The Role Of Insulin-related Factor NUCKS In Chondrocyte Metabolism And Injury Repair And Its Mechanism

OA(Osteoarthritis)is a chronic degenerative disease characterized by articular cartilage injury,bone hyperplasia and narrowing of joint space,which is characterized by pain and limitation of activity,and seriously affects the quality of life.More than 150 million of the patients in our country are involved,which is one of the main causes of disability in the elderly,but the pathological mechanism is still unclear.Chondrocytes are the main components of cartilage tissue,the reduction and dysfunction of chondrocytes is one of primary causes of Osteoarthritis.The study on the mechanism of pathological changes in chondrocyte will be helpful to understand the disease and interference of OA.NUCKS(nuclear ubiquitous casein and cyclin-dependent kinase substrate)can control the energy metabolism and homeostasis of cells through modulation the transcription of insulin receptor,while insulin is an important material for the metabolism of chondrocyte,the regulation of insulin dependent autophagy affects the fate of chondrocyte.Therefore,the aim of this study is to determine whether the defect of the NUCKS gene could change the fate of chondrocytes in OA model mouse by insulin dependent autophagy.In the model of DMM(destabilization of the medial meniscus),by histopathology detection,compared with wild-type mouse the injury degree of articular cartilage in NUCKS gene deficient mouse significantly reduced.Therefore,the defect of NUCKS could protect the chondrocyte in OA.In further study,we extracted and cultured two kinds of chondrocytes from wild-type and NUCKS gene deficient mouse,the apoptosis assay showed that the number of apoptotic chondrocytes in the NUCKS deficient mouse decreased significantly compared with in the wild-type mouse.By detecting the expression of the related signal protein in the insulin dependent autophagy pathway,we found that the level of autophagy in NUCKS deficient mouse was significantly higher than that in wild-type mice,and the expression of IR was significantly decreased.Under the high levels of insulin stimulated the expression of IR is increased,the level of autophagy lower and the apoptosis increase in the chondrocytes from wild-type mouse,on the contrary,in NUCKS gene deficient mouse the expression of IR decrease,maintain a high level of autophagy and apoptosis is decreased.Futher,in vivo the two kinds of mouse were induced insulin resistance by high fat diet,to make their insulin levels increased in the blood,and,all the right hind legs of the experimental mice need to be done by DMM,through the organization of pathology detection showed that compared with NUCKS deficient mouse the articular cartilage injury more serious in wild type mice.So,the NUCKS gene defect can be protective for cartilage by insulin dependent autophagy.In summary,this study found that NUCKS gene defect could protect the chondrocyte,which through inhibiting the expression of IR,cut off the inhibition of high concentration insulin for the autophagy of chondrocytes,thereby enhancing the relative level of autophagy in chondrocytes,protect them from apoptosis.Therefore,NUCKS is an important regulatory molecule in the process of OA which may be an important target for OA therapy and drug discovery.