Summary
Urine and blood biomarkers of collagen metabolism change during the first after ACL reconstruction and suggest a reparative type 2 collegen response
Abstract
Introduction
Changes in urinary and serum biomarkers of chondral metabolism have been identified after anterior cruciate ligament (ACL) injury and reconstruction. Systemic biomarkers may provide a minimally-invasive way of identifying changes occurring at the cellular level within the knee. As such, biomarkers may hold value in identifying patients at risk of premature osteoarthritis (OA) or predicting other outcomes following ACL reconstruction.
Methods
From a prospective longitudinal study of 692 ACL injured patients, urine and serum samples were taken immediately prior to primary ACL reconstruction and at the 6 and 12 months post operative time points. 666 patients (96.3%) provided samples for at least one time point and formed the study population. 547 patients (82.1%) had blood samples at all 3 timepoints and 552 (82.9%) had urine samples at all 3 timepoints. Mean (SD) patient age at surgery was 24.9 (7.20); 60.5% were male; median time from injury to surgery was 58 days (IQR 193); mean (SD) pre-injury Marx Activity Rating Scale was 12.3 (3.98). Levels of urinary C-terminal cross-linked telopeptide of type II collagen (CTX-II) – a marker of type 2 collagen degradation, serum N-propeptide of collagen IIA (PIIANP) – a marker of type 2 collagen synthesis, and serum Matrix Metalloproteinase 3 (MMP-3) - a mediator in pathological cartilage matrix degradation, were measured using commercially available enzyme-linked immunosorbent assays (ELISA). CTX-II levels were normalized to urinary creatinine. Biomarker levels were log transformed and linear mixed modelling analyses performed to evaluate changes over time.
Results
Levels of urinary CTX-II significantly decreased during the study period. The log-transformed baseline level of CTX-II was 501.2 ng/mmol Cr. At the 6-month mark there was a 25% decrease relative to baseline (P < 0.001). At the 12-month mark there was a 37% decrease relative to baseline (p < 0.001). There was a significant increase in serum PIIIANP levels seen with time. Log-transformed PIIANP levels at baseline were 21.57 ng/ml. At the 6-month time point, there was a 41% increase relative to baseline (t = 16.6, p < 0.001). At the 12-month timepoint, there was a 42% increase relative to baseline (t = 16.7, p < 0.001). Levels of serum MMP3 significantly increased with time. The log-transformed baseline level of MMP3 was 26.9 ng/ml. At the 6-month time point, there was a 35% increase from baseline (t = 14, p < 0.001) and at the 12-month timepoint there was a 45% increase from baseline (t = 16.6, p < 0.001).
Conclusions
Reducing urinary CTX-II levels coupled with increasing serum PIIANP levels, (indicating reduced type 2 collagen degradation and increasing type 2 collagen synthesis respectively), is suggestive of a reparative chondral response in the first year following ACL injury and reconstruction. Increasing levels of MMP3 suggests ongoing articular cartilage extracellular matrix degradation and remodeling. The changes were most marked at the 6-month time point. Correlation of these markers to clinical and radiological outcomes may help define their value in predicting OA.
• An analysis exploring clinical and radiological factors as explanatory variables for biomarker variability is underway and will also be presented if this abstract is selected.