Abstract
ObjectiveTo investigate whether molecules found to be up‐regulated within hours of surgical joint destabilization in the mouse are also elevated in the analogous human setting of acute knee injury, how this molecular response varies between individuals, and whether it is related to patient‐reported outcomes in the 3 months after injury.MethodsSeven candidate molecules were analyzed in blood and synovial fluid (SF) from 150 participants with recent structural knee injury at baseline (<8 weeks from injury) and in blood at 14 days and 3 months following baseline. Knee Injury and Osteoarthritis Outcome Score 4 (KOOS4) was obtained at baseline and 3 months. Patient and control samples were compared using Meso Scale Discovery platform assays or enzyme‐linked immunosorbent assay.ResultsSix of the 7 molecules were significantly elevated in human SF immediately after injury: interleukin‐6 (IL‐6), monocyte chemotactic protein 1, matrix metalloproteinase 3 (MMP‐3), tissue inhibitor of metalloproteinases 1 (TIMP‐1), activin A, and tumor necrosis factor–stimulated gene 6 (TSG‐6). There was low‐to‐moderate correlation with blood measurements. Three of the 6 molecules were significantly associated with baseline KOOS4 (those with higher SF IL‐6, TIMP‐1, or TSG‐6 had lower KOOS4). These 3 molecules, MMP‐3, and activin A were all significantly associated with greater improvement in KOOS4 over 3 months, after adjustment for other relevant factors. Of these, IL‐6 alone significantly accounted for the molecular contribution to baseline KOOS4 and change in KOOS4 over 3 months.ConclusionOur findings validate relevant human biomarkers of tissue injury identified in a mouse model. Analysis of SF rather than blood more accurately reflects this response. The response is associated with patient‐reported outcomes over this early period, with SF IL‐6 acting as a single representative marker. Longitudinal outcomes will determine if these molecules are biomarkers of subsequent disease risk.
Highlights
Six of the 7 molecules were significantly elevated in human synovial fluid (SF) immediately after injury: interleukin-6 (IL-6), monocyte chemotactic protein 1, matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), activin A, and tumor necrosis factor–stimulated gene 6 (TSG-6)
Three of the 6 molecules were significantly associated with baseline Knee Injury and Osteoarthritis Outcome Score 4 (KOOS4)
These 3 molecules, MMP-3, and activin A were all significantly associated with greater improvement in KOOS4 over 3 months, after adjustment for other relevant factors
Summary
Participants were referred for screening by the orthopedic surgeon investigator (AW) from a population with acute knee injury assessed by him at various sites in London, UK. The Knee Injury and Osteoarthritis Outcome Score (KOOS), from which KOOS4, a single composite score, can be calculated (an average of 4 of the 5 KOOS subscales including pain, symptoms, sports/recreation, and quality of life) [24] and Tegner score [25] were obtained at baseline and 3 months (Figure 1A). KOOS4 increased by 10 points more over 3 months in those with IL-6 levels in the highest quartile at baseline compared to those with IL-6 levels in the lowest quartile at baseline (Figure 4B) The differences between those with low IL-6 levels and those with high IL-6 levels held true if participants were divided into subgroups based on the severity of injury. Scores for the KOOS domains pain, symptoms, and sports and physical activity were all significantly reduced (worse) at baseline in those with high SF IL-6 levels (P 5 0.0002, P 5 0.0035, and P 5 0.04, respectively), and the quality of life domain score was reduced to a lesser extent (P 5 0.07)
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