Sonic Hedgehog Regulates Proliferation, Migration and Invasion of Synoviocytes in Rheumatoid Arthritis via JNK Signaling
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 p...
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01300/full |
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| author | Shangling Zhu Yuanmei Ye Yiming Shi Junlong Dang Xiaoxue Feng Yingdi Chen Fang Liu Nancy Olsen Jianlin Huang Song Guo Zheng |
| author_facet | Shangling Zhu Yuanmei Ye Yiming Shi Junlong Dang Xiaoxue Feng Yingdi Chen Fang Liu Nancy Olsen Jianlin Huang Song Guo Zheng |
| author_sort | Shangling Zhu |
| collection | DOAJ |
| description | 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 in vivo 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) (P < 0.001). FLSs proliferation, migration and invasion were promoted by SHH agonist (P < 0.05). However, the enhanced aggressiveness of FLSs was abolished in the presence of JNK inhibitor (P < 0.05). In vivo 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 (P < 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. |
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| id | doaj.art-809835a8669d4e659f518b7afa349f54 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T23:19:05Z |
| publishDate | 2020-06-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-809835a8669d4e659f518b7afa349f542022-12-21T19:23:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-06-011110.3389/fimmu.2020.01300518326Sonic Hedgehog Regulates Proliferation, Migration and Invasion of Synoviocytes in Rheumatoid Arthritis via JNK SignalingShangling Zhu0Yuanmei Ye1Yiming Shi2Junlong Dang3Xiaoxue Feng4Yingdi Chen5Fang Liu6Nancy Olsen7Jianlin Huang8Song Guo Zheng9Department of Rheumatology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDepartment of Rheumatology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDepartment of Internal Care Unit, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDepartment of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDepartment of Rheumatology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDepartment of Rheumatology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDepartment of Rheumatology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDepartment of Medicine, Penn State Hershey Medical Center, Hershey, PA, United StatesDepartment of Rheumatology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaDepartment of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, United StatesActivated 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 in vivo 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) (P < 0.001). FLSs proliferation, migration and invasion were promoted by SHH agonist (P < 0.05). However, the enhanced aggressiveness of FLSs was abolished in the presence of JNK inhibitor (P < 0.05). In vivo 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 (P < 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.https://www.frontiersin.org/article/10.3389/fimmu.2020.01300/fullrheumatoid arthritisfibroblast-like synoviocyteproliferationmigrationinvasionsonic hedgehog |
| spellingShingle | Shangling Zhu Yuanmei Ye Yiming Shi Junlong Dang Xiaoxue Feng Yingdi Chen Fang Liu Nancy Olsen Jianlin Huang Song Guo Zheng Sonic Hedgehog Regulates Proliferation, Migration and Invasion of Synoviocytes in Rheumatoid Arthritis via JNK Signaling Frontiers in Immunology rheumatoid arthritis fibroblast-like synoviocyte proliferation migration invasion sonic hedgehog |
| title | Sonic Hedgehog Regulates Proliferation, Migration and Invasion of Synoviocytes in Rheumatoid Arthritis via JNK Signaling |
| title_full | Sonic Hedgehog Regulates Proliferation, Migration and Invasion of Synoviocytes in Rheumatoid Arthritis via JNK Signaling |
| title_fullStr | Sonic Hedgehog Regulates Proliferation, Migration and Invasion of Synoviocytes in Rheumatoid Arthritis via JNK Signaling |
| title_full_unstemmed | Sonic Hedgehog Regulates Proliferation, Migration and Invasion of Synoviocytes in Rheumatoid Arthritis via JNK Signaling |
| title_short | Sonic Hedgehog Regulates Proliferation, Migration and Invasion of Synoviocytes in Rheumatoid Arthritis via JNK Signaling |
| title_sort | sonic hedgehog regulates proliferation migration and invasion of synoviocytes in rheumatoid arthritis via jnk signaling |
| topic | rheumatoid arthritis fibroblast-like synoviocyte proliferation migration invasion sonic hedgehog |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01300/full |
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