Cryptotanshinone Protects Cartilage against Developing Osteoarthritis through the miR-106a-5p/GLIS3 Axis

Molecular Therapy: Nucleic Acids

Xiaojie Xu¹  Lei Kang²  Zhongyi Fan³  Qi Song³  Stuart B. Goodman⁴  William J. Maloney⁴  Dengbin Qi⁵  Quanbo Ji⁵  Yan Wang⁵  Yameng Xu⁶ 

[1] Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China;Department of Nuclear Medicine, Peking University First Hospital, Beijing 100034, China;Department of Oncology, General Hospital of Chinese People’s Liberation Army, Beijing 100853, China;Department of Orthopaedic Surgery, Stanford University, Stanford, CA 94305, USA;Department of Orthopaedics, General Hospital of Chinese People’s Liberation Army, Beijing 100853, China;Department of Traditional Chinese Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China;

关键词: osteoarthritis;    cryptotanshinone;    miRNA;    GLIS3;    PAX5;   

DOI  :  10.1016/j.omtn.2018.02.001

来源: DOAJ

【 摘 要 】

Cryptotanshinone (CTS) has emerged as an anti-inflammatory agent in osteoarthritis (OA). However, the molecular mechanism underlying its potent therapeutic effect on OA remains largely unknown. MicroRNAs (miRNAs) act as crucial regulators in maintaining cartilage homeostasis. To investigate whether CTS protects against developing OA through regulation of miRNAs, we examined the potential CTS-mediated miRNA molecules using microarray analysis. We found that CTS significantly promoted miR-106a-5p expression in chondrocytes. Using the OA mouse model created by anterior cruciate ligament transection, we revealed that intra-articular injection of miR-106a-5p agomir attenuated OA. In addition, miR-106a-5p inhibited GLI-similar 3 (GLIS3) production by directly targeting the 3′ untranslated region. CTS promoted miR-106a-5p expression through recruitment of a member of the paired box (PAX) family of transcription factors, PAX5, to the miR-106a-5p promoter. Inhibition of PAX5 mimicked the effect of miR-106a-5p and abolished the CTS ability to regulate miR-106a-5p expression. In OA patients, miR-106-5p is downregulated which is accompanied by downregulation of PAX5 and upregulation of GLIS3. Collectively, these data highlight that the PAX5/miR-106a-5p/GLIS3 axis acts as a novel pleiotropic regulator in CTS-mediated OA cartilage protection, suggesting that miR-106a-5p and PAX5 activation and GLIS3 inhibition might be useful and attractive for therapeutic strategies to treat OA patients.

【 授权许可】

Unknown