Abstract
IntroductionBiomarkers to identify osteoarthritis (OA) patients at risk for disease progression are needed. As part of a proteomic analysis of knee synovial fluid from normal and OA patients, differentially expressed proteins were identified that could represent potential biomarkers for OA. This study aimed to use mass spectrometry assays to identify representative peptides from several proteins in synovial fluid and peripheral blood, and assess their levels as biomarkers of OA progression.MethodsMultiplexed high throughput selected reaction monitoring (SRM) assays were developed to measure tryptic peptides representative of 23 proteins in matched serum and synovial fluid samples from late OA subjects at the time of joint replacement. Subsequently plasma samples from the baseline visit of 173 subjects in an observational OA cohort were tested by SRM for peptides from nine of these proteins: afamin, clusterin, cartilage oligomeric matrix protein, hepatocyte growth factor, kallistatin, insulin-like growth factor binding protein, acid labile subunit, lubricin, lumican, and pigment epithelium-derived factor. Linear regression was used to determine the association between the peptide biomarker level at baseline and change in joint space width (ΔJSW) from baseline to 30 months, adjusting for age and sex.ResultsIn the matched cohort, 17 proteins could be identified in synovial fluid and 16 proteins were detected in serum. For the progression cohort, the average age was 62 and average ΔJSW over 30 months was 0.68 mm. A high correlation between different peptides from individual proteins was observed, indicating our assays correctly measured their target proteins. Peptides representative of clusterin, lumican and lubricin showed statistically significant associations with joint space narrowing after adjustment for age and sex. Partial R2 values showed clusterin FMETVAEK and lubricin LVEVNPK peptide biomarkers explains about 2 to 3% of the variability of ΔJSW, similar to that explained by age. A biomarker score combining normalized data for both lubricin and clusterin peptides increased the model R2 to 0.079.ConclusionsOur results suggest that when combined, levels of peptides representative of clusterin and lubricin in plasma are as predictive of OA progression as age. Replication of these findings in other prospective OA cohorts is planned.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0456-6) contains supplementary material, which is available to authorized users.
Highlights
Biomarkers to identify osteoarthritis (OA) patients at risk for disease progression are needed
As a secondary analysis we examined the association between each peptide biomarker level at baseline and 30-month change in the Western Ontario and McMaster Universities Arthritis Index (WOMAC)
Translation of peptide biomarkers from synovial fluid to serum We initially selected 23 proteins as possible biomarkers (Table 1). These proteins were selected from discovery proteomics experiments comparing OA and normal synovial fluid ([8,9] and data not shown) and lists of previously published OA biomarkers
Summary
Biomarkers to identify osteoarthritis (OA) patients at risk for disease progression are needed. As part of a proteomic analysis of knee synovial fluid from normal and OA patients, differentially expressed proteins were identified that could represent potential biomarkers for OA. This study aimed to use mass spectrometry assays to identify representative peptides from several proteins in synovial fluid and peripheral blood, and assess their levels as biomarkers of OA progression. The drug development pipeline has been limited by the heterogeneity of OA, the slowly progressive nature of the disease and the fact that there can be long periods of asymptomatic degeneration. Biomarkers that can detect those at risk for disease progression would be beneficial and could minimize the duration and cost of drug discovery [2]. The cost and time needed to develop specific, well-performing antibodies for immunoassays is limiting [3]. Recent studies have shown mass spectrometry-based assays can have the excellent reproducibility that is necessary for tests in clinical laboratories [6,7]
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