Synovial fluid biomarkers associated with osteoarthritis severity reflect macrophage and neutrophil related inflammation

BackgroundTo identify a synovial fluid (SF) biomarker profile characteristic of individuals with an inflammatory osteoarthritis (OA) endotype.MethodsA total of 48 knees (of 25 participants) were characterized for an extensive array of SF biomarkers quantified by Rules Based Medicine using the high-sensitivity multiplex immunoassay, Myriad Human InflammationMAP (R) 1.0, which included 47 different cytokines, chemokines, and growth factors related to inflammation. Multivariable regression with generalized estimating equations (GEE) and false discovery rate (FDR) correction was used to assess associations of SF RBM biomarkers with etarfolatide imaging scores reflecting synovial inflammation; radiographic knee OA severity (based on Kellgren-Lawrence (KL) grade, joint space narrowing, and osteophyte scores); knee joint symptoms; and SF biomarkers associated with activated macrophages and knee OA progression including CD14 and CD163 (shed by activated macrophages) and elastase (shed by activated neutrophils).ResultsSignificant associations of SF biomarkers meeting FDR <0.05 included soluble (s)VCAM-1 and MMP-3 with synovial inflammation (FDR-adjusted p=0.025 and 1.06x10(-7)); sVCAM-1, sICAM-1, TIMP-1, and VEGF with radiographic OA severity (p=1.85x10(-5) to 3.97x10(-4)); and VEGF, MMP-3, TIMP-1, sICAM-1, sVCAM-1, and MCP-1 with OA symptoms (p=2.72x10(-5) to 0.050). All these SF biomarkers were highly correlated with macrophage markers CD163 and CD14 in SF (r=0.43 to 0.90, FDR <0.05); all but MCP-1 were also highly correlated with neutrophil elastase in SF (r=0.62 to 0.89, FDR <0.05).ConclusionsA subset of six SF biomarkers was related to synovial inflammation in OA, as well as radiographic and symptom severity. These six OA-related SF biomarkers were specifically linked to indicators of activated macrophages and neutrophils. These results attest to an inflammatory OA endotype that may serve as the basis for therapeutic targeting of a subset of individuals at high risk for knee OA progression.Trial registrationWritten informed consent was received from participants prior to inclusion in the study; the study was registered at ClinicalTrials.gov (NCT01237405) on November 9, 2010, prior to enrollment of the first participant.