identified as a key mediator of disease pathogenesis. Interleukin-17A (IL-17) is a pro-inflammatory cytokine that has been implicated in inflammatory diseases such as rheumatoid arthritis. IL-17 can upregulate expression of inflammatory cytokines and adipocytokines. The aim of this study was to evaluate IL-17 levels in the synovial fluid of patients with end-stage knee and hip OA in relation to inflammation- and pain-related cytokines and adipocytokines in synovial fluid and serum, and clinical and radiographic disease parameters.

Methods: This is a cross-sectional study of 152 patients undergoing total hip and knee arthroplasty for OA. IL-17, IL-6, leptin, adiponectin, visfatin, resistin, C-C Motif Chemokine Ligand 2 (CCL2), C-C Motif Chemokine Ligand 7 (CCL7) and nerve growth factor (NGF) protein levels were measured in synovial fluid and serum using enzyme-linked immunosorbent assay (ELISA). Baseline characteristics included age, sex, body mass index, co-morbidities, pain and function, and radiographic analyses (OA features, K&L grade, minimal joint space width).

Results: 14 patients (9.2%) had detectable IL-17 in synovial fluid. These patients had significantly higher median concentrations of IL-6, leptin, resistin, CCL7 and NGF. Osteophytes, sclerosis and minimum joint space width were significantly reduced in patients with detectable IL-17 in synovial fluid. No differences were found in pain, function and comorbidities. IL-17 concentrations in synovial fluid and serum were moderately correlated (r = 0.482).

Conclusion: The presence of IL-17 in the synovial fluid therefore identifies a substantial subset of primary end-stage OA patients with distinct biological and clinical features. Stratification of patients on the basis of IL-17 may identify those responsive to therapeutic targeting.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Synovial fluid concentrations of IL-6,…
Fig 1. Synovial fluid concentrations of IL-6, Leptin, Resistin, CCL7 and NGF in patients with and without detectable synovial fluid IL-17
Error bars show median ± 95% confidence intervals, *p

Fig 2. Synovial fluid concentrations of IL-17…

Fig 2. Synovial fluid concentrations of IL-17 and IL-6 in patients following stratification by hip…

Fig 2. Synovial fluid concentrations of IL-17 and IL-6 in patients following stratification by hip or knee OA.
Error bars show median ± 95% confidence intervals, *p

Fig 3. Correlation between synovial fluid and…

Fig 3. Correlation between synovial fluid and serum IL-17 concentrations in patients with detectable IL-17…

Fig 3. Correlation between synovial fluid and serum IL-17 concentrations in patients with detectable IL-17 in synovial fluid.

Fig 4. Correlation between synovial fluid IL-17…

Fig 4. Correlation between synovial fluid IL-17 and IL-6 concentrations in patients with detectable IL-17…

Fig 4. Correlation between synovial fluid IL-17 and IL-6 concentrations in patients with detectable IL-17 in synovial fluid.
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References
    1. Atukorala I, Kwoh CK, Guermazi A, Roemer FW, Boudreau RM, Hannon MJ, et al. Synovitis in knee osteoarthritis: a precursor of disease? Annals of the rheumatic diseases. 2014. Epub 2014/12/10. - PMC - PubMed
    1. Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nature reviews Rheumatology. 2011;7(1):33–42. Epub 2010/12/02. doi: 10.1038/nrrheum.2010.196 - DOI - PubMed
    1. Schett G, Elewaut D, McInnes IB, Dayer JM, Neurath MF. How cytokine networks fuel inflammation: Toward a cytokine-based disease taxonomy. Nat Med. 2013;19(7):822–4. doi: 10.1038/nm.3260 - DOI - PubMed
    1. Karvonen-Gutierrez CA, Zheng H, Mancuso P, Harlow SD. Higher Leptin and Adiponectin Concentrations Predict Poorer Performance-based Physical Functioning in Midlife Women: the Michigan Study of Women's Health Across the Nation. The journals of gerontology Series A, Biological sciences and medical sciences. 2015. Epub 2015/08/26. - PMC - PubMed
    1. Song YZ, Guan J, Wang HJ, Ma W, Li F, Xu F, et al. Possible Involvement of Serum and Synovial Fluid Resistin in Knee Osteoarthritis: Cartilage Damage, Clinical, and Radiological Links. Journal of clinical laboratory analysis. 2015. Epub 2015/10/24. - PMC - PubMed
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Fig 2. Synovial fluid concentrations of IL-17…
Fig 2. Synovial fluid concentrations of IL-17 and IL-6 in patients following stratification by hip or knee OA.
Error bars show median ± 95% confidence intervals, *p

Fig 3. Correlation between synovial fluid and…

Fig 3. Correlation between synovial fluid and serum IL-17 concentrations in patients with detectable IL-17…

Fig 3. Correlation between synovial fluid and serum IL-17 concentrations in patients with detectable IL-17 in synovial fluid.

Fig 4. Correlation between synovial fluid IL-17…

Fig 4. Correlation between synovial fluid IL-17 and IL-6 concentrations in patients with detectable IL-17…

Fig 4. Correlation between synovial fluid IL-17 and IL-6 concentrations in patients with detectable IL-17 in synovial fluid.
Fig 3. Correlation between synovial fluid and…
Fig 3. Correlation between synovial fluid and serum IL-17 concentrations in patients with detectable IL-17 in synovial fluid.
Fig 4. Correlation between synovial fluid IL-17…
Fig 4. Correlation between synovial fluid IL-17 and IL-6 concentrations in patients with detectable IL-17 in synovial fluid.

References

    1. Atukorala I, Kwoh CK, Guermazi A, Roemer FW, Boudreau RM, Hannon MJ, et al. Synovitis in knee osteoarthritis: a precursor of disease? Annals of the rheumatic diseases. 2014. Epub 2014/12/10.
    1. Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nature reviews Rheumatology. 2011;7(1):33–42. Epub 2010/12/02. doi:
    1. Schett G, Elewaut D, McInnes IB, Dayer JM, Neurath MF. How cytokine networks fuel inflammation: Toward a cytokine-based disease taxonomy. Nat Med. 2013;19(7):822–4. doi:
    1. Karvonen-Gutierrez CA, Zheng H, Mancuso P, Harlow SD. Higher Leptin and Adiponectin Concentrations Predict Poorer Performance-based Physical Functioning in Midlife Women: the Michigan Study of Women's Health Across the Nation. The journals of gerontology Series A, Biological sciences and medical sciences. 2015. Epub 2015/08/26.
    1. Song YZ, Guan J, Wang HJ, Ma W, Li F, Xu F, et al. Possible Involvement of Serum and Synovial Fluid Resistin in Knee Osteoarthritis: Cartilage Damage, Clinical, and Radiological Links. Journal of clinical laboratory analysis. 2015. Epub 2015/10/24.
    1. Poonpet T, Honsawek S. Adipokines: Biomarkers for osteoarthritis? World journal of orthopedics. 2014;5(3):319–27. PubMed Central PMCID: PMCPMC4095025. doi:
    1. Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm. 2013;2013:139239 PubMed Central PMCID: PMCPMC3881510. doi:
    1. Shahrara S, Pickens SR, Mandelin AM 2nd, Karpus WJ, Huang Q, Kolls JK, et al. IL-17-mediated monocyte migration occurs partially through CC chemokine ligand 2/monocyte chemoattractant protein-1 induction. J Immunol. 2010;184(8):4479–87 PubMed Central PMCID: PMCPMC2858914. doi:
    1. Benedetti G, Miossec P. Interleukin 17 contributes to the chronicity of inflammatory diseases such as rheumatoid arthritis. Eur J Immunol. 2014;44(2):339–47. doi:
    1. Kimura A, Naka T, Kishimoto T. IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci U S A. 2007;104(29):12099–104. PubMed Central PMCID: PMCPMC1924582. doi:
    1. Camporeale A, Poli V. IL-6, IL-17 and STAT3: a holy trinity in auto-immunity? Front Biosci (Landmark Ed). 2012;17:2306–26.
    1. Vida M, Gavito AL, Pavon FJ, Bautista D, Serrano A, Suarez J, et al. Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice. Dis Model Mech. 2015;8(7):721–31. PubMed Central PMCID: PMCPMC4486858. doi:
    1. Mabey T, Honsawek S. Cytokines as biochemical markers for knee osteoarthritis. World journal of orthopedics. 2015;6(1):95–105. PubMed Central PMCID: PMCPMC4303794. doi:
    1. Koshy PJ, Henderson N, Logan C, Life PF, Cawston TE, Rowan AD. Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines. Annals of the rheumatic diseases. 2002;61(8):704–13. Epub 2002/07/16. PubMed Central PMCID: PMC1754191. doi:
    1. Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, et al. Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis and rheumatism. 1999;42(5):963–70. Epub 1999/05/14. doi:
    1. Wilke CM, Bishop K, Fox D, Zou W. Deciphering the role of Th17 cells in human disease. Trends in immunology. 2011;32(12):603–11. Epub 2011/10/01. PubMed Central PMCID: PMC3224806. doi:
    1. Richter F, Natura G, Ebbinghaus M, von Banchet GS, Hensellek S, Konig C, et al. Interleukin-17 sensitizes joint nociceptors to mechanical stimuli and contributes to arthritic pain through neuronal interleukin-17 receptors in rodents. Arthritis and rheumatism. 2012;64(12):4125–34. Epub 2012/11/30. doi:
    1. Murphy L, Helmick CG. The impact of osteoarthritis in the United States: a population-health perspective: A population-based review of the fourth most common cause of hospitalization in U.S. adults. Orthop Nurs. 2012;31(2):85–91. doi:
    1. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis and rheumatism. 2008;58(1):26–35. PubMed Central PMCID: PMCPMC3266664. doi:
    1. Chen L, Li DQ, Zhong J, Wu XL, Chen Q, Peng H, et al. IL-17RA aptamer-mediated repression of IL-6 inhibits synovium inflammation in a murine model of osteoarthritis. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2011;19(6):711–8.
    1. van Baarsen LG, Lebre MC, van der Coelen D, Aarrass S, Tang MW, Ramwadhdoebe TH, et al. Heterogeneous expression pattern of interleukin 17A (IL-17A), IL-17F and their receptors in synovium of rheumatoid arthritis, psoriatic arthritis and osteoarthritis: possible explanation for nonresponse to anti-IL-17 therapy? Arthritis research & therapy. 2014;16(4):426. Epub 2014/08/26. PubMed Central PMCID: PMC4292832.
    1. Mease PJ, McInnes IB, Kirkham B, Kavanaugh A, Rahman P, van der Heijde D, et al. Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis. N Engl J Med. 2015;373(14):1329–39. doi:
    1. Conrozier T, Ferrand F, Poole AR, Verret C, Mathieu P, Ionescu M, et al. Differences in biomarkers of type II collagen in atrophic and hypertrophic osteoarthritis of the hip: implications for the differing pathobiologies. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2007;15(4):462–7. Epub 2006/10/24.
    1. Garnero P, Charni N, Juillet F, Conrozier T, Vignon E. Increased urinary type II collagen helical and C telopeptide levels are independently associated with a rapidly destructive hip osteoarthritis. Annals of the rheumatic diseases. 2006;65(12):1639–44. Epub 2006/03/30. PubMed Central PMCID: PMC1798449. doi:
    1. Kim YG, Park JW, Lee JM, Suh JY, Lee JK, Chang BS, et al. IL-17 inhibits osteoblast differentiation and bone regeneration in rat. Archives of oral biology. 2014;59(9):897–905. Epub 2014/06/08. doi:
    1. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. The Journal of clinical investigation. 1999;103(9):1345–52. Epub 1999/05/04. PubMed Central PMCID: PMC408356. doi:
    1. Deligne C, Casulli S, Pigenet A, Bougault C, Campillo-Gimenez L, Nourissat G, et al. Differential expression of interleukin-17 and interleukin-22 in inflamed and non-inflamed synovium from osteoarthritis patients. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2015;23(11):1843–52. Epub 2015/11/03.
    1. Toh ML, Gonzales G, Koenders MI, Tournadre A, Boyle D, Lubberts E, et al. Role of interleukin 17 in arthritis chronicity through survival of synoviocytes via regulation of synoviolin expression. PloS one. 2010;5(10):e13416 Epub 2010/10/27. PubMed Central PMCID: PMC2955522. doi:
    1. Hwang SY, Kim JY, Kim KW, Park MK, Moon Y, Kim WU, et al. IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways. Arthritis research & therapy. 2004;6(2):R120–8. Epub 2004/04/03. PubMed Central PMCID: PMC400429.
    1. Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011;11(11):762–74. doi:
    1. Gagliani N, Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature. 2015;523(7559):221–5. Epub 2015/04/30. PubMed Central PMCID: PMC4498984. doi:
    1. Sandy JD, Chan DD, Trevino RL, Wimmer MA, Plaas A. Human genome-wide expression analysis reorients the study of inflammatory mediators and biomechanics in osteoarthritis. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2015;23(11):1939–45. Epub 2015/11/03. PubMed Central PMCID: PMC4630670.
    1. Chen B, Deng Y, Tan Y, Qin J, Chen LB. Association between severity of knee osteoarthritis and serum and synovial fluid interleukin 17 concentrations. The Journal of international medical research. 2014;42(1):138–44. Epub 2013/12/10. doi:
    1. Liu Y, Peng H, Meng Z, Wei M. Correlation of IL-17 Level in Synovia and Severity of Knee Osteoarthritis. Med Sci Monit. 2015;21:1732–6. PubMed Central PMCID: PMCPMC4480114. doi:
    1. Lau EM, Lin F, Lam D, Silman A, Croft P. Hip osteoarthritis and dysplasia in Chinese men. Annals of the rheumatic diseases. 1995;54(12):965–9. PubMed Central PMCID: PMCPMC1010061.
    1. Kang X, Fransen M, Zhang Y, Li H, Ke Y, Lu M, et al. The high prevalence of knee osteoarthritis in a rural Chinese population: the Wuchuan osteoarthritis study. Arthritis and rheumatism. 2009;61(5):641–7. PubMed Central PMCID: PMCPMC2758273. doi:
    1. Nevitt MC, Xu L, Zhang Y, Lui LY, Yu W, Lane NE, et al. Very low prevalence of hip osteoarthritis among Chinese elderly in Beijing, China, compared with whites in the United States: the Beijing osteoarthritis study. Arthritis and rheumatism. 2002;46(7):1773–9. doi:
    1. Dai J, Ikegawa S. Recent advances in association studies of osteoarthritis susceptibility genes. J Hum Genet. 2010;55(2):77–80. doi:
    1. Griffin TM, Huebner JL, Kraus VB, Guilak F. Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis. Arthritis and rheumatism. 2009;60(10):2935–44. Epub 2009/10/01. PubMed Central PMCID: PMC2829313. doi:
    1. Richter M, Trzeciak T, Owecki M, Pucher A, Kaczmarczyk J. The role of adipocytokines in the pathogenesis of knee joint osteoarthritis. International orthopaedics. 2015;39(6):1211–7. Epub 2015/02/27. doi:
    1. Deng J, Liu Y, Yang M, Wang S, Zhang M, Wang X, et al. Leptin exacerbates collagen-induced arthritis via enhancement of Th17 cell response. Arthritis and rheumatism. 2012;64(11):3564–73. Epub 2012/07/27. doi:
    1. Noh M. Interleukin-17A increases leptin production in human bone marrow mesenchymal stem cells. Biochemical pharmacology. 2012;83(5):661–70. Epub 2011/12/27. doi:
    1. Shin JH, Shin DW, Noh M. Interleukin-17A inhibits adipocyte differentiation in human mesenchymal stem cells and regulates pro-inflammatory responses in adipocytes. Biochemical pharmacology. 2009;77(12):1835–44. Epub 2009/05/12. doi:
    1. Furst DE, Emery P. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets. Rheumatology (Oxford). 2014;53(9):1560–9. PubMed Central PMCID: PMCPMC4135582.

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