Potential key biomarkers of osteoarthritis by integrative genome-wide gene expression profiling analysis

Abstract

study found that increases in both a degradation marker (C1,2C) and synthesis marker (CS846) in response to a 30 minute walk were correlated with cartilage thickness changes over 5 years. However, that study did not include knee loading during gait or compositional MRI. Thus, the goal of the study was to test this stimulus-response protocol on ACLR subjects and include mechanical knee loading during walking and compositional MRI. The structural outcome measure, compositional MRI ultrashort echo time enhanced T2* (UTE-T2*) mapping, was selected because it has been shown to be sensitive to subsurface cartilage matrix changes both acutely after ACL injury and in longitudinal followup. In addition, UTE-T2* mapping was recently found to correlate with knee adduction moment (KAM) during gait. This study tested the hypotheses that changes to serum C1,2C and CS846 after a mechanical stimulus correlate with deep cartilage compositional MRI UTE-T2*, and with knee flexion moment (KFM) and KAM during walking after ACLR. Methods: Serum concentrations of CS846 and C1,2C were measured in 25 subjects (14F, Age: 34.5±9.8, BMI: 24.6±3.2) with unilateral ACLR (2.20±0.22 yr post-op) by enzyme-linked immunosorbent assays (ELISA) from blood drawn at rest and 5.5 hours after a 30 minute treadmill walk. Twenty-one subjects received MRI and UTE-T2* maps were calculated via mono-exponential fitting on a series of T2*-weighted MR images acquired at 8 TEs (32ms -16 ms). All subjects completed gait analysis, and KFM and KAM were calculated during stance phase of walking. Paired t-tests were used to assess differences in concentrations before and 5.5 hours after walking. Correlations were tested between the biomarker response and both knee loading (KFM and KAM) and UTE-T2* in the deep weight bearing regions of cartilage in the central and posterior, medial and lateral femur (cMFC, pMFC, cLFC, pLFC). Results: The response of the synthesis marker (CS846) from resting to 5.5 hours varied among subjects but was correlated with both UTE-T2* in all regions of deep weight bearing cartilage analyzed (cMFC, Figure 1A; cLFC, Figure 1B; pMFC, R¼0.494, P¼0.023; pLFC, R¼0.525, P¼0.021), and with knee loading during walking (KFM, Figure 2A; KAM, Figure 2B). However, there were no significant correlations between the degradation marker (C1,2C) response and UTE-T2* or knee loading. There were also no significant mean differences between concentrations of CS846 and C1,2C before and after the walking activity (P¼0.17, 0.82, respectively).