Sonic Hedgehog Regulates Proliferation, Migration and Invasion of Synoviocytes in Rheumatoid Arthritis via JNK Signaling

• Published in: Frontiers in immunology Vol. 11; p. 1300
• Main Authors: Zhu, Shangling, Ye, Yuanmei, Shi, Yiming, Dang, Junlong, Feng, Xiaoxue, Chen, Yingdi, Liu, Fang, Olsen, Nancy, Huang, Jianlin, Zheng, Song Guo
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 24.06.2020
• Subjects: Arthritis, Rheumatoid - etiology; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Biomarkers; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cytokines - metabolism; Female; fibroblast-like synoviocyte; Flow Cytometry; Hedgehog Proteins - agonists; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - metabolism; Humans; Immunohistochemistry; Immunology; invasion; JNK Mitogen-Activated Protein Kinases - metabolism; Male; MAP Kinase Signaling System - drug effects; Matrix Metalloproteinase 1 - metabolism; Middle Aged; migration; proliferation; rheumatoid arthritis; sonic hedgehog; Synoviocytes - metabolism; Veratrum Alkaloids - pharmacology; c-Jun N-terminal kinase; invasion; proliferation; fibroblast-like synoviocyte; migration; sonic hedgehog; rheumatoid arthritis
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.01300

Activated fibroblast-like synoviocytes (FLSs) play a central role in the formation of synovial pannus and joint destruction in rheumatoid arthritis (RA). Targeting FLSs could be a potential therapeutic strategy. The objective of this study is to explore the role of c-Jun N-terminal kinase (JNK) in proliferation, migration and invasion of FLSs promoted by the sonic hedeghog (SHH) signaling pathway in patients with RA. Activation of SHH signaling was evaluated by real-time PCR and Western Blot. Levels of phosphorylation of JNK and c-Jun were detected by Western Blot. FLSs proliferation was quantified by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Cell migration and invasion were assessed by wound healing assay and Transwell chamber assay. Invasiveness of FLSs was evaluated using a humanized synovitis animal model. We observed that treatment of SHH agonist (SAG) significantly increased the levels of phosphorylation of JNK and c-Jun, while SHH antagonist (cyclopamine) significantly decreased the expression of phospho-JNK and phospho-c-Jun in FLSs. The elevated level of phospho-c-Jun stimulated by SAG was decreased in the presence of JNK inhibitor (SP600125) ( < 0.001). FLSs proliferation, migration and invasion were promoted by SHH agonist ( < 0.05). However, the enhanced aggressiveness of FLSs was abolished in the presence of JNK inhibitor ( < 0.05). study showed that the invasion of FLSs into cartilage was increased by SHH overexpression and the excessive invasiveness was inhibited by blockade of JNK signaling ( < 0.01). These results suggest that JNK is one of the downstream molecules mediating the effect of SHH signaling in FLSs. These findings indicate that SHH-JNK signaling could be a potential therapeutic target to suppress the aggressiveness of FLSs and prevent articular damage of RA.