MicroRNA Biomarkers in Joint Tissues

The critical role of miRNA regulation during skeletal development has been highlighted by a study with mice where chondrocytes from these mice displayed reduced proliferation and accelerated differentiation into cell hypertrophy [9].

MiR-140 is the most studied miRNA involved in OA. It was first reported as cartilage-specific miRNA in mouse. Microarray profiling by Miyaki et al. discovered that miR-140 was upregulated during chondrogenesis but downregulated in OA chondrocytes compared to normal [4].

A further study demonstrated that IL-1βtreatment of normal chondrocytes suppressed miR-140 expression, while overexpression of miR-140 downregulated

IL-1β-induced ADAMTS5 expression and rescued the IL-1β-dependent repression of AGGRECAN gene expression. An additional study in vivo in mice by the same group showed that MiR-140-null mice developed age-related OA-like phenotypes, including proteoglycan loss and articular cartilage fibrillation. The crucial role of miR-140 in OA cartilage protection was further demonstrated by resistance to antigen-induced arthritis through miR-140 overexpression. Meanwhile, another group identified matrix metalloproteinases-13 (MMP-13) and insulin-like growth factor-binding protein 5 as two more targets for miR-140 [19].

Similar as miR-140, miR-27b has been shown to be downregulated in IL-1β- stimulated OA chondrocytes. MiR-27b directly targeted MMP-13, indicating that

decreased miR-27b might be responsible for the overexpression of MMP-13 in response to IL-1β. Yamasaki et al. reported expression of miR-146a in early-stage OA cartilage compared to normal. Interestingly, miR-146a levels were decreased in later stage OA when Mankin scores were increased. MiR-146a is inducible by IL-1βstimulation in normal human chondrocytes and by mechanical pressure injury. MiRNA-146a has also been linked to pain by modulating inflammatory cytokines such as tumor necrosis factor-alpha, IL-6, IL-8. Therefore, miRNA-146a may serve as target for therapeutic intervention to alleviate OA-related pain [16].

Given the essential regulatory roles of miRNAs in mRNA stability and protein translation, identification of differentially expressed miRNAs in OA joint tissue will deepen our understanding of the mechanism underlying cartilage degradation and OA pathology. Moreover, aberrantly expressed miRNAs involved in the pathogenesis of OA could serve as potential therapeutic targets to treat OA, as well as diagnostic biomarkers.