RESUMEN
Osteonecrosis of femoral head (ONFH) is one of the complications of systemic lupus erythematosus (SLE), which is characterized by complex pathogenesis and difficult treatment, and is the main cause of SLE-induced disability. Previous studies have confirmed that the JAK/STAT signaling pathway is involved in the pathological process of SLE, and the activation of JAK/STAT has also been found to be related to the occurrence of ONFH. Therefore, we speculated that the JAK/STAT signaling pathway may play an important role in the occurrence and development of SLE-ONFH. 30 female MRL/lpr mice were randomly divided into three groups: the model group (Lipopolysaccharide/24 hours, twice + Methylprednisolone/24 hours, 3 times), the control group (equal amount of PBS) and the treatment group (the model group + JAK1/2 inhibitors Baricitinib/day, 6 weeks), with 10 mice in each group. The results showed that the grip value of the model group was significantly lower than that of the control group at the 4th and 6th week (P < 0. 05), and that of the treatment group was better than that of the model group at the 6th week (P < 0. 05). At the 6th week, the mice were sacrificed to take the bilateral femoral head, and the morphology and HE staining pathological changes of the femoral head were observed. The results showed that the femoral head of the control group was spherical, transparent, hard and without cartilage defects, while that of the model group was irregular, rough, gray in color and partial defects of the femoral head. The performance of the mice in the treatment group was basically similar to that in the model group. And the overall appearance of the femoral head was more irregular than that in the control group. The color was darker than that in the control group, and there was a partial defect of the femoral head, but the degree was not as serious as that in the model group. The empty bone lacuna rate in the model group and treatment group were significantly higher than that in the control group (P < 0. 05), and the empty bone lacuna rate in the treatment group was lower than that in the model group (P < 0. 05). Western blotting, ELISA and RT-qPCR were used to detect the protein expression, phosphorylation levels, mRNA expression of the JAK/STAT pathway (JAK1, JAK2, JAK3, STAT3) in local bone tissues, and the expression of IL-6 and TNF- α in serum and local tissues. The mRNA expression of IL-6, TNF-α and STAT3 in bone tissues of the model group were significantly higher than that of the control group and treatment group, and the content of serum IL-6 and TNF- α of the model group were significantly higher than that of the treatment group and control group. The cartilage catabolic metabolites ADAMTS-4, MMP-13 and JAK/STAT pathway related proteins JAK1, p-JAK1, JAK2, p-JAK2, STAT3 and pSTAT3 in the model group were significantly higher than those in the control group and treatment group. In summary, the JAK/STAT signaling pathway is involved in the pathogenesis of ONFH in MRL/lpr lupus erythematosus mice. Selective JAK1/2 inhibitors can effectively inhibit ONFH inflammation, improve bone structures and joint functions, and may become an effective therapeutic drug for SLE ONFH.
RESUMEN
Objective To explore the dynamic change and meaning of JAK/STAT signal path in the invasive course of collagen-induced arthritis(CIA).Methods Forty-eight rats were divided into 6 groups ran- domly,eight rats served as the control group,the rest were for the development of CIA models.Rats were sac- rificed at the 2nd,3rd,4th,5th and 6th week after the initial immunity respectively.Then HE staining,im- munohistochemistry and immunoblotting were used to detect the pathological changes of synovium in different st ages and the expression of p-STAT1 and p-STAT3.Results On the second week after initial immunity,the rats had arthritis,and the inflammation achieved its peak at the 4th week,then gradually relieved,and a few joints developed rigidity,synovium hyperplasia and inflammatory cell infiltration could be seen at the second week of initial immunity,and pannus could be seen at the 4th week as well as cartilage destroy at the 6th week by HE staining.In the invasive course of CIA,STAT1 and STAT3 were all in activated state detected by im- munohistochemistry and immunoblotting,which were significantly different from those of control group and they had a positive correlation with arthritis index,the Pearson's value of them were 0.798 and 0.873 respectively. However,there was some difference on time.STAT3 kept at activated state and had positive correlation with pathology score of synovium,and the Pearson's value was 0.622.On the contrary,the activation of STAT1 was obviously delayed and only confined to the middle and advanced stage of the disease.Conclusion JAK/STAT signal pathway participates the pathological course of CIA,and blocking the different point of JAK/STAT path- way'activation process may reach the goal of reversing the RA's pathological course.