The intra-articular immune response after ligamentous, meniscal, or focal chondral knee injuries likely plays a role in intra-articular healing and the onset and progression of posttraumatic osteoarthritis.
Purpose:
To evaluate the association of synovial fluid cytokine concentrations measured at the time of knee arthroscopy with intermediate-term functional outcomes after knee arthroscopy based on the Lysholm score.
Study Design:
Cohort study; Level of evidence, 2.
Methods:
This was a prospective cohort study of patients undergoing arthroscopic knee surgery. Synovial fluid was aspirated from the injured knee immediately before surgical incision, and the concentrations of 10 cytokines were analyzed using immunoassay. Principal component regression was used to create a model to predict patient-reported Lysholm score at a minimum of 5 years postoperatively. Hierarchical clustering was performed to identify groups of patients with similar synovial fluid inflammatory phenotypes. Lysholm scores and cytokine concentrations were compared between clusters.
Results:
A total of 26 patients (mean age, 40.33 ± 16.40 years) were included in the analysis. The mean duration between surgery and follow-up was 6.69 ± 0.72 years. A model consisting of 2 principal components (PC1, PC2) explained 62.48% of the variance in the cytokine data and 52.03% of the variance in intermediate-term Lysholm score. Hierarchical clustering resulted in 3 patient clusters based on the principal components used in the regression model. Despite no baseline differences in Lysholm score, cluster 3 demonstrated significantly greater intermediate-term Lysholm score compared with cluster 2 (94.33 vs 76.09, respectively; 95% CI, 5.96-30.52; P = .006) and cluster 1 (94.33 vs 52.33, respectively; 95% CI, 24.09-59.91; P = .003). Cluster 3, when compared with the overall means, was characterized by greater PC1 value (1.01 vs 0.00, respectively; P = .030) and greater PC2 value (0.86 vs 0.00, respectively; P = .002).
Conclusion:
The concentrations of select synovial fluid cytokines assessed at the time of knee arthroscopy can be used to explain more than half of the variance in intermediate-term functional outcomes.
AgereSAAkhtarNWatsonJMAhmedS.RANTES/CCL5 induces collagen degradation by activating MMP-1 and MMP-13 expression in human rheumatoid arthritis synovial fibroblasts. Front Immunol. 2017;8:1341.
2.
AkesenBDemiragBBudakF.Evaluation of intra-articular collagenase, TIMP-1, and TNF-α levels before and after anterior cruciate ligament reconstruction. Acta Orthop Traumatol Turc. 2009;43(3):214-218.
3.
AmanoKHuebnerJLStablerTV, et al. Synovial fluid profile at the time of anterior cruciate ligament reconstruction and its association with cartilage matrix composition 3 years after surgery. Am J Sports Med. 2018;46(4):890-899.
4.
AndersonDChubinskayaSGuilakF, et al. Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention. J Orthop Res. 2011;29(6):802-809.
5.
BaekSJKangSKRaJC.In vitro migration capacity of human adipose tissue-derived mesenchymal stem cells reflects their expression of receptors for chemokines and growth factors. Exp Molecular Med. 2011;43(10):596-603.
6.
BriggsKKKocherMSRodkeyWGSteadmanJR.Reliability, validity, and responsiveness of the Lysholm knee score and Tegner activity scale for patients with meniscal injury of the knee. J Bone Joint Surg Am. 2006;88(4):698-705.
7.
BriggsKKLysholmJTegnerY, et al. The reliability, validity, and responsiveness of the Lysholm score and Tegner activity scale for anterior cruciate ligament injuries of the knee: 25 years later. Am J Sports Med. 2009;37(5):890-897.
8.
ChiaSLSawajiYBurleighA, et al. Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis. Arthritis Rheumatism. 2009;60(7):2019-2027.
9.
ChuCRRodeoSBhutaniN, et al. Optimizing clinical use of biologics in orthopaedic surgery: consensus recommendations from the 2018 AAOS/NIH U-13 Conference. J Am Acad Orthop Surg. 2019;27(2):e50-e63.
10.
ClairAJKingeryMTAnilU, et al. Alterations in synovial fluid biomarker levels in knees with meniscal injury as compared with asymptomatic contralateral knees. Am J Sports Med. 2019;47(4):847-856.
11.
CuellarJMScuderiGJCuellarVGGolishSRYeomansDC.Diagnostic utility of cytokine biomarkers in the evaluation of acute knee pain. J Bone Joint Surg Am. 2009;91(10):2313-2320.
12.
CuellarVStraussE.Molecular biomarkers of knee pathology. Bull Hosp Jt Dis (2013). 2017;75(1):30-36.
13.
CuellarVGCuellarJMGolishSRYeomansDCScuderiGJ.Cytokine profiling in acute anterior cruciate ligament injury. Arthroscopy. 2010;26(10):1296-1301.
14.
CuellarVGCuellarJMKirschTStraussEJ.Correlation of synovial fluid biomarkers with cartilage pathology and associated outcomes in knee arthroscopy. Arthroscopy. 2016;32(3):475-485.
EmonardHGrimaudJA.Matrix metalloproteinases: a review. Cell Mol Biol. 1990;36(2):131-153.
17.
FeeleyBTLauBC.Biomechanics and clinical outcomes of partial meniscectomy. J Am Acad Orthop Surg. 2018;26(24):853-863.
18.
Gomis-RuthFXMaskosKBetzM, et al. Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature. 1997;389(6646):77-81.
19.
GriswoldAJPerezJNuytemansK, et al. Transcriptomic analysis of synovial extracellular RNA following knee trauma: a pilot study. J Orthop Res. 2018;36(6):1659-1665.
20.
HarkeyMSLucBAGolightlyYM, et al. Osteoarthritis-related biomarkers following anterior cruciate ligament injury and reconstruction: a systematic review. Osteoarthritis Cartilage. 2015;23(1):1-12.
21.
HiguchiHShirakuraKKimuraM, et al. Changes in biochemical parameters after anterior cruciate ligament injury. Int Orthop. 2006;30(1):43-47.
22.
ImHJMuddasaniPNatarajanV, et al. Basic fibroblast growth factor stimulates matrix metalloproteinase-13 via the molecular cross-talk between the mitogen-activated protein kinases and protein kinase Cdelta pathways in human adult articular chondrocytes. J Biol Chemistry. 2007;282(15):11110-11121.
23.
JiRRXuZZWangXLoEH.Matrix metalloprotease regulation of neuropathic pain. Trends Pharmacol Sci. 2009;30(7):336-340.
24.
KaplanDJCuellarVGJazrawiLMStraussEJ.Biomarker changes in anterior cruciate ligament–deficient knees compared with healthy controls. Arthroscopy. 2017;33(5):1053-1061.
25.
KassambaraAMundtF.Factoextra: extract and visualize the results of multivariate data analyses. R package version 1.0.7.
26.
KaulGCucchiariniMArntzenD, et al. Local stimulation of articular cartilage repair by transplantation of encapsulated chondrocytes overexpressing human fibroblast growth factor 2 (FGF-2) in vivo. J Gene Med. 2006;8(1):100-111.
27.
KocherMSSteadmanJRBriggsKKSterettWIHawkinsRJ.Reliability, validity, and responsiveness of the Lysholm knee scale for various chondral disorders of the knee. J Bone Joint Surg Am. 2004;86(6):1139-1145.
28.
KramerWCHendricksKJWangJ.Pathogenetic mechanisms of posttraumatic osteoarthritis: opportunities for early intervention. Int J Clin Exper Med. 2011;4(4):285-298.
29.
KrausVBBurnettBCoindreauJ, et al. Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis. Osteoarthritis Cartilage. 2011;19(5):515-542.
30.
LarssonSEnglundMStruglicsALohmanderLS.The association between changes in synovial fluid levels of ARGS-aggrecan fragments, progression of radiographic osteoarthritis and self-reported outcomes: a cohort study. Osteoarthritis Cartilage. 2012;20(5):388-395.
31.
LêSJosseJHussonF.FactoMineR: an R package for multivariate analysis. J Stat Softw. 2008;25(1):1-18.
32.
LiLJiangB-E.Serum and synovial fluid chemokine ligand 2/monocyte chemoattractant protein 1 concentrations correlates with symptomatic severity in patients with knee osteoarthritis. Ann Clin Biochem. 2014;52(2):276-282.
33.
LiWDuCWangHZhangC.Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages. Genet Mol Res. 2014;13(4):9642-9649.
34.
LiXEllmanMBKroinJS, et al. Species-specific biological effects of FGF-2 in articular cartilage: implication for distinct roles within the FGF receptor family. J Cellular Biochem. 2012;113(7):2532-2542.
35.
LiuBGoodeAPCarterTE, et al. Matrix metalloproteinase activity and prostaglandin E2 are elevated in the synovial fluid of meniscus tear patients. Connect Tissue Res. 2017;58(3-4):305-316.
36.
LohmanderLSEnglundPMDahlLLRoosEM.The long-term consequence of anterior cruciate ligament and meniscus injuries: osteoarthritis. Am J Sports Med. 2007;35(10):1756-1769.
37.
MarkusDHBerlinbergEJStraussEJ.Current state of synovial fluid biomarkers in sports medicine. JBJS Rev. 2021;9(8):e21.00024.
38.
MartinJABrownTDHeinerABuckwalterJA.Post-traumatic osteoarthritis: the role of accelerated chondrocyte senescence. Biorheology. 2004;41:479-491.
39.
MuddasaniPNormanJCEllmanMvan WijnenAJImHJ.Basic fibroblast growth factor activates the MAPK and NFkappaB pathways that converge on Elk-1 to control production of matrix metalloproteinase-13 by human adult articular chondrocytes. J Biol Chem. 2007;282(43):31409-31421.
40.
NelsonFBillinghurstRCPidouxI, et al. Early post-traumatic osteoarthritis-like changes in human articular cartilage following rupture of the anterior cruciate ligament. Osteoarthritis Cartilage. 2006;14(2):114-119.
41.
NeumanPDahlbergLEEnglundMStruglicsA.Concentrations of synovial fluid biomarkers and the prediction of knee osteoarthritis 16 years after anterior cruciate ligament injury. Osteoarthritis Cartilage. 2017;25(4):492-498.
42.
PapathanasiouIMichalitsisSHantesM, et al. Molecular changes indicative of cartilage degeneration and osteoarthritis development in patients with anterior cruciate ligament injury. BMC Musculoskelet Disord. 2016;17:21.
43.
PasternakBAspenbergP.Metalloproteinases and their inhibitors— diagnostic and therapeutic opportunities in orthopedics. Acta Orthop. 2009;80(6):693-703.
44.
PelletierJPRaynauldJPCaronJ, et al. Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis. Ann Rheum Dis. 2010;69(12):2095-2101.
45.
PengasIEldridgeSAssiotisA, et al. MMP-3 in the peripheral serum as a biomarker of knee osteoarthritis, 40 years after open total knee meniscectomy. J Exp Orthop. 2018;5(1):21.
46.
PetersonRA.A meta-analysis of variance accounted for and factor loadings in exploratory factor analysis. Mark Lett. 2000;11(3):261-275.
47.
PonteALMaraisEGallayN, et al. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells. 2007;25(7):1737-1745.
48.
PunziLGalozziPLuisettoR, et al. Post-traumatic arthritis: overview on pathogenic mechanisms and role of inflammation. RMD Open. 2016;2(2):e000279.
49.
RaghuHLepusCMWangQ, et al. CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis. Ann Rheum Dis. 2017;76(5):914-922.
50.
SpindlerKPHustonLJChaginKM, et al. Ten-year outcomes and risk factors after anterior cruciate ligament reconstruction: a MOON longitudinal prospective cohort study. Am J Sports Med. 2018; 46(4):815-825.
51.
StoneAVLoeserRFVandermanKS, et al. Pro-inflammatory stimulation of meniscus cells increases production of matrix metalloproteinases and additional catabolic factors involved in osteoarthritis pathogenesis. Osteoarthritis Cartilage. 2014;22(2):264-274.
52.
SunJHYangBDonnellyDFMaCLaMotteRH.MCP-1 enhances excitability of nociceptive neurons in chronically compressed dorsal root ganglia. J Neurophysiol. 2006;96(5):2189-2199.
53.
TangCHHsuCJFongYC.The CCL5/CCR5 axis promotes interleukin-6 production in human synovial fibroblasts. Arthritis Rheum. 2010;62(12):3615-3624.
54.
van der KraanPM. The interaction between joint inflammation and cartilage repair. Tissue Eng Regen Med. 2019;16(4):327-334.
55.
WehrensRMevikB-H.The pls package: principal component and partial least squares regression in R. J Stat Softw. 2007;18(2):1-23. doi:10.18637/jss.v018.i02
56.
WhiteFASunJWatersSM, et al. Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc Natl Acad Sci U S A. 2005;102(39):14092-14097.
57.
WojdasiewiczPPoniatowskiŁASzukiewiczD.The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm. 2014;2014:561459.
58.
XuY-KKeYWangBLinJ-H.The role of MCP-1-CCR2 ligand-receptor axis in chondrocyte degradation and disease progress in knee osteoarthritis. Biol Res. 2015;48:64.
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