Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254)

Acute trauma involving the anterior cruciate ligament is believed to be a major risk factor for the development of post-traumatic osteoarthritis 10 to 20 years post-injury. In this study, to better understand the early biological changes which occur after acute injury, we investigated synovial fluid and serum biomarkers. We collected serum from 11 patients without pre-existing osteoarthritis from a pilot intervention trial (5 placebo and 6 drug treated) using an intra-articular interleukin-1 receptor antagonist (IL-1Ra) therapy, 9 of which also supplied matched synovial fluid samples at presentation to the clinic after acute knee injury (mean 15.2 ± 7.2 days) and at the follow-up visit for reconstructive surgery (mean 47.6 ± 12.4 days). To exclude patients with pre-existing osteoarthritis (OA), the study was limited to individuals younger than 40 years of age (mean 23 ± 3.5) with no prior history of joint symptoms or trauma. We profiled a total of 21 biomarkers; 20 biomarkers in synovial fluid and 13 in serum with 12 biomarkers measured in both fluids. Biomarkers analyzed in this study were found to be independent of treatment (P > 0.05) as measured by Mann-Whitney and two-way ANOVA. We observed significant decreases in synovial fluid (sf) biomarker concentrations from baseline to follow-up for (sf)C-Reactive protein (CRP) (P = 0.039), (sf)lubricin (P = 0.008) and the proteoglycan biomarkers: (sf)Glycosaminoglycan (GAG) (P = 0.019), and (sf)Alanine-Arginine-Glycine-Serine (ARGS) aggrecan (P = 0.004). In contrast, we observed significant increases in the collagen biomarkers: (sf)C-terminal crosslinked telopeptide type II collagen (CTxII) (P = 0.012), (sf)C1,2C (P = 0.039), (sf)C-terminal crosslinked telopeptide type I collagen (CTxI) (P = 0.004), and (sf)N-terminal telopeptides of type I collagen (NTx) (P = 0.008). The concentrations of seven biomarkers were significantly higher in synovial fluid than serum suggesting release from the signal knee: IL-1β (P < 0.0001), fetal aggrecan FA846 (P = 0.0001), CTxI (P = 0.0002), NTx (P = 0.012), osteocalcin (P = 0.012), Cartilage oligomeric matrix protein (COMP) (P = 0.0001) and matrix metalloproteinase (MMP)-3 (P = 0.0001). For these seven biomarkers we found significant correlations between the serum and synovial fluid concentrations for only CTxI (P = 0.0002), NTx (P < 0.0001), osteocalcin (P = 0.0002) and MMP-3 (P = 0.038). These data strongly suggest that the biology after acute injury reflects that seen in car