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Ca 2+ signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
Author(s) -
Wong Vincent Kam Wai,
Qiu Congling,
Xu SuWei,
Law Betty Yuen Kwan,
Zeng Wu,
Wang Hui,
Michelangeli Francesco,
Dias Ivo Ricardo De Seabra Rodrigues,
Qu Yuan Qing,
Chan Tsz Wai,
Han Yu,
Zhang Ni,
Mok Simon Wing Fai,
Chen Xi,
Yu Lu,
Pan Hudan,
Hamdoun Sami,
Efferth Thomas,
Yu Wen Jing,
Zhang Wei,
Li Zheng,
Xie Yuesheng,
Luo Riqiang,
Jiang Quan,
Liu Liang
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14718
Subject(s) - celastrol , arthritis , pi3k/akt/mtor pathway , chemistry , autophagy , serca , microbiology and biotechnology , synovial membrane , inflammation , proinflammatory cytokine , cancer research , medicine , signal transduction , immunology , apoptosis , biology , biochemistry , atpase , enzyme
Background and Purpose Celastrol exhibits anti‐arthritic effects in rheumatoid arthritis (RA), but the role of celastrol‐mediated Ca 2+ mobilization in treatment of RA remains undefined. Here, we describe a regulatory role for celastrol‐induced Ca 2+ signalling in synovial fibroblasts of RA patients and adjuvant‐induced arthritis (AIA) in rats. Experimental Approach We used computational docking, Ca 2+ dynamics and functional assays to study the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase pump (SERCA). In rheumatoid arthritis synovial fibroblasts (RASFs)/rheumatoid arthritis fibroblast‐like synoviocytes (RAFLS), mechanisms of Ca 2+ ‐mediated autophagy were analysed by histological, immunohistochemical and flow cytometric techniques. Anti‐arthritic effects of celastrol, autophagy induction, and growth rate of synovial fibroblasts in AIA rats were monitored by microCT and immunofluorescence staining. mRNA from joint tissues of AIA rats was isolated for transcriptional analysis of inflammatory genes, using siRNA methods to study calmodulin, calpains, and calcineurin. Key Results Celastrol inhibited SERCA to induce autophagy‐dependent cytotoxicity in RASFs/RAFLS via Ca 2+ /calmodulin‐dependent kinase kinase‐β–AMP‐activated protein kinase–mTOR pathway and repressed arthritis symptoms in AIA rats. BAPTA/AM hampered the in vitro and in vivo effectiveness of celastrol. Inflammatory‐ and autoimmunity‐associated genes down‐regulated by celastrol in joint tissues of AIA rat were restored by BAPTA/AM. Knockdown of calmodulin, calpains, and calcineurin in RAFLS confirmed the role of Ca 2+ in celastrol‐regulated gene expression. Conclusion and Implications Celastrol triggered Ca 2+ signalling to induce autophagic cell death in RASFs/RAFLS and ameliorated arthritis in AIA rats mediated by calcium‐dependent/‐binding proteins facilitating the exploitation of anti‐arthritic drugs based on manipulation of Ca 2+ signalling.