The Pathological Mechanism Of Nox4 Regulation Of Chondrocyte Senescence In Osteoarthritis

Objective:Osteoarthritis(OA)is a highly heterogeneous disease characterized by progressive degeneration of articular cartilage,which is the common reason of pain and disability in patients.With the aggravation of population aging worldwide,its incidence rate is increasing year by year,and it has gradually become an important global health problem.At present,some studies have considered aging as the most important risk factor for the occurrence and development of OA,but the specific pathological mechanism has not been clearly studied.NADPH oxidase 4(Nox4)is believed to play an important role in the process of osteoarthritis,but its exact role in chondrocyte senescence remains unclear.In addition,little is known about the downstream effector signaling pathway activated by Nox4-derived ROS during chondrocyte senescence.By studying the pathological mechanism of Nox4-mediated ROS accumulation promoting chondrocyte senescence in osteoarthritis,we further clarified the important role of chondrocyte senescence in OA,provided new targets for inhibiting chondrocyte senescence,and provided new ideas for the development of targeted anti-OA drugs.Methods:We verified the high expression of Nox4 in chondrocytes in OA through knee pathological specimens of OA patients,knee specimens of OA model of ACLT mouse and in vitro cell models.Nox4 overexpression in chondrocytes was used to detect its effect on chondrocyte senescence,and NAC(ROS inhibitor)and SB203580(P38/MAPK inhibitor)were used to verify Nox4-mediated chondrocyte senescence signaling pathway mechanism.In vivo experiments,we performed ACLT on C57 mice and then administered GKT(Nox4 inhibitor)and SB203580 inhibitor,proving that blocking Nox4 or its downstream P38/MAPK signaling pathway can effectively alleviate the pathological process of OA.Finally,we further confirmed the important role of Nox4 in the pathological process of OA through gene knockout mice(Nox4-/-).Results:High Nox4 expression was found in both human OA pathological specimens and knee joint of OA model mice.In vitro,Nox4 high expression can increase the protein levels of p16,P21 and P53,which are related to chondrocyte senescence,and increase the activity of β-galactosidase and decrease the proliferation ability of chondrocytes.Nac inhibitor and SB203580 inhibitor can effectively alleviate chondrocyte senescence caused by high Nox4 expression.In vivo experiments,the use of drugs to inhibit Nox4 or P38/MAPK can effectively alleviate the pathological progression of OA.In Nox4-/-mice OA model,compared with wild-type mice(WT)OA model,Nox4 articular cartilage phosphorylation level of P38 was significantly down-regulated,senescence related indicators were reduced,and knee cartilage degeneration was effectively protected.Conclusions:In OA,high Nox4 expression in articular cartilage leads to ROS accumulation,which activates P3 8/MAPK signaling pathway and induces degeneration of articular cartilage.Blocking Nox4 and its downstream signaling pathway can effectively alleviate the pathological process of OA,and Nox4 may be an important target for the prevention and treatment of OA.