Significant Changes in Serum MicroRNAs after High Tibial Osteotomy in Medial Compartmental Knee Osteoarthritis: Potential Prognostic Biomarkers

Abstract

High tibial osteotomy (HTO) is an effective alternative for medial compartmental knee osteoarthritis (OA). Circulating microRNAs (miRNAs) are known to serve as OA-related biomarkers. The present study investigated the differential expression of serum miRNAs before and after HTO to identify potential miRNAs as prognostic biomarkers. miRNA-polymerase chain reaction (PCR) arrays were used to screen for miRNAs in the serum at preoperative and 6-month postoperative time points from six patients, and the differentially expressed miRNAs identified in the profiling stage were validated using real-time PCR at post-operative months 6 and 18 in 27 other HTO-treated patients. Among 84 miRNAs involved in the inflammatory process, three (miR-19b-3p, miR-29c-3p, and miR-424-5p) showed differential expression patterns in the profiling stage (p = 0.011, 0.015, and 0.021, respectively). Levels of these three and four other miRNAs (miR-140-3p, miR-454-3p, miR-let-7e-5p, and miR-885-5p) known to be related to OA progression were evaluated in the serum of 27 patients. Only four miRNAs (miR-19b-3p, miR-140-3p, miR-454-3p, and miR-let-7e-5p) were significantly upregulated at postoperative month 6 (p = 0.003, 0.005, 0.004, and 0.004, respectively), and only miR-140-3p was significantly upregulated up to 18 months after operation (p = 0.003). Together, this study reveals the significantly upregulated serum miRNAs after HTO as potential prognostic biomarkers; however, further studies are warranted to elucidate their clinical implications.

Keywords: high tibial osteotomy; knee; medial compartmental osteoarthritis; prognosis; serum miRNA.

Figure 1

Study design. Three candidate miRNAs were identified in the serum from six patients with high tibial osteotomy at preoperative and postoperative time points. We evaluated their expression together with other four previously identified miRNAs (total seven miRNAs) in 27 patients at postoperative 6 months and 20 patients at postoperative 18 months for validation. Data of seven patients were excluded, owing to different collection time points.

Figure 2

Heatmap showing the expression levels of 84 target miRNAs from miRNA PCR array screening performed for serum samples collected from six patients at preoperative and postoperative month-6 time points.

Figure 3

Box plot showing the interquartile range and median values of the expression levels of miR-19b-3p (A), miR-29c-3p (B), miR-424-5p (C), miR-140-3p (D), miR-454-3p (E), miR-let-7e-5p (F), and miR-885-5p (G) before surgery and 6 months after surgery at the validation stage. The values represent the relative levels normalized to the level of the reference gene, SNORD61. ** indicates a Bonferroni-corrected p-value < 0.0071 (0.05/7) corresponding to the statistical significance.