Cartilage MicroRNA Dysregulation During the Onset and Progression of Mouse Osteoarthritis Is Independent of Aggrecanolysis and Overlaps With Candidates From End-Stage Human Disease

Objective To identify candidate microRNAs (miRNAs) that potentially regulate the initiation and progression of osteoarthritis (OA). Methods OA was induced in 10–12‐week‐old male wild‐type C57BL/6 mice and in mice resistant to aggrecanase cleavage ( Acan p.374ALGS→374NVYS) by destabilization of the medial meniscus (DMM). Pathologic changes of OA were scored histologically. RNA from cartilage and subchondral bone was harvested in parallel by laser microdissection at 1 week and 6 weeks postsurgery. Global miRNA expression profiling was performed using Agilent microarrays and was validated by quantitative polymerase chain reaction analysis. Results Wild‐type DMM mice had characteristic cartilage degeneration, subchondral bone sclerosis, and osteophyte formation. While no miRNA dysregulation was seen in subchondral bone, 139 miRNAs were differentially expressed in cartilage obtained at 1 and/or 6 weeks after OA initiation from wild‐type mice that underwent DMM. To prioritize OA candidates, dysregulated miRNAs with human orthologs were filtered, and paired miRNA/messenger RNA (mRNA) expression analysis was conducted to identify those with corresponding changes in mRNA target transcripts in the DMM mouse cartilage. An important cohort also overlapped with miRNAs identified in human end‐stage OA. Comparisons of miRNA dysregulation in DMM mouse cartilage where aggrecan cleavage was genetically ablated demonstrated that all candidates were independent of aggrecan breakdown, earmarking these as important to the critical stages of OA initiation. Furthermore, functional enrichment analysis and data annotation revealed the responses to mechanical stimuli, apoptotic processes, and core extracellular matrix structural and regulatory factors to be potentially influenced by OA‐dysregulated miRNA/mRNA networks. Conclusion Our comprehensive analyses identified high‐priority miRNA candidates that have potential as biomarkers and therapeutic targets in human OA.