Activation of the P38/CREB/MMP13 axis is associated with osteoarthritis

Abstract

Purposes

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

Acknowledgments

This research was supported by the Zhejiang Provincial Natural Science Foundation of China (grant number LQ18H250001) and Medical and Health Science and Technology Planning Project of Zhejiang Province (2018ky493). We thank GuoXiang Fu and Tao Zhu MD (Pathology Department, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China) for their technical support with the histology and immunohistochemistry.

Disclosure

The authors report no conflicts of interest in this work.