Dickkopf-related protein 1 and gremlin 1 show different response than frizzled-related protein in human synovial fluid following knee injury and in patients with osteoarthritis

OBJECTIVE: To explore the involvement of the wingless-type MMTV integration site (WNT) and bone morphogenetic protein (BMP) antagonists dickkopf-related protein 1 (DKK1), frizzled-related protein (FRZB) and gremlin 1 (GREM1) in knee injury and osteoarthritis (OA). DESIGN: The antagonists were immunoassayed in synovial fluid from a cross-sectional cohort of nine knee healthy reference subjects, patients with recent (0-77 days, n = 158) or old (1-37 years, n = 50) knee injuries, and OA (n = 22). Cartilage (ARGS-aggrecan, cartilage oligomeric matrix protein and C2C type II collagen) and other biomarkers were assessed in synovial fluid in a subset of samples. Statistical analysis was by Kendall's tau (tau) correlation, Mann-Whitney U test, and linear regression analysis. RESULTS: Compared to references, median concentration of GREM1 (but not DKK1 and FRZB) was elevated 1.5-fold immediately after injury, and FRZB was reduced 1000-folds in OA. All three antagonists decreased with increasing time after injury as well as with increasing age, but the temporal change after injury was less accentuated for FRZB (peaked 8-22 days after injury) compared to that of DKK1 and GREM1 (peaked immediately after injury). In the recent injury group, there was a correlation between GREM1 and DKK1 (tau = 0.172); FRZB concentrations correlated with concentrations of cartilage biomarkers (tau between 0.257 and 0.369), while DKK1 and GREM1 were inversely correlated (tau between -0.177 and -0.217) with these markers. CONCLUSIONS: Our results indicate separate roles for the antagonists, where DKK1 and GREM1 had similarities in response to injury and in OA, with a different response for FRZB.