Periodic Mechanical Stress Inhibits the Development of Osteoarthritis via Regulating ATF3-Akt Axis

Yi Lou; Fanglong Song; Yifan Kang; Yaozeng Xu

doi:10.2147/JIR.S419186

Periodic Mechanical Stress Inhibits the Development of Osteoarthritis via Regulating ATF3-Akt Axis

J Inflamm Res. 2023 Nov 28:16:5613-5628. doi: 10.2147/JIR.S419186. eCollection 2023.

Authors

Yi Lou^#^{1

2}, Fanglong Song^#³, Yifan Kang², Yaozeng Xu¹

Affiliations

¹ Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.
² Department of Orthopaedics, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Military Medical University, Shanghai, 201805, People's Republic of China.
³ Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: The development of osteoarthritis (OA) has been linked to mechanical factors. Studies suggest that periodic mechanical stress (PMS) may be a factor contributing to cartilage repair and the onset of OA. Therefore, this study was designed to explore the effects and underlying mechanisms of PMS on OA development.

Patients and methods: Firstly, surgery and interleukin (IL)-1β were used for the establishment of rat/cell models of OA, respectively. Subsequently, activating transcription factor (ATF) 3 expression was knocked down in OA rats, and OA chondrocytes were treated with different heights (0, 1, 2, 4, 8 cm) of PMS or si-ATF. Safranin O staining was used to observe the histological changes in the rat knee joint, and enzyme-linked immunosorbent assay (ELISA) was performed to detect levels of tumor necrosis factor (TNF)-α, IL-6, and IL-8 in vivo and in vitro. Further, the expression of extracellular matrix (ECM) proteins in the rat knee joint was assessed immunohistochemistry. Flow cytometry was used to evaluate chondrocyte apoptosis. Lastly, Western blot was performed to detect the expression of related proteins of the protein kinase B (Akt) signaling pathway and ECM.

Results: The OA rat model was successfully constructed. Further experiments indicated that the knockdown of ATF3 not only alleviated joint swelling, pain, inflammatory response and pathological damage, but also promoted ECM synthesis and the phosphorylation of Akt in OA rats. In vitro experiments showed that PMS (4 cm) effectively inhibited cell apoptosis, decreased the levels of TNF-α, IL-6 and IL-8, promoted ECM synthesis, and activated the Akt signaling pathway in osteoarthritic chondrocytes. However, ATF3 overexpression reversed the positive effects of PMS on osteoarthritic chondrocytes.

Conclusion: PMS can effectively inhibit the development of OA, and its protective effects may be attributed to the down-regulation of ATF3 expression and activation of the Akt signaling pathway.

Keywords: ATF3-Akt axis; apoptosis; joint damage; osteoarthritis; pain; periodic mechanical stress.

Grants and funding

This study was supported by the National Natural Science Foundation of China (No. 81902241).