Identification of Novel Synovial Fluid Biomarkers Associated with Meniscal Pathology

Abstract

The menisci are integral components within the knee for ensuring optimal joint function. The overall goal of this study was to identify proteomic markers of meniscal disease within synovial fluid samples obtained from control knees versus knees affected with varying degrees of meniscal injury and osteoarthritis. Joint fluid samples were collected before the patient underwent an arthroscopic knee procedure or total knee arthroplasty. Normal controls included patients younger than 30 years with no history of anterior cruciate ligament, posterior cruciate ligament, or meniscal injury. A total of 21 joint fluid aspirates were analyzed using mass spectrometry, and a total of 296 proteins were identified. Among these, 50 proteins were determined to be of interest as potential biomarkers based on initial analysis and known functions in articular metabolism. Further statistical analysis comparing protein concentrations among clinical groups identified 13 proteins with significant differences between at least two of the patient cohorts. These data provide novel information for the investigation of synovial fluid biomarkers and treatment strategies for meniscal pathology.

Keywords

synovial fluid - biomarkers - proteomics - knee - pathology

• References

• 1 Buckwalter JA, Saltzman C, Brown T. The impact of osteoarthritis: implications for research. Clin Orthop Relat Res 2004; ;(427, Suppl): S6-S15
• 2 Helmick CG, Felson DT, Lawrence RC , et al; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 2008; 58 (1) 15-25
• 3 Fithian DC, Kelly MA, Mow VC. Material properties and structure-function relationships in the menisci. Clin Orthop Relat Res 1990; 252 (252) 19-31
• 4 Andersson-Molina H, Karlsson H, Rockborn P. Arthroscopic partial and total meniscectomy: A long-term follow-up study with matched controls. Arthroscopy 2002; 18 (2) 183-189
• 5 Bonneux I, Vandekerckhove B. Arthroscopic partial lateral meniscectomy long-term results in athletes. Acta Orthop Belg 2002; 68 (4) 356-361
• 6 Chatain F, Robinson AHN, Adeleine P, Chambat P, Neyret P. The natural history of the knee following arthroscopic medial meniscectomy. Knee Surg Sports Traumatol Arthrosc 2001; 9 (1) 15-18
• 7 Cicuttini FM, Forbes A, Yuanyuan W, Rush G, Stuckey SL. Rate of knee cartilage loss after partial meniscectomy. J Rheumatol 2002; 29 (9) 1954-1956
• 8 McKinley TO, English DK, Bay BK. Trabecular bone strain changes resulting from partial and complete meniscectomy. Clin Orthop Relat Res 2003; 407 (407) 259-267
• 9 van Tienen TG, Heijkants RG, de Groot JH , et al. Presence and mechanism of knee articular cartilage degeneration after meniscal reconstruction in dogs. Osteoarthritis Cartilage 2003; 11 (1) 78-84
• 10 Wyland DJ, Guilak F, Elliott DM, Setton LA, Vail TP. Chondropathy after meniscal tear or partial meniscectomy in a canine model. J Orthop Res 2002; 20 (5) 996-1002
• 11 Walker PS, Erkman MJ. The role of the menisci in force transmission across the knee. Clin Orthop Relat Res 1975; (109) 184-192
• 12 Ghosh P, Taylor TK. The knee joint meniscus. A fibrocartilage of some distinction. Clin Orthop Relat Res 1987; (224) 52-63
• 13 Setton LA, Guilak F, Hsu EW, Vail TP. Biomechanical factors in tissue engineered meniscal repair. Clin Orthop Relat Res 1999; ;(367, Suppl): S254-S272
• 14 Roller BL, Stoker AM, Marberry KM , et al. Characterization of meniscal pathology with molecular and proteomic analyses. Paper presented at: 56th Annual Meeting of the Orthopaedic Research Society; March 6–9, 2010 ; New Orleans, LA
• 15 Roller BL, Monibi FA, Stoker AM, Kuroki K, Bal BS, Cook JL. Characterization of knee meniscal pathology: correlation of gross, histologic, biochemical, molecular, and radiographic measures of disease. J Knee Surg 2014; ; May 7 (Epub ahead of print); doi: 10.1055/s-0034-1376333
• 16 Goldring MB. The role of cytokines as inflammatory mediators in osteoarthritis: lessons from animal models. Connect Tissue Res 1999; 40 (1) 1-11
• 17 Ray A, Kuroki K, Cook JL , et al. Induction of matrix metalloproteinase 1 gene expression is regulated by inflammation-responsive transcription factor SAF-1 in osteoarthritis. Arthritis Rheum 2003; 48 (1) 134-145
• 18 Kuroki K, Stoker AM, Cook JL. Effects of proinflammatory cytokines on canine articular chondrocytes in a three-dimensional culture. Am J Vet Res 2005; 66 (7) 1187-1196
• 19 Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol 2007; 213 (3) 626-634
• 20 Scanzello CR, Plaas A, Crow MK. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound?. Curr Opin Rheumatol 2008; 20 (5) 565-572
• 21 Borden P, Solymar D, Sucharczuk A, Lindman B, Cannon P, Heller RA. Cytokine control of interstitial collagenase and collagenase-3 gene expression in human chondrocytes. J Biol Chem 1996; 271 (38) 23577-23581
• 22 Borzì RM, Mazzetti I, Cattini L, Uguccioni M, Baggiolini M, Facchini A. Human chondrocytes express functional chemokine receptors and release matrix-degrading enzymes in response to C-X-C and C-C chemokines. Arthritis Rheum 2000; 43 (8) 1734-1741
• 23 Tetlow LC, Adlam DJ, Woolley DE. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum 2001; 44 (3) 585-594
• 24 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 (3) 151-156
• 25 Klatt AR, Paul-Klausch B, Klinger G , et al. A critical role for collagen II in cartilage matrix degradation: collagen II induces pro-inflammatory cytokines and MMPs in primary human chondrocytes. J Orthop Res 2009; 27 (1) 65-70
• 26 Lohmander LS, Dahlberg L, Eyre D, Lark M, Thonar EJ, Ryd L. Longitudinal and cross-sectional variability in markers of joint metabolism in patients with knee pain and articular cartilage abnormalities. Osteoarthritis Cartilage 1998; 6 (5) 351-361
• 27 Pulsatelli L, Dolzani P, Piacentini A , et al. Chemokine production by human chondrocytes. J Rheumatol 1999; 26 (9) 1992-2001
• 28 Steiner G, Tohidast-Akrad M, Witzmann G , et al. Cytokine production by synovial T cells in rheumatoid arthritis. Rheumatology (Oxford) 1999; 38 (3) 202-213
• 29 Sugiyama T. Involvement of interleukin-6 and prostaglandin E2 in periarticular osteoporosis of postmenopausal women with rheumatoid arthritis. J Bone Miner Metab 2001; 19 (2) 89-96
• 30 Irie K, Uchiyama E, Iwaso H. Intraarticular inflammatory cytokines in acute anterior cruciate ligament injured knee. Knee 2003; 10 (1) 93-96
• 31 Higuchi H, Shirakura K, Kimura M , et al. Changes in biochemical parameters after anterior cruciate ligament injury. Int Orthop 2006; 30 (1) 43-47
• 32 Cuellar JM, Scuderi GJ, Cuellar VG, Golish SR, Yeomans DC. Diagnostic utility of cytokine biomarkers in the evaluation of acute knee pain. J Bone Joint Surg Am 2009; 91 (10) 2313-2320
• 33 Scuderi GJ, Woolf N, Dent K , et al. Identification of a complex between fibronectin and aggrecan G3 domain in synovial fluid of patients with painful meniscal pathology. Clin Biochem 2010; 43 (10-11) 808-814
• 34 Garner BC, Stoker AM, Kuroki K, Evans R, Cook CR, Cook JL. Using animal models in osteoarthritis biomarker research. J Knee Surg 2011; 24 (4) 251-264
• 35 Rosenkranz ME, Wilson DC, Marinov AD , et al. Synovial fluid proteins differentiate between the subtypes of juvenile idiopathic arthritis. Arthritis Rheum 2010; 62 (6) 1813-1823
• 36 Baillet A, Trocmé C, Berthier S , et al. Synovial fluid proteomic fingerprint: S100A8, S100A9 and S100A12 proteins discriminate rheumatoid arthritis from other inflammatory joint diseases. Rheumatology (Oxford) 2010; 49 (4) 671-682
• 37 Dufield DR, Nemirovskiy OV, Jennings MG, Tortorella MD, Malfait AM, Mathews WR. An immunoaffinity liquid chromatography-tandem mass spectrometry assay for detection of endogenous aggrecan fragments in biological fluids: use as a biomarker for aggrecanase activity and cartilage degradation. Anal Biochem 2010; 406 (2) 113-123
• 38 Giera M, Ioan-Facsinay A, Toes R , et al. Lipid and lipid mediator profiling of human synovial fluid in rheumatoid arthritis patients by means of LC-MS/MS. Biochim Biophys Acta 2012; 1821 (11) 1415-1424
• 39 Mateos J, Lourido L, Fernández-Puente P , et al. Differential protein profiling of synovial fluid from rheumatoid arthritis and osteoarthritis patients using LC-MALDI TOF/TOF. J Proteomics 2012; 75 (10) 2869-2878
• 40 Pan X, Huang L, Chen J, Dai Y, Chen X. Analysis of synovial fluid in knee joint of osteoarthritis:5 proteome patterns of joint inflammation based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Int Orthop 2012; 36 (1) 57-64
• 41 Larsson S, Lohmander LS, Struglics A. Synovial fluid level of aggrecan ARGS fragments is a more sensitive marker of joint disease than glycosaminoglycan or aggrecan levels: a cross-sectional study. Arthritis Res Ther 2009; 11 (3) R92
• 42 Swearingen CA, Carpenter JW, Siegel R , et al. Development of a novel clinical biomarker assay to detect and quantify aggrecanase-generated aggrecan fragments in human synovial fluid, serum and urine. Osteoarthritis Cartilage 2010; 18 (9) 1150-1158
• 43 Sandy JD, Westling J, Kenagy RD , et al. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem 2001; 276 (16) 13372-13378
• 44 Arner EC. Aggrecanase-mediated cartilage degradation. Curr Opin Pharmacol 2002; 2 (3) 322-329
• 45 Matsumoto K, Shionyu M, Go M , et al. Distinct interaction of versican/PG-M with hyaluronan and link protein. J Biol Chem 2003; 278 (42) 41205-41212
• 46 Binette F, Cravens J, Kahoussi B, Haudenschild DR, Goetinck PF. Link protein is ubiquitously expressed in non-cartilaginous tissues where it enhances and stabilizes the interaction of proteoglycans with hyaluronic acid. J Biol Chem 1994; 269 (29) 19116-19122
• 47 McDevitt CA, Webber RJ. The ultrastructure and biochemistry of meniscal cartilage. Clin Orthop Relat Res 1990; (252) 8-18
• 48 Lemke AK, Sandy JD, Voigt H , et al. Interleukin-1alpha treatment of meniscal explants stimulates the production and release of aggrecanase-generated, GAG-substituted aggrecan products and also the release of pre-formed, aggrecanase-generated G1 and m-calpain-generated G1-G2. Cell Tissue Res 2010; 340 (1) 179-188
• 49 Voigt H, Lemke AK, Mentlein R, Schünke M, Kurz B. Tumor necrosis factor alpha-dependent aggrecan cleavage and release of glycosaminoglycans in the meniscus is mediated by nitrous oxide-independent aggrecanase activity in vitro. Arthritis Res Ther 2009; 11 (5) R141
• 50 Li TW, Zheng BR, Huang ZX , et al. Screening disease-associated proteins from sera of patients with rheumatoid arthritis: a comparative proteomic study. Chin Med J (Engl) 2010; 123 (5) 537-543
• 51 Ahmadzadeh N, Shingu M, Nobunaga M. Iron-binding proteins and free iron in synovial fluids of rheumatoid arthritis patients. Clin Rheumatol 1989; 8 (3) 345-351
• 52 Ahmadzadeh N, Shingu M, Nobunaga M, Yasuda M. Correlation of metal-binding proteins and proteinase inhibitors with immunological parameters in rheumatoid synovial fluids. Clin Exp Rheumatol 1990; 8 (6) 547-551
• 53 Yamagiwa H, Sarkar G, Charlesworth MC, McCormick DJ, Bolander ME. Two-dimensional gel electrophoresis of synovial fluid: method for detecting candidate protein markers for osteoarthritis. J Orthop Sci 2003; 8 (4) 482-490
• 54 Willumsen L, Friis J. A comparative study of the protein pattern in serum and synovial fluid. Scand J Rheumatol 1975; 4 (4) 234-240
• 55 Conner JG, Eckersall PD, Ferguson J, Douglas TA. Acute phase response in the dog following surgical trauma. Res Vet Sci 1988; 45 (1) 107-110
• 56 McCord JM. Free radicals and inflammation: protection of synovial fluid by superoxide dismutase. Science 1974; 185 (4150) 529-531
• 57 Gao F, Koenitzer JR, Tobolewski JM , et al. Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan. J Biol Chem 2008; 283 (10) 6058-6066
• 58 Lotz M. Osteoarthritis year 2011 in review: biology. Osteoarthritis Cartilage 2012; 20 (3) 192-196
• 59 Young AA, McLennan S, Smith MM , et al. Proteoglycan 4 downregulation in a sheep meniscectomy model of early osteoarthritis. Arthritis Res Ther 2006; 8 (2) R41
• 60 Elsaid KA, Fleming BC, Oksendahl HL , et al. Decreased lubricin concentrations and markers of joint inflammation in the synovial fluid of patients with anterior cruciate ligament injury. Arthritis Rheum 2008; 58 (6) 1707-1715
• 61 Jay GD, Fleming BC, Watkins BA , et al. Prevention of cartilage degeneration and restoration of chondroprotection by lubricin tribosupplementation in the rat following anterior cruciate ligament transection. Arthritis Rheum 2010; 62 (8) 2382-2391
• 62 Jay GD, Torres JR, Warman ML, Laderer MC, Breuer KS. The role of lubricin in the mechanical behavior of synovial fluid. Proc Natl Acad Sci U S A 2007; 104 (15) 6194-6199
• 63 Teeple E, Elsaid KA, Jay GD , et al. Effects of supplemental intra-articular lubricin and hyaluronic acid on the progression of posttraumatic arthritis in the anterior cruciate ligament-deficient rat knee. Am J Sports Med 2011; 39 (1) 164-172
• 64 Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006; 19 (2) CD005321
• 65 Campbell J, Bellamy N, Gee T. Differences between systematic reviews/meta-analyses of hyaluronic acid/hyaluronan/hylan in osteoarthritis of the knee. Osteoarthritis Cartilage 2007; 15 (12) 1424-1436
• 66 Sakurai K, Miyazaki K, Kodera Y, Nishimura H, Shingu M, Inada Y. Anti-inflammatory activity of superoxide dismutase conjugated with sodium hyaluronate. Glycoconj J 1997; 14 (6) 723-728