Abstract
Osteoarthritis (OA) is a common age-related disease that is correlated with a high number of senescent chondrocytes in joint tissues. Heterogeneous nuclear ribonucleoprotein D (HNRNPD) is an RNA-binding protein whose expression imbalance is associated with cell senescence, but the role of HNRNPD in the occurrence and development of OA has not been reported. In this study, HNRNPD was found to be associated with the chondrocyte senescence process. We determined the factors at the posttranscriptional level that regulated the expression of the genes that induce OA and found that HNRNPD was specifically highly expressed in OA-induced rat cartilage and in human OA cartilage. Recombinant adeno-associated virus (rAAV)-mediated HNRNPD gene overexpression alone did not significantly regulate the occurrence and development of OA in the physiological state of the joint. However, rAAV-HNRNPD significantly exacerbated experimental OA in rats subjected to destabilization of the medial meniscus. Overexpression of HNRNPD promoted mitochondrial dysfunction and the expression of FOXM1, which acts as a direct target. Furthermore, downregulation of FOXM1 in chondrocytes weakened the HNRNPD-mediated promotion of chondrocyte senescence and mitochondrial dysfunction. Our results suggest that the RNA-binding protein HNRNPD promotes chondrocyte senescence in the pathology of OA by upregulating FOXM1.