Investigating the Impact of Circulating MicroRNAs on Knee and Hip Osteoarthritis: Causal Links, Biological Mechanisms, and Drug Interactions.

Osteoarthritis (OA), particularly in the knee and hip, poses a significant global health challenge due to limited therapeutic options. To elucidate the molecular mechanisms of OA and identify potential biomarkers and therapeutic targets, we utilized genome-wide association studies (GWAS) and cis-miRNA expression quantitative trait loci (cis-miR-eQTL) datasets to identify miRNAs associated with OA, revealing 16 that were linked to knee OA and 21 to hip OA. Among these, hsa-miR-1303 was significantly upregulated in both knee and hip OA (IVW: = 6.8164×10-36 and 4.7919×10-2 respectively, OR > 1) and identified as a key factor in disease progression. Hsa-miR-1303 potentially regulates 30 genes involved in critical signaling pathways, such as the neurotrophin signaling pathway, and interacts with competing endogenous RNAs (ceRNAs) like circ_0041843 and LINC01338, thereby influencing key regulatory proteins such as SUMO2 and PARP1. Pharmacologically, hsa-miR-1303 targets nine druggable genes, including NRAS, H2AZ1, and RPS3, which have implications for drugs like cantharidin and diindolylmethane, potentially critical for developing novel OA treatments. Conversely, hsa-miR-125a-5p and hsa-miR-125b-5p, which are downregulated in both knee and hip OA, are associated with pathways such as HIF-1 and JAK-STAT, which modulate apoptotic signaling and transcriptional regulation. These miRNAs also interact with ceRNAs such as circ_0000254 and SPACA6P-AS, impacting proteins like STAT3, MCL1, and TRAF6. A drug interaction analysis identified 47 potential treatments, including Resveratrol and Acetaminophen, suggesting new therapeutic possibilities for OA management. This study not only highlights the role of miRNAs like hsa-miR-1303 and hsa-miR-125 in OA but also opens avenues for miRNA-based therapeutic development.