Cytokine Profiling in Acute Anterior Cruciate Ligament Injury

Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, New York, USA.
Arthroscopy The Journal of Arthroscopic and Related Surgery (Impact Factor: 3.21). 10/2010; 26(10):1296-301. DOI: 10.1016/j.arthro.2010.02.011
Source: PubMed


To evaluate the presence and relative concentrations of cytokines, known to be involved in the inflammatory cascade, in acute anterior cruciate ligament (ACL) injury.
We evaluated an extensive cytokine profile in synovial fluid from 12 patients with acute ACL injury undergoing arthroscopy compared with 15 control subjects using a BioPlex assay (Bio-Rad Laboratories, Hercules, CA) to measure the concentration of 17 inflammatory cytokines.
In patients with acute ACL injury compared with asymptomatic control subjects, the following cytokines were identified at significantly increased concentrations (P < .001, Mann-Whitney U test) compared with control samples: interleukin 6 (105 ± 72 v 0 ± 0 pg/ml), interferon γ (1,544 ± 608 v 9 ± 7.5 pg/ml), macrophage inflammatory protein 1β (16 ± 3.8 v 0.3 ± 0.2 pg/ml), and monocyte chemotactic protein 1 (35 ± 13 v 0.5 ± 0.4 pg/ml). There was no case of a cytokine exhibiting increased levels in asymptomatic compared with symptomatic knee samples.
This investigation identified 4 specific cytokines (interleukin 6, interferon γ, monocyte chemotactic protein 1, and macrophage inflammatory protein 1β) out of a panel of 17 inflammatory molecules for which the levels were consistently elevated in the context of ACL injury compared with non-painful, non-acutely injured knees in a volunteer population.
Level IV, prognostic case series.

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    • "Therefore, baseline information on mediator release from ‘normal’ synovium was not possible. However, cytokine profiling of synovial fluid from healthy controls using a similar Bio-Plex assay setup (Bio-Rad Laboratories, Hercules, CA, USA) showed that the synovial fluid quantities of the four mediators were extremely low, with MCP-1 having the highest mean concentration at 0.5 ± 0.4 pg/ml [30]. We therefore believe that cytokine levels above assay detection limits (lowest detection limit of IL-8 = 26 pg/ml) should reflect synovial pathology. "
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    ABSTRACT: Introduction Despite the widespread use of magnetic resonance imaging (MRI) and Doppler ultrasound for the detection of rheumatoid arthritis (RA) disease activity, little is known regarding the association of imaging-detected activity and synovial pathology. The purpose of this study was to compare site-specific release of inflammatory mediators and evaluate the corresponding anatomical sites by examining colour Doppler ultrasound (CDUS) and MRI scans. Methods RA patients were evaluated on the basis of CDUS and 3-T MRI scans and subsequently underwent synovectomy using a needle arthroscopic procedure of the hand joints. The synovial tissue specimens were incubated for 72 hours, and spontaneous release of monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), macrophage inflammatory protein 1β (MIP-1β) and IL-8 was measured by performing multiplex immunoassays. Bone marrow oedema (BME), synovitis and erosion scores were estimated on the basis of the rheumatoid arthritis magnetic resonance imaging score (RAMRIS). Mixed models were used for the statistical analyses. Parsimony was achieved by omitting covariates with P > 0.1 from the statistical model. Results Tissue samples from 58 synovial sites were obtained from 25 patients. MCP-1 was associated with CDUS activity (P = 0.009, approximate Spearman’s ρ = 0.41), RAMRIS BME score (P = 0.01, approximate Spearman’s ρ = 0.42) and RAMRIS erosion score (P = 0.03, approximate Spearman’s ρ = 0.31). IL-6 was associated with RAMRIS synovitis score (P = 0.04, approximate Spearman’s ρ = 0.50), BME score (P = 0.04, approximate Spearman’s ρ = 0.31) and RAMRIS erosion score (P = 0.03, approximate Spearman’s ρ = 0.35). MIP-1β was associated with CDUS activity (P = 0.02, approximate Spearman’s ρ = 0.38) and RAMRIS synovitis scores (P = 0.02, approximate Spearman’s ρ = 0.63). IL-8 associations with imaging outcome measures did not reach statistical significance. Conclusions The association between imaging activity and synovial inflammatory mediators underscores the high sensitivity of CDUS and MRI in the evaluation of RA disease activity. The associations found in our present study have different implications for synovial mediator releases and corresponding imaging signs. For example, MCP-1 and IL-6 were associated with both general inflammation and bone destruction, in contrast to MIP-1β, which was involved solely in general synovitis. The lack of association of IL-8 with synovitis was likely underestimated because of a large proportion of samples above assay detection limits among the patients with the highest synovitis scores.
    Arthritis Research & Therapy 05/2014; 16(3). DOI:10.1186/ar4557 · 3.75 Impact Factor
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    • "However, the presence of IL-6 in joints with symptomatic cartilage defects has not been evaluated until now. In other joint injuries known to predispose to OA, such as anterior cruciate ligament (ACL) injuries [19-21] and meniscal tears [12,22], increased levels of IL-6 have been detected in the synovial fluid. High levels of intra-articular inflammatory cytokines may, in addition to causing degeneration, also hamper tissue regeneration as cartilage repair is affected by the composition of the synovial fluid [23-25]. "
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    ABSTRACT: Introduction This study aimed to determine whether, as in osteoarthritis, increased levels of interleukin-6 (IL-6) are present in the synovial fluid of patients with symptomatic cartilage defects and whether this IL-6 affects cartilage regeneration as well as the cartilage in the degenerated knee. Methods IL-6 concentrations were determined by ELISA in synovial fluid and in conditioned media of chondrocytes regenerating cartilage. Chondrocytes were obtained from donors with symptomatic cartilage defects, healthy and osteoarthritic donors. The effect of IL-6 on cartilage regeneration and on metabolism of the resident cartilage in the knee was studied by both inhibition of endogenous IL-6 and addition of IL-6, in a regeneration model and in osteoarthritic explants in the presence of synovial fluid, respectively. Readout parameters were DNA and glycosaminoglycan (GAG) content and release. Differences between controls and IL-6 blocked or supplemented samples were determined by univariate analysis of variance using a randomized block design. Results Synovial fluid of patients with symptomatic cartilage defects contained more IL-6 than synovial fluid of healthy donors (P = 0.001) and did not differ from osteoarthritic donors. IL-6 production of osteoarthritic chondrocytes during cartilage regeneration was higher than that of healthy and defect chondrocytes (P < 0.001). Adding IL-6 increased GAG production by healthy chondrocytes and decreased GAG release by osteoarthritic chondrocytes (P < 0.05). Inhibition of IL-6 present in osteoarthritic synovial fluid showed a trend towards decreased GAG content of the explants (P = 0.06). Conclusions Our results support a modest anabolic role for IL-6 in cartilage matrix production. Targeting multiple cytokines, including IL-6, may be effective in improving cartilage repair in symptomatic cartilage defects and osteoarthritis.
    Arthritis research & therapy 12/2012; 14(6):R262. DOI:10.1186/ar4107 · 3.75 Impact Factor
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    • "In contrast, no substantive changes in IL-1B levels were found among the study's 11 participants [70]. In another study, higher concentrations of IL-6, IFNγ, MIP-1β, and MCP-1 were measured in the synovial fluid of ACL-injured patients versus uninjured controls [71]. Synovial biomarkers from meniscus-injured populations, including both acute and chronic injury, had higher levels of cytokines IFNγ, IL-6, MCP-1, MIP-1β, IL-2, IL-4, IL-10, and IL-13 compared with asymptomatic populations with IL-6, MCP-1, MIP-1β, and IFNγ concentrations correlating with patient-reported pain outcome scores [72]. "
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    ABSTRACT: Osteoarthritis is a prevalent and disabling disease affecting an increasingly large swathe of the world population. While clinical osteoarthritis is a late-stage condition for which disease-modifying opportunities are limited, osteoarthritis typically develops over decades, offering a long window of time to potentially alter its course. The etiology of osteoarthritis is multifactorial, showing strong associations with highly modifiable risk factors of mechanical overload, obesity and joint injury. As such, characterization of pre-osteoarthritic disease states will be critical to support a paradigm shift from palliation of late disease towards prevention, through early diagnosis and early treatment of joint injury and degeneration to reduce osteoarthritis risk. Joint trauma accelerates development of osteoarthritis from a known point in time. Human joint injury cohorts therefore provide a unique opportunity for evaluation of pre-osteoarthritic conditions and potential interventions from the earliest stages of degeneration. This review focuses on recent advances in imaging and biochemical biomarkers suitable for characterization of the pre-osteoarthritic joint as well as implications for development of effective early treatment strategies.
    Arthritis research & therapy 06/2012; 14(3):212. DOI:10.1186/ar3845 · 3.75 Impact Factor
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