Molecular changes in synovial fluid following human knee injury are associated with early clinical outcomes

Purpose: We studied whether molecules which were up-regulated within hours of surgical joint destabilisation in the mouse were also elevated in the analogous human setting of acute knee injury, how this molecular response varied between individuals,and whether it related to patient-reported outcomes in the 3 months after injury. Methods: 7 candidate molecules were analysed in blood and synovial fluid (SF) at baseline,14 days and 3 months following baseline visit of 150 participants in the Knee Injury Cohort @ Kennedy (KICK), who had recent structural knee injury (<8 weeks from injury). Knee injury and Osteoarthritis Outcome Score (KOOS) was collected at baseline and 3 months. Assays were by MesoScale Discovery™platform or ELISA, and compared with age and sex-matched control samples. Results: Participants' median age was 25, median time from injury to baseline visit was 17 days and there was substantial impairment by KOOS at baseline visit. 6/7 molecules were significantly elevated in human synovial fluid immediately after injury: IL-6, MCP-1, MMP-3, TIMP-1, activin A and TSG-6. 3/6 molecules were significantly associated with baseline KOOS4 (those with higher SF IL-6, TIMP-1 or TSG-6 had lower KOOS4). Each of these 3, MMP-3 and activin A were all significantly associated with greater improvement in KOOS4 over 3 months, adjusting for relevant, pre-defined factors including time from injury to sampling, extent of injury, age and presence of heavy blood staining of synovial fluid. When all 5 synovial fluid biomarkers were included in a linear regression model, only synovial fluid IL-6 was independently associated with either baseline KOOS4 (Coeff.-4.0 (−5.92,−2.08), P<0.001), or difference in KOOS4 over 3 months (Coeff.2.80 (0.89,5.52), P = 0.043). Conclusions: Our findings validate relevant human biomarkers of joint injury identified from a mouse model. The response, represented best by synovial fluid IL-6, has clinical relevance over this early period: a greater quantifiable inflammatory response soon after the injury is associated with increased impairment and pain by KOOS4 at that time. Paradoxically, this same response at baseline would appear to be a good prognostic factor for change in clinical outcome over 3 months, or at least not an adverse one, in this predominantly surgically-managed cohort. Longitudinal outcomes will determine if these molecules are biomarkers of subsequent osteoarthritis risk.