The Role of the JAK/STAT Signaling Pathway in Steroid-induced Necrosis of Femoral Heads in MRL/lpr Iupus Mice / 中国生物化学与分子生物学报

ABSTRACT

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.