Drug Design, Development and Therapy (Jul 2019)
Activation of the P38/CREB/MMP13 axis is associated with osteoarthritis
Abstract
Bin Ji,*,1,2 Yan Ma,*,1 Haimin Wang,*,1,3 Xiangqian Fang,1 Peihua Shi11Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang Province 310016, People’s Republic of China; 2Department of Orthopaedic Surgery, First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang Province 314000, People’s Republic of China; 3Orthopedics Department, Taizhou Bo Ai Hospital, Taizhou, Zhejiang Province 318050, People’s Republic of China*These authors contributed equally to this workPurposes: Osteoarthritis (OA) is a common joint disease characterized by the degradation of articular cartilage and joint inflammation. Interleukin-1ß induces P38/cAMP response element binding protein (CREB) pathway activation, resulting in increased expression of matrix metallopeptidase-13 (MMP13) in chondrocytes. However, the role of the P38/CREB/MMP13 axis is unclear in the progression of OA. In this study, we aimed to answer the following questions: (1) how does the P38/CREB/MMP13 axis in cartilage from patients with OA compare with control specimens? (2) Can the P38 agonist anisomycin (ANS) induce mouse OA?Materials and methods: Surgical specimens of human cartilage were divided into OA and control groups. Surgical specimens of mouse cartilage were divided into control and ANS-induced groups. Safranin O staining of the cartilage tissues was performed to evaluate the extracellular matrix. Reverse transcription-polymerase chain reaction was performed using these tissues to investigate messenger RNA expressions of type II collagen, aggrecan, MMP13, and ADAM metallopeptidase with thrombospondin type 1 motif 5. Phosphorylated (p)-P38, p-CREB, and MMP13 were evaluated by Western blot analysis. Anisomycin was used to activate P38, and p-P38, p-CREB, and MMP13 were evaluated by immunofluorescence and Western blot analysis.Results: Safranin O staining showed that the extracellular matrix degraded in humans with OA and ANS-induced mouse cartilage samples. The expressions of p-P38, p-CREB, and MMP13 were all upregulated in osteoarthritic cartilage or anisomycin-induced chondrocytes, suggesting that the P38/CREB/MMP13 axis may play a role in the progression of OA.Conclusions: The P38/CREB/MMP13 axis is active in osteoarthritic chondrocytes and may cause the degeneration of cartilage. Effective new therapy directed against this pathway could be developed.Keywords: degenerative joint disease, CREB, anisomycin, mice
