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

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INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: These data strongly suggest that the biology after acute injury reflects that seen in cartilage explant models stimulated with pro-inflammatory cytokines, which are characterized by an initial wave of proteoglycan loss followed by subsequent collagen loss. As the rise of collagen biomarkers in synovial fluid occurs within the first month after injury, and as collagen loss is thought to be irreversible, very early treatment with agents to either reduce inflammation and/or reduce collagen loss may have the potential to reduce the onset of future post-traumatic osteoarthritis. TRIAL REGISTRATION: The samples used in this study were derived from a clinical trial NCT00332254 registered with





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Catterall, Jonathan B, Thomas V Stabler, Carl R Flannery and Virginia B Kraus (2010). Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254). Arthritis Res Ther, 12(6). p. R229. 10.1186/ar3216 Retrieved from

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Virginia Byers Kraus

Professor of Medicine

Virginia Byers Kraus, MD, PhD, is the Mary Bernheim Distinguished Professor of Medicine, Professor of Orthopaedic Surgery, Professor of Pathology and a faculty member of the Duke Molecular Physiology Institute in the Duke University School of Medicine. She is a practicing Rheumatologist with over 30 years’ experience in translational musculoskeletal research focusing on osteoarthritis, the most common of all arthritides. She trained at Brown University (ScB 1979), Duke University (MD 1982, PhD 1993) and the Duke University School of Medicine (Residency in Internal Medicine and Fellowship in Rheumatology). Her career has focused on elucidating osteoarthritis pathogenesis and translational research into the discovery and validation of biomarkers for early osteoarthritis detection, prediction of progression, monitoring of disease status, and facilitation of therapeutic developments. She is co-PI of the Foundation for NIH Biomarkers Consortium Osteoarthritis project. Trained as a molecular biologist and a Rheumatologist, she endeavors to study disease from bedside to bench.

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