Cartilage microRNA dysregulation in mouse osteoarthritis overlaps with patient disease candidates

Abstract

The regulatory interplay between the joint cartilage and subchondral bone (SCB) is known be important in osteoarthritis (OA) pathology. Thus, to explore the role of microRNAs in osteoarthritis, we conducted global microRNA microarray expression profiling on microdissected medial tibial cartilage and SCB in a mouse model of OA produced by medial meniscus destabilization (DMM). Compared to sham-operated mice, DMM-operated mice had characteristic cartilage degeneration, SCB sclerosis and osteophyte formation. miRNA expression profiling revealed no statistically significant dysregulation of SCB miRNAs between DMM and sham-operated mice. In contrast, 139 miRNAs were found to be differentially expressed in DMM cartilage at 1 or 6 weeks post-surgery. To prioritize OAcandidates, dysregulated miRNAs were filtered against miRNAs identified in human OA and then using paired miRNA:mRNA expression analysis we identified a cohort of down-regulated microRNAs 26b, 30c, 98, 149, 210, 342, 140, with corresponding changes in predicted target transcripts. Comparisons with microRNA dysregulation in DMM mouse cartilage where aggrecan cleavage was genetically ablated demonstrated that all, except Let-7e, were independent of aggrecan breakdown, earmarking this cohort of microRNAs of relevance to the critical early stages of OA initiation.