Osteoarthritis (OA), a disabling joint inflammatory disease, is characterized by the progressive destruction of cartilage, subchondral bone remodeling, and chronic synovitis. Due to the prolongation of the human lifespan, OA has become a serious public health problem that deserves wide attention. The development of OA is related to numerous factors. Among the factors, nitric oxide (NO) plays a key role in mediating this process. NO is a small gaseous molecule that is widely distributed in the human body, and its synthesis is dependent on NO synthase (NOS). NO plays an important role in various physiological processes such as the regulation of blood volume and nerve conduction. Notably, NO acts as a double-edged sword in inflammatory diseases. Recent studies have shown that NO and its redox derivatives might be closely related to both normal and pathophysiological joint conditions. They can play vital roles as normal bone cell-conditioning agents for osteoclasts, osteoblasts, and chondrocytes. Moreover, they can also induce cartilage catabolism and cell apoptosis. Based on different conditions, the NO/NOS system can act as an anti-inflammatory or pro-inflammatory agent for OA. This review summarizes the studies related to the effects of NO on all normal and OA joints as well as the possible new treatment strategies targeting the NO/NOS system.

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.