Top

05-02-2018 | Osteoarthritis | Article

Serum and synovial fluid cytokine profiling in hip osteoarthritis: distinct from knee osteoarthritis and correlated with pain

Journal: BMC Musculoskeletal Disorders

Authors: Guomin Ren, Ian Lutz, Pamela Railton, J. Preston Wiley, Jenelle McAllister, James Powell, Roman J. Krawetz

Publisher: BioMed Central

Abstract

Background

Inflammation is associated with the onset and progression of osteoarthritis in multiple joints. It is well known that mechanical properties differ between different joints, however, it remains unknown if the inflammatory process is similar/distinct in patients with hip vs. knee OA. Without complete understanding of the role of any specific cytokine in the inflammatory process, understanding the ‘profile’ of inflammation in a given patient population is an essential starting point. The aim of this study was to identify serum cytokine profiles in hip Osteoarthritis (OA), and investigate the association between cytokine concentrations and clinical measurements within this patient population and compare these findings to knee OA and healthy control cohorts.

Methods

In total, 250 serum samples (100 knee OA, 50 hip OA and 100 control) and 37 synovial fluid samples (8 knee OA, 14 hip OA and 15 control) were analyzed using a multiplex ELISA based approach. Synovial biopsies were also obtained and examined for specific cytokines. Pain, physical function and activity within the hip OA cohort were examined using the HOOS, SF-36, HHS and UCLA outcome measures.

Results

The three cohorts showed distinct serum cytokine profiles. EGF, FGF2, MCP3, MIP1α, and IL8 were differentially expressed between hip and knee OA cohorts; while FGF2, GRO, IL8, MCP1, and VEGF were differentially expressed between hip OA and control cohorts. Eotaxin, GRO, MCP1, MIP1β, VEGF were differentially expressed between knee OA and control cohorts. EGF, IL8, MCP1, MIP1β were differentially expressed in synovial fluid from a sub-set of patients from each cohort. Specifically within the hip OA cohort, IL-6, MDC and IP10 were associated with pain and were also found to be present in synovial fluid and synovial membrane (except IL-6) of patients with hip OA.

Conclusion

OA may include different inflammatory subtypes according to affected joints and distinct inflammatory processes may drive OA in these joints. IL6, MDC and IP10 are associated with hip OA pain and these proteins may be able to provide additional information regarding pain in hip OA patients.

Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, Gabriel S, Hirsch R, Hochberg MC, Hunder GG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58(1):26–35.CrossRefPubMedPubMedCentral

Wright EA, Katz JN, Cisternas MG, Kessler CL, Wagenseller A, Losina E. Impact of knee osteoarthritis on health care resource utilization in a US population-based national sample. Med Care. 2010;48(9):785–91.CrossRefPubMedPubMedCentral

Ganz R, Leunig M, Leunig-Ganz K, Harris WH. The etiology of osteoarthritis of the hip: an integrated mechanical concept. Clin Orthop Relat Res. 2008;466(2):264–72.CrossRefPubMedPubMedCentral

Sandell LJ. Etiology of osteoarthritis: genetics and synovial joint development. Nat Rev Rheumatol. 2012;8(2):77–89.CrossRefPubMed

Heard BJ, Rosvold JM, Fritzler MJ, El-Gabalawy H, Wiley JP, Krawetz RJ. A computational method to differentiate normal individuals, osteoarthritis and rheumatoid arthritis patients using serum biomarkers. J R Soc Interface. 2014;11(97):20140428.CrossRefPubMedPubMedCentral

Rousseau J, Garnero P. Biological markers in osteoarthritis. Bone. 2012;51(2):265–77.CrossRefPubMed

Poole AR. Biochemical/immunochemical biomarkers of osteoarthritis: utility for prediction of incident or progressive osteoarthritis. Rheum Dis Clin N Am. 2003;29(4):803–18.CrossRef

Van Spil W, Jansen N, Bijlsma J, Reijman M, DeGroot J, Welsing P, Lafeber F. Clusters within a wide spectrum of biochemical markers for osteoarthritis: data from CHECK, a large cohort of individuals with very early symptomatic osteoarthritis. Osteoarthr Cartil. 2012;20(7):745–54.CrossRefPubMed

Balakrishnan L, Nirujogi RS, Ahmad S, Bhattacharjee M, Manda SS, Renuse S, Kelkar DS, Subbannayya Y, Raju R, Goel R, et al. Proteomic analysis of human osteoarthritis synovial fluid. Clin Proteomics. 2014;11(1):6.CrossRefPubMedPubMedCentral

10.

Hunter DJ, Nevitt M, Losina E, Kraus V. Biomarkers for osteoarthritis: current position and steps towards further validation. Best Pract Res Clin Rheumatol. 2014;28(1):61–71.CrossRefPubMedPubMedCentral

11.

Erhart-Hledik J, Favre J, Asay J, Smith R, Giori N, Mündermann A, Andriacchi T. A relationship between mechanically-induced changes in serum cartilage oligomeric matrix protein (COMP) and changes in cartilage thickness after 5 years. Osteoarthr Cartil. 2012;20(11):1309–15.CrossRefPubMed

12.

Heard BJ, Martin L, Rattner JB, Frank CB, Hart DA, Krawetz R. Matrix metalloproteinase protein expression profiles cannot distinguish between normal and early osteoarthritic synovial fluid. BMC Musculoskelet Disord. 2012;13(1):126.CrossRefPubMedPubMedCentral

13.

van Spil WE, Drossaers-Bakker KW, Lafeber FP. Associations of CTX-II with biochemical markers of bone turnover raise questions on its tissue origin: data from CHECK, a cohort study of early osteoarthritis. Ann Rheum Dis. 2013;72(1):29–36.CrossRefPubMed

14.

Bernard NJ. Osteoarthritis: circulating miRNAs-early osteoarthritis biomarkers? Nat Rev Rheumatol. 2014;10(4):197.

15.

Mabey T, Honsawek S. Cytokines as biochemical markers for knee osteoarthritis. World J Orthod. 2015;6(1):95.CrossRef

16.

Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7(1):33–42.CrossRefPubMed

17.

Saberi Hosnijeh F, Runhaar J, van Meurs JB, Bierma-Zeinstra SM. Biomarkers for osteoarthritis: can they be used for risk assessment? A systematic review. Maturitas. 2015;82:36.CrossRef

18.

Schett G, Kiechl S, Bonora E, Zwerina J, Mayr A, Axmann R, Weger S, Oberhollenzer F, Lorenzini R, Willeit J. Vascular cell adhesion molecule 1 as a predictor of severe osteoarthritis of the hip and knee joints. Arthritis Rheum. 2009;60(8):2381–9.CrossRefPubMed

19.

Rego-Perez I, Fernandez-Moreno M, Deberg M, Pertega S, Fenandez-Lopez C, Oreiro N, Henrotin Y, Blanco FJ. Mitochondrial DNA haplogroups modulate the serum levels of biomarkers in patients with osteoarthritis. Ann Rheum Dis. 2010;69(5):910–7.CrossRefPubMed

20.

Reijman M, Pols HA, Bergink AP, Hazes JM, Belo JN, Lievense AM, Bierma-Zeinstra SM. Body mass index associated with onset and progression of osteoarthritis of the knee but not of the hip: the Rotterdam study. Ann Rheum Dis. 2007;66(2):158–62.CrossRefPubMed

21.

Bennell KL, Hunt MA, Wrigley TV, Hunter DJ, FJ MM, Hodges PW, Li L, Hinman RS. Hip strengthening reduces symptoms but not knee load in people with medial knee osteoarthritis and varus malalignment: a randomised controlled trial. Osteoarthr Cartil. 2010;18(5):621–8.CrossRefPubMed

22.

Van Spil WE, Welsing PM, Bierma-Zeinstra SM, Bijlsma JW, Roorda LD, Cats HA, Lafeber FP. The ability of systemic biochemical markers to reflect presence, incidence, and progression of early-stage radiographic knee and hip osteoarthritis: data from CHECK. Osteoarthr Cartil. 2015;23:1388.CrossRefPubMed

23.

Tseng S, Reddi AH, Di Cesare PE. Cartilage Oligomeric Matrix Protein (COMP): a biomarker of arthritis. Biomark Insights. 2009;4:33–44.PubMedPubMedCentral

24.

Felson DT. The sources of pain in knee osteoarthritis. Curr Opin Rheumatol. 2005;17(5):624–8.CrossRefPubMed

25.

Somers TJ, Keefe FJ, Godiwala N, Hoyler GH. Psychosocial factors and the pain experience of osteoarthritis patients: new findings and new directions. Curr Opin Rheumatol. 2009;21(5):501–6.CrossRefPubMed

26.

Sofat N, Ejindu V, Kiely P. What makes osteoarthritis painful? The evidence for local and central pain processing. Rheumatology. 2011;50(12):2157–65.CrossRefPubMed

27.

Miller RE, Miller RJ, Malfait AM. Osteoarthritis joint pain: the cytokine connection. Cytokine. 2014;70(2):185–93.CrossRefPubMedPubMedCentral

28.

Miller RE, Tran PB, Das R, Ghoreishi-Haack N, Ren D, Miller RJ, Malfait AM. CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis. Proc Natl Acad Sci U S A. 2012;109(50):20602–7.CrossRefPubMedPubMedCentral

29.

Boettger MK, Hensellek S, Richter F, Gajda M, Stockigt R, von Banchet GS, Brauer R, Schaible HG. Antinociceptive effects of tumor necrosis factor alpha neutralization in a rat model of antigen-induced arthritis: evidence of a neuronal target. Arthritis Rheum. 2008;58(8):2368–78.CrossRefPubMed

30.

Ebbinghaus M, Uhlig B, Richter F, von Banchet GS, Gajda M, Brauer R, Schaible HG. The role of interleukin-1beta in arthritic pain: main involvement in thermal, but not mechanical, hyperalgesia in rat antigen-induced arthritis. Arthritis Rheum. 2012;64(12):3897–907.CrossRefPubMed

31.

Harris W. Traumatic arthritis of the hip after dislocation and acetabular fractures: treatment by mold arthroplasty. An end-result study using a new method of result evaluation. J Bone Joint Surg Am. 1969;51(4):737.CrossRefPubMed

32.

Klassbo M, Larsson E, Mannevik E. Hip disability and osteoarthritis outcome score. An extension of the Western Ontario and McMaster Universities Osteoarthritis Index. Scand J Rheumatol. 2003;32(1):46–51.CrossRefPubMed

33.

Jenkinson C, Wright L, Coulter A. Criterion validity and reliability of the SF-36 in a population sample. Qual Life Res. 1994;3(1):7–12.CrossRefPubMed

34.

Zahiri CA, Schmalzried TP, Szuszczewicz ES, Amstutz HC. Assessing activity in joint replacement patients. J Arthroplast. 1998;13(8):890–5.CrossRef

35.

Pietschmann P, Gollob E, Brosch S, Hahn P, Kudlacek S, Willheim M, Woloszczuk W, Peterlik M, Tragl KH. The effect of age and gender on cytokine production by human peripheral blood mononuclear cells and markers of bone metabolism. Exp Gerontol. 2003;38(10):1119–27.CrossRefPubMed

36.

Vangsness CT Jr, Burke WS, Narvy SJ, RD MP, Fedenko AN. Human knee synovial fluid cytokines correlated with grade of knee osteoarthritis--a pilot study. Bull NYU Hosp Jt Dis. 2011;69(2):122–7.PubMed

37.

Hosnijeh FS, Runhaar J, van Meurs JB, Bierma-Zeinstra SM. Biomarkers for osteoarthritis: can they be used for risk assessment? A systematic review. Maturitas. 2015;82(1):36–49.CrossRefPubMed

38.

Castaneda S, Roman-Blas JA, Largo R, Herrero-Beaumont G. Osteoarthritis: a progressive disease with changing phenotypes. Rheumatology (Oxford). 2014;53(1):1–3.CrossRef

39.

Zhang W, Likhodii S, Zhang Y, Aref-Eshghi E, Harper PE, Randell E, Green R, Martin G, Furey A, Sun G, et al. Classification of osteoarthritis phenotypes by metabolomics analysis. BMJ Open. 2014;4(11):e006286.CrossRefPubMedPubMedCentral

40.

Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, Cesari M, Nourhashemi F. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc. 2013;14(12):877–82.CrossRefPubMed

41.

Leung L, Cahill CM. TNF-alpha and neuropathic pain--a review. J Neuroinflammation. 2010;7:27.CrossRefPubMedPubMedCentral

42.

Lee EY, Lee ZH, Song YW. The interaction between CXCL10 and cytokines in chronic inflammatory arthritis. Autoimmun Rev. 2013;12(5):554–7.CrossRefPubMed

43.

Bu H, Shu B, Gao F, Liu C, Guan X, Ke C, Cao F, Hinton AO Jr, Xiang H, Yang H, et al. Spinal IFN-gamma-induced protein-10 (CXCL10) mediates metastatic breast cancer-induced bone pain by activation of microglia in rat models. Breast Cancer Res Treat. 2014;143(2):255–63.CrossRefPubMed

44.

Lim HW, Lee J, Hillsamer P, Kim CH. Human Th17 cells share major trafficking receptors with both polarized effector T cells and FOXP3+ regulatory T cells. J Immunol. 2008;180(1):122–9.CrossRefPubMed

45.

Andrew DP, Chang M-s, McNinch J, Wathen ST, Rihanek M, Tseng J, Spellberg JP, Elias CG. STCP-1 (MDC) CC chemokine acts specifically on chronically activated Th2 lymphocytes and is produced by monocytes on stimulation with Th2 cytokines IL-4 and IL-13. J Immunol. 1998;161(9):5027–38.PubMed

46.

Madson KL, Moore TL, Lawrence JM 3rd, Osborn TG. Cytokine levels in serum and synovial fluid of patients with juvenile rheumatoid arthritis. J Rheumatol. 1994;21(12):2359–63.PubMed

47.

Kaneko S, Satoh T, Chiba J, Ju C, Inoue K, Kagawa J. Interleukin-6 and interleukin-8 levels in serum and synovial fluid of patients with osteoarthritis. Cytokines Cell Mol Ther. 2000;6(2):71–9.CrossRefPubMed