Isoimperatorin Reduces Synovial Inflammation and Fibrosis in Knee Osteoarthritis via the cAMP Signalling Pathway

To explore the mechanism of pharmacological action of Isoimperatorin (ISO), a small molecule compound with anti-inflammatory properties extracted from the rhizome of Notopterygium incisum, in attenuating synovial inflammation in knee osteoarthritis (KOA). By establishing a rat model of KOA and using histopathology and molecular biology methods, we evaluated the pharmacological effect of ISO on synovitis. Synovial fluid from the knee joint was collected for transcriptomic and metabolomic analyses. Fibroblast-like synoviocytes were cultured in vitro, and calcium fluorescence imaging and mitochondrial membrane potential assays were performed to assess the effects of ISO on the cAMP signalling pathway and KOA-related synovial inflammation. Preliminary pharmacodynamic observations showed that ISO was able to reduce synovial inflammation in KOA rats. Further transcriptomic findings in synovial tissues indicated that the mechanism of action of ISO was related to the cAMP signalling pathway and calcium ion signalling pathway. The results of metabolomics showed that the progression of synovial fibrosis was related to the abnormal metabolism of glycerophospholipids, and the intervention of ISO could significantly promote the metabolism of glycerophospholipids in synovial tissues. Finally, the results of in vitro experiments showed that ISO improved the level of inflammation and the degree of fibrosis in synovial cells, activated the cAMP signalling pathway and promoted PPAR expression, whereas inhibition of the activation of the cAMP signalling pathway attenuated the effects of ISO. ISO promotes PPAR function by upregulating the cAMP signalling pathway to modulate glycerophospholipid metabolism, thereby alleviating synovial inflammation and slowing fibrosis progression in KOA.