Osteoarthritic Extracellular RNA Biomarkers in Synovial Fluid

Abstract

The molecular mechanisms influencing the initiation and progression of osteoarthritis (OA) are unclear. Therefore, current clinical management of predominately involves symptomatic treatment of end-stage diagnosed OA. Understanding the pathogenesis of OA at the pre-clinical stage may aid in both diagnostic and preventative modalities in the management of this chronic disease. PURPOSE: To determine the synovial extracellular RNA (exRNA) changes associated with OA. METHODS: Synovial fluid was collected from the injured knee of a cohort of 14 individuals (ages 15-47, 10 males and 4 females) undergoing surgical repair following ACL and/or meniscus injuries. Each knee had arthroscopically graded OA and divided the cohort into 5 individuals in the OA group (OA in >1 knee compartment) and 9 individuals in the non-OA group (OA in ≤1 knee compartment). Total exRNA was extracted from the synovial fluid collected at the time of surgery, >30 million reads generated per sample using massively parallel sequencing, and differential abundance of RNA was calculated between the two groups. RESULTS: A total of 19 protein coding exRNAs were significantly different (FDR ≤ 0.05) between the two groups: 13 increased in the OA group, 6 decreased. While no specific pathways were enriched, these genes included several genes known to influence OA pathways including ADAM12 (metalloprotease-disintegrin 12) and BMPR1A (bone morphogenetic protein receptor type 1A). In addition, 3 miRNAs were different: 2 increased, 1 decreased. One of these increased miRNAs was mir30a which has a known role in promotion of extracellular matrix degradation. CONCLUSIONS: These data suggest that the profile of extracellular RNA molecules are dysregulated arthroscopically diagnosed OA. While the specific intercellular signaling role of these exRNA are yet to be elucidated, they offer intriguing biomarkers and suggestions of dysregulated molecular pathways in OA. Changes in the genes ADAM12, BMPR1A, and mir30a suggest that exRNA markers of extracellular matrix degradation are biomarkers for the initiation and/or progression of OA. These findings have the potential clinical utility to differentiate patients at risk for the development of OA, introducing the possibility for intervention at pre-symptomatic stages.