{"doi":"10.3389/fimmu.2020.01300","title":"Sonic Hedgehog Regulates Proliferation, Migration and Invasion of Synoviocytes in Rheumatoid Arthritis via JNK Signaling","abstract":"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.","journal":"Frontiers in Immunology","year":2020,"id":95942,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":476423,"name":"Yuanmei Ye","orcid":null,"position":1,"is_corresponding":false},{"id":475822,"name":"Yiming Shi","orcid":"0000-0002-1633-7957","position":2,"is_corresponding":false},{"id":352119,"name":"Junlong Dang","orcid":null,"position":3,"is_corresponding":false},{"id":475823,"name":"Xiaoxue Feng","orcid":"0009-0009-7675-3600","position":4,"is_corresponding":false},{"id":475824,"name":"Yingdi Chen","orcid":"0000-0002-4953-9790","position":5,"is_corresponding":false},{"id":281634,"name":"Fang Liu","orcid":"0000-0003-1707-5183","position":6,"is_corresponding":false},{"id":292940,"name":"Nancy J. Olsen","orcid":"0000-0002-6588-3364","position":7,"is_corresponding":false},{"id":475825,"name":"Jianlin Huang","orcid":"0000-0003-3353-2313","position":8,"is_corresponding":false},{"id":232996,"name":"Song Guo Zheng","orcid":"0000-0002-5611-4774","position":9,"is_corresponding":false},{"id":476422,"name":"Shangling Zhu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-18T22:33:57.534608Z","pmid":"32670287","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}