DUSP1 PROTECTS OSTEOARTHRITIS BY INHIBITING P38MAPK AND JNK SIGNALING PATHWAYS

Chuancheng Zhang^{1, #}, Fang Yu^{2, #}, Jing Diao^{3, *}, Jun Ren^{4, *}

¹Wuhan University of Science and Technology, Wuhan 430065, Hubei Province, China - ²Department of Traditional Chinses Medicine (Geriatrics), The Third People’s Hospital of Hubei Province (Zhongshan Hospital of Hubei Province), Wuhan 430030, Hubei Province, China - ³Department of The First Ward of Neurolgy, The Third People’s Hospital of Hubei Province (Zhongshan Hospital of Hubei Province), Wuhan 430030, Hubei Province, China - ⁴Department of Emergency Medicine, The Third People’s Hospital of Hubei Province (Zhongshan Hospital of Hubei Province), Wuhan 430030, Hubei Province, China

Objective: To investigate the protective mechanism of dual-specificity phosphatase 1 (DUSP1) on osteoarthritis by inhibiting p38 mitogen-activated protein kinase (p38MAPK) and c-jun amino-terminal kinase (JNK) signaling pathways. 

Methods: Forty-five SD rats were randomly divided into three groups: blank control group, osteoarthritis model group, and DUSP1 overexpression group, with 15 rats in each group. A rat knee osteoarthritis model was established by performing medial meniscectomy on the rat knee joint. One week after the operation, the DUSP1 overexpression model was established by injecting the DUSP5 gene overexpressing lentivirus into the rat joint cavity. Rats were sacrificed 5 weeks after modeling, and HE staining was used to observe the morphological changes of knee cartilage under light microscope; enzyme-linked immunosorbent assay (ELISA) was used to detect interleukin-6 (IL-6), leukocyte The levels of interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α); Western blot was used to detect the protein levels of DUSP1, p38MAPK and JNK in cartilage tissue; qRT-PCR was used to detect the mRNA of p38MAPK, JNK and DUSP1 in cartilage tissue relative expression. 

Results: The knee joint cartilage Mankin's score and knee joint diameter of the osteoarthritis model group were significantly higher than those of the blank control group (P<0.05); the knee joint cartilage Mankin's score and knee joint diameter of the DUSP1 overexpression group were significantly lower than those of the bone The arthritis model group was higher than the blank control group (P<0.05). The relative expressions of p38MAPK, JNK and DUSP1 mRNA and the protein expressions of DUSP1, p38MAPK and JNK in the knee cartilage tissue of the osteoarthritis model group were significantly higher than those of the blank control group (P<0.05); the knee joint of the rats in the DUSP1 overexpression group The relative expression of DUSP1 mRNA and DUSP1 protein in cartilage tissue were significantly higher than those in the osteoarthritis model group and the blank control (P<0.05). The protein expression levels of p38MAPK and JNK were significantly lower than those in the osteoarthritis model group, but higher than those in the blank control group (P<0.05). The expression level of DUSP1 protein was negatively correlated with the protein expression levels of p38MAPK and JNK (P<0.05), and the relative expression of DUSP1 mRNA was negatively correlated with the relative expression levels of p38MAPK and JNK mRNA (P<0.05). The levels of IL-6, TNF-α and IL-1β in the knee joint fluid of the rats in the osteoarthritis model group were significantly higher than those in the blank control group (P<0.05). The levels of α and IL-1β were significantly lower than those in the osteoarthritis model group, but higher than those in the blank control group (P<0.05). 

Conclusion: DUSP1 can improve the level of inflammatory factors in the joint by inhibiting the p38MAPK and JNK signaling pathways, thereby reducing the inflammatory response in the joint and protecting the patients with osteoarthritis.