The Synovium Attenuates Cartilage Degeneration in KOA through Activation of the Smad2/3-Runx1 Cascade and Chondrogenesis-related miRNAs

Xiaoyi Zhao; Fangang Meng; Shu Hu; Zibo Yang; Hao Huang; Rui Pang; Xingzhao Wen; Yan Kang; Zhiqi Zhang

doi:10.1016/j.omtn.2020.10.004

The Synovium Attenuates Cartilage Degeneration in KOA through Activation of the Smad2/3-Runx1 Cascade and Chondrogenesis-related miRNAs

Mol Ther Nucleic Acids. 2020 Oct 10:22:832-845. doi: 10.1016/j.omtn.2020.10.004. eCollection 2020 Dec 4.

Authors

Xiaoyi Zhao¹, Fangang Meng¹, Shu Hu², Zibo Yang¹, Hao Huang³, Rui Pang⁴, Xingzhao Wen¹, Yan Kang¹, Zhiqi Zhang¹

Affiliations

¹ Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, Guangdong 510080, PR China.
² Department of Orthopedics, Academy of Orthopedics-Guangdong Province, Orthopedic Hospital of Guangdong Province, Third Affiliated Hospital of Southern Medical University, Guangzhou, PR China.
³ Department of Laboratory Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China.
⁴ State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, PR China.

Abstract

Knee osteoarthritis (KOA) is a highly prevalent disabling joint disease in aged people. Progressive cartilage degradation is the hallmark of KOA, but its deeper mechanism remains unclear. Substantial evidence indicates the importance of the synovium for joint homeostasis. The present study aimed to determine whether the synovium regulates cartilage metabolism through chondrogenesis-related microRNAs (miRNAs) in the KOA microenvironment. Clinical sample testing and in vitro cell experiments screened out miR-455 and miR-210 as effective miRNAs. The levels of both were significantly reduced in KOA cartilage but increased in KOA synovial fluid compared with controls. We further revealed that transforming growth factor β1 (TGF-β1) can significantly upregulate miR-455 and miR-210 expression in synoviocytes. The upregulated miRNAs can be secreted into the extracellular environment and prevent cartilage degeneration. Through bioinformatics and in vitro experiments, we found that Runx1 can bind to the promoter regions of miR-455 and miR-210 and enhance their transcription in TGF-β1-treated synoviocytes. Collectively, our findings demonstrate a protective effect of the synovium against cartilage degeneration mediated by chondrogenesis-related miRNAs, which suggests that Runx1 is a potential target for KOA therapy.

Keywords: Smad2/3-Runx1 cascade; cartilage degeneration; knee osteoarthritis; microRNA; synovium.