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BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2011

Open Access 01-12-2011 | Research article

Associations between proinflammatory cytokines in the synovial fluid and radiographic grading and pain-related scores in 47 consecutive patients with osteoarthritis of the knee

Authors: Sumihisa Orita, Takana Koshi, Takeshi Mitsuka, Masayuki Miyagi, Gen Inoue, Gen Arai, Tetsuhiro Ishikawa, Eiji Hanaoka, Keishi Yamashita, Masaomi Yamashita, Yawara Eguchi, Tomoaki Toyone, Kazuhisa Takahashi, Seiji Ohtori

Published in: BMC Musculoskeletal Disorders | Issue 1/2011

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Abstract

Background

One of the sources of knee pain in osteoarthritis (OA) is believed to be related to local chronic inflammation of the knee joints, which involves the production of inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin (IL)-6, and nerve growth factor (NGF) in the synovial membrane, and these cytokines are believed to promote pathological OA. In the present study, correlations between proinflammatory cytokines in knee synovial fluid and radiographic changes and functional scores and pain scores among OA patients were examined.

Methods

Synovial fluid was harvested from the knees of 47 consecutive OA patients, and the levels of TNFα, IL-6, and NGF were measured using enzyme-linked immunosorbent assays. Osteoarthritic knees were classified using Kellgren-Lawrence (KL) grading (1-4). The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) was used to assess self-reported physical function, pain, and stiffness.

Results

TNFα and IL-6 were detectable in knee synovial, whereas NGF was not. TNFα was not correlated with the KL grade, whereas IL-6 had a significantly negative correlation. We observed differences in the correlations between TNFα and IL-6 with WOMAC scores and their subscales (pain, stiffness, and physical function). TNFα exhibited a significant correlation with the total score and its 3 subscales, whereas IL-6 exhibited a moderately significant negative correlation only with the subscale of stiffness.

Conclusions

The present study demonstrated that the concentrations of proinflammatory cytokines are correlated with KL grades and WOMAC scores in patients with knee OA. Although TNFα did not have a significant correlation with the radiographic grading, it was significantly associated with the WOMAC score. IL-6 had a significant negative correlation with the KL grading, whereas it had only a weakly significant correlation with the subscore of stiffness. The results suggest that these cytokines play a role in the pathogenesis of synovitis in osteoarthritic knees in different ways: TNFα is correlated with pain, whereas IL-6 is correlated with joint function.
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Literature
1.
Todhunter PG, Kincaid SA, Todhunter RJ, Kammermann JR, Johnstone B, Baird AN, Hanson RR, Wright JM, Lin HC, Purohit RC: Immunohistochemical analysis of an equine model of synovitis-induced arthritis. Am J Vet Res. 1996, 57: 1080-1093.PubMed
2.
Guccione AA, Felson DT, Anderson JJ, Anthony JM, Zhang Y, Wilson PW, Kelly-Hayes M, Wolf PA, Kreger BE, Kannel WB: The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am J Public Health. 1994, 84: 351-358. 10.2105/AJPH.84.3.351.CrossRefPubMedPubMedCentral
3.
Fiorito S, Magrini L, Adrey J, Mailhe D, Brouty-Boye D: Inflammatory status and cartilage regenerative potential of synovial fibroblasts from patients with osteoarthritis and chondropathy. Rheumatology (Oxford). 2005, 44: 164-171.CrossRef
4.
Pearle AD, Scanzello CR, George S, Mandl LA, DiCarlo EF, Peterson M, Sculco TP, Crow MK: Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis. Osteoarthr Cartilage. 2007, 15: 516-523. 10.1016/j.joca.2006.10.010.CrossRef
5.
Smith MD, Triantafillou S, Parker A, Youssef PP, Coleman M: Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol. 1997, 24: 365-371.PubMed
6.
Iannone F, De Bari C, Dell'Accio F, Covelli M, Patella V, Lo Bianco G, Lapadula G: Increased expression of nerve growth factor (NGF) and high affinity NGF receptor (p140 TrkA) in human osteoarthritic chondrocytes. Rheumatology (Oxford). 2002, 41: 1413-1418. 10.1093/rheumatology/41.12.1413.CrossRef
7.
Ohtori S, Takahashi K, Moriya H, Myers RR: TNFα and TNFα receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord. Spine. 2004, 29: 1082-1088. 10.1097/00007632-200405150-00006.CrossRefPubMed
8.
Lotz M, Guerne PA: Interleukin-6 induces the synthesis of tissue inhibitor of metalloproteinases-1/erythroid potentiating activity (TIMP-1/EPA). J Biol Chem. 1991, 266: 2017-2020.PubMed
9.
Manni L, Lundeberg T, Fiorito S, Bonini S, Vigneti E, Aloe L: Nerve growth factor release by human synovial fibroblasts prior to and following exposure to tumor necrosis factor-alpha, interleukin-1 beta and cholecystokinin-8: the possible role of NGF in the inflammatory response. Clin Exp Rheumatol. 2003, 21: 617-624.PubMed
10.
Kay McNamee, Annika Burleigh, Luke Gompels, Marc Feldmann, Shelley Allen, Richard Williams, David Dawbarn, Tonia Vincent, Julia Inglis: Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain. Pain. 2010, 149: 386-92. 10.1016/j.pain.2010.03.002.CrossRef
11.
Neogi T, Felson D, Niu J, Nevitt M, Lewis CE, Aliabadi P, Sack B, Torner J, Bradley L, Zhang Y: Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies. BMJ. 2009, 21: 339-
12.
13.
Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW: Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988, 15: 1833-1840.PubMed
14.
Thumboo J, Chew LH, Soh CH: Validation of the Western Ontario and Mcmaster University osteoarthritis index in Asians with osteoarthritis in Singapore. Osteoarthritis Cartilage. 2001, 9: 440-446. 10.1053/joca.2000.0410.CrossRefPubMed
15.
Joosten LA, Helsen MM, Saxne T, van De Loo FA, Heinegard D, van Den Berg WB: 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: 5049-5055.PubMed
16.
van de Loo FA, Kuiper S, van Enckevort FH, Arntz OJ, van den Berg WB: Interleukin-6 reduces cartilage destruction during experimental arthritis. A study in interleukin-6-deficient mice. Am J Pathol. 1997, 151: 177-191.PubMedPubMedCentral
17.
Van Lent PL, Van De Loo FA, Holthuysen AE, Van Den Bersselaar LA, Vermeer H, Van Den Berg WB: Major role for interleukin 1 but not for tumor necrosis factor in early cartilage damage in immune complex arthritis in mice. J Rheumatol. 1995, 22: 2250-2258.PubMed
18.
van de Loo FA, Joosten LA, van Lent PL, Arntz OJ, van den Berg WB: Role of interleukin-1, tumor necrosis factor alpha, and interleukin-6 in cartilage proteoglycan metabolism and destruction. Effect of in situ blocking in murine antigen- and zymosan-induced arthritis. Arthritis Rheum. 1995, 38: 164-172. 10.1002/art.1780380204.CrossRefPubMed
19.
Brenner SS, Klotz U, Alscher DM, Mais A, Lauer G, Schweer H, Seyberth HW, Fritz P, Bierbach : Osteoarthritis of the knee-clinical assessments and inflammatory markers. Osteoarthr Cartilage. 2004, 12: 469-475. 10.1016/j.joca.2004.02.011.CrossRef
20.
Hay CW, Chu Q, Budsberg SC, Clayton MK, Johnson KA: Synovial fluid interleukin 6, tumor necrosis factor, and nitric oxide values in dogs with osteoarthritis secondary to cranial cruciate ligament rupture. Am J Vet Res. 1997, 58: 1027-1032.PubMed
21.
Holt I, Cooper RG, Denton J, Meager A, Hopkins S: Cytokine inter-relationships and their association with disease activity in arthritis. Br J Rheumatol. 1992, 31: 725-733. 10.1093/rheumatology/31.11.725.CrossRefPubMed
22.
Futani H, Okayama A, Matsui K, Kashiwamura S, Sasaki T, Hada T, Nakanishi K, Tateishi H, Maruo S, Okamura H: Relation between interleukin-18 and PGE2 in synovial fluid of osteoarthritis: a potential therapeutic target of cartilage degradation. J Immunother. 2002, 25: S61-64.CrossRefPubMed
23.
Westacott CI, Whicher JT, Barnes IC, Thompson D, Swan AJ, Dieppe PA: Synovial fluid concentration of five different cytokines in rheumatic diseases. Ann Rheum Dis. 1990, 49: 676-681. 10.1136/ard.49.9.676.CrossRefPubMedPubMedCentral
24.
Venn G, Nietfeld JJ, Duits AJ, Brennan FM, Arner E, Covington M, Billingham ME, Hardingham TE: Elevated synovial fluid levels of interleukin-6 and tumor necrosis factor associated with early experimental canine osteoarthritis. Arthritis Rheum. 1993, 36: 819-826. 10.1002/art.1780360613.CrossRefPubMed
25.
Smith MD, Triantafillou S, Parker A, Youssef PP, Coleman M: Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol. 1997, 24: 365-371.PubMed
26.
Johnson SJ, Freemont AJ: A 10 year retrospective comparison of the diagnostic usefulness of synovial fluid and synovial biopsy examination. J Clin Pathol. 2001, 54: 605-607. 10.1136/jcp.54.8.605.CrossRefPubMedPubMedCentral
27.
Barthel C, Yeremenko N, Jacobs R, Schmidt RE, Bernateck M, Zeidler H, Tak PP, Baeten D, Rihl M: Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis. Arthritis Res Ther. 2009, 11: R82-10.1186/ar2716.CrossRefPubMedPubMedCentral
28.
Goldstein LD, Reynolds CP, Perez-Polo JR: Isolation of human nerve growth factor from placental tissue. Neurochem Res. 1978, 3: 175-183. 10.1007/BF00964058.CrossRefPubMed
29.
Hulejová H, Baresová V, Klézl Z, Polanská M, Adam M, Senolt L: Increased level of cytokines and matrix metalloproteinases in osteoarthritic subchondral bone. Cytokine. 2007, 38: 151-156. 10.1016/j.cyto.2007.06.001.CrossRefPubMed
30.
Marks PH, Donaldson ML: Inflammatory cytokine profiles associated with chondral damage in the anterior cruciate ligament-deficient knee. Arthroscopy. 2005, 21: 1342-1347. 10.1016/j.arthro.2005.08.034.CrossRefPubMed
31.
Neidel J, Schulze M, Lindschau J: Association between degree of bone-erosion and synovial fluid-levels of tumor necrosis factor alpha in the knee-joints of patients with rheumatoid arthritis. Inflamm Res. 1995, 44: 217-221. 10.1007/BF01782262.CrossRefPubMed
32.
Long D, Blake S, Song XY, Lark M, Loeser RF: Human articular chondrocytes produce IL-7 and respond to IL-7 with increased production of matrix metalloproteinase-13. Arthritis Res Ther. 2008, 10: R23-10.1186/ar2376.CrossRefPubMedPubMedCentral
33.
Attur M, Wang H, Kraus BV, Bukowski FJ, Aziz N, Krasnokutsky S, Samuels J, Greenberg J, McDaniel G, Abramson BS, Kornman SK: Radiographic severity of knee osteoarthritis is conditional on interleukin-1 receptor antagonist gene variations. Ann Rheum Dis. 2010, 69: 856-861. 10.1136/ard.2009.113043.CrossRefPubMed
34.
Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H: Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci USA. 1987, 84: 7251-7255. 10.1073/pnas.84.20.7251.CrossRefPubMedPubMedCentral
35.
Lee KM, Jeon SM, Cho HJ: Tumor necrosis factor receptor 1 induces interleukin-6 upregulation through NF-kappaB in a rat neuropathic pain model. Eur J Pain. 2009, 13: 794-806. 10.1016/j.ejpain.2008.09.009.CrossRefPubMed
36.
Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H: Mechanisms of tumor necrosis factor-alpha-induced interleukin-6 synthesis in glioma cells. J Neuroinflamm. 2010, 7: 16-10.1186/1742-2094-7-16.CrossRef
37.
Kahraman S, Yilmaz R, Arici M, Altun B, Erdem Y, Yasavul U, Turgan C: IL-10 genotype predicts serum levels of adhesion molecules, inflammation and atherosclerosis in hemodialysis patients. J Nephrol. 2006, 19: 50-56.PubMed
38.
Reiner AP, Wurfel MM, Lange LA, Carlson CS, Nord AS, Carty CL, Rieder MJ, Desmarais C, Jenny NS, Iribarren C, Walston JD, Williams OD, Nickerson DA, Jarvik GP: Polymorphisms of the IL1-receptor antagonist gene (IL1RN) are associated with multiple markers of systemic inflammation. Arterioscler Thromb Vasc Biol. 2008, 28: 1407-1412. 10.1161/ATVBAHA.108.167437.CrossRefPubMedPubMedCentral
39.
Rogus J, Beck JD, Offenbacher S, Huttner K, Iacoviello L, Latella MC, de Gaetano M, Wang HY, Kornman KS, Duff GW: IL1B gene promoter haplotype pairs predict clinical levels of interleukin-1beta and C-reactive protein. Hum Genet. 2008, 123: 387-398. 10.1007/s00439-008-0488-6.CrossRefPubMed
40.
Loughlin J, Dowling B, Mustafa Z, Chapman K: Association of the interleukin-1 gene cluster on chromosome 2q13 with knee osteoarthritis. Arthritis Rheum. 2002, 46: 1519-1527. 10.1002/art.10260.CrossRefPubMed
41.
Moos V, Rudwaleit M, Herzog V, Höhlig K, Sieper J, Müller B: Association of genotypes affecting the expression of interleukin-1beta or interleukin-1 receptor antagonist with osteoarthritis. Arthritis Rheum. 2000, 43: 2417-2422. 10.1002/1529-0131(200011)43:11<2417::AID-ANR7>3.0.CO;2-R.CrossRefPubMed
42.
Riyazi N, Kurreeman FA, Huizinga TW, Dekker FW, Stoeken-Rijsbergen G, Kloppenburg M: The role of interleukin 10 promoter polymorphisms in the susceptibility of distal interphalangeal osteoarthritis. J Rheumatol. 2005, 32: 1571-1575.PubMed
43.
Smith AJ, Keen LJ, Billingham MJ, Perry MJ, Elson CJ, Kirwan JR, Sims JE, Doherty M, Spector TD, Bidwell JL: Extended haplotypes and linkage disequilibrium in the IL1R1-IL1A-IL1B-IL1RN gene cluster: association with knee osteoarthritis. Genes Immun. 2004, 5: 451-460. 10.1038/sj.gene.6364107.CrossRefPubMed
44.
Valdes AM, Van Oene M, Hart DJ, Surdulescu GL, Loughlin J, Doherty M, Spector TD: Reproducible genetic associations between candidate genes and clinical knee osteoarthritis in men and women. Arthritis Rheum. 2006, 54: 533-539. 10.1002/art.21621.CrossRefPubMed
Metadata
Title
Associations between proinflammatory cytokines in the synovial fluid and radiographic grading and pain-related scores in 47 consecutive patients with osteoarthritis of the knee
Authors
Sumihisa Orita
Takana Koshi
Takeshi Mitsuka
Masayuki Miyagi
Gen Inoue
Gen Arai
Tetsuhiro Ishikawa
Eiji Hanaoka
Keishi Yamashita
Masaomi Yamashita
Yawara Eguchi
Tomoaki Toyone
Kazuhisa Takahashi
Seiji Ohtori
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2011
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/1471-2474-12-144

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