Ca2+ signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
Identifieur interne : 000977 ( Main/Exploration ); précédent : 000976; suivant : 000978Ca2+ signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
Auteurs : Vincent Kam Wai Wong ; Congling Qiu ; Su-Wei Xu ; Betty Yuen Kwan Law ; Wu Zeng ; Hui Wang ; Francesco Michelangeli ; Ivo Ricardo De Seabra Rodrigues Dias ; Yuan Qing Qu ; Tsz Wai Chan ; Yu Han ; Ni Zhang ; Simon Wing Fai Mok ; Xi Chen ; Lu Yu ; Hudan Pan ; Sami Hamdoun ; Thomas Efferth ; Wen Jing Yu ; Wei Zhang ; Zheng Li ; Yuesheng Xie ; Riqiang Luo ; Quan Jiang ; Liang LiuSource :
- British Journal of Pharmacology [ 0007-1188 ] ; 2019.
Abstract
Celastrol exhibits anti‐arthritic effects in rheumatoid arthritis (RA), but the role of celastrol‐mediated Ca2+ mobilization in treatment of RA remains undefined. Here, we describe a regulatory role for celastrol‐induced Ca2+ signalling in synovial fibroblasts of RA patients and adjuvant‐induced arthritis (AIA) in rats.
We used computational docking, Ca2+ dynamics and functional assays to study the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA). In rheumatoid arthritis synovial fibroblasts (RASFs)/rheumatoid arthritis fibroblast‐like synoviocytes (RAFLS), mechanisms of Ca2+‐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.
Celastrol inhibited SERCA to induce autophagy‐dependent cytotoxicity in RASFs/RAFLS via Ca2+/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 Ca2+ in celastrol‐regulated gene expression.
Celastrol triggered Ca2+ 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 Ca2+ signalling.
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DOI: 10.1111/bph.14718
PubMed: 31124139
PubMed Central: 6637043
Affiliations:
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sortKey="Qiu, Congling" sort="Qiu, Congling" uniqKey="Qiu C" first="Congling" last="Qiu">Congling Qiu</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Xu, Su Ei" sort="Xu, Su Ei" uniqKey="Xu S" first="Su-Wei" last="Xu">Su-Wei Xu</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="bph14718-aff-0006"></nlm:aff></affiliation></author><author><name sortKey="Law, Betty Yuen Kwan" sort="Law, Betty Yuen Kwan" uniqKey="Law B" first="Betty Yuen Kwan" last="Law">Betty Yuen Kwan Law</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Zeng, Wu" sort="Zeng, Wu" uniqKey="Zeng W" first="Wu" last="Zeng">Wu Zeng</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Wang, Hui" sort="Wang, Hui" uniqKey="Wang H" first="Hui" last="Wang">Hui Wang</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Michelangeli, Francesco" sort="Michelangeli, Francesco" uniqKey="Michelangeli F" first="Francesco" last="Michelangeli">Francesco Michelangeli</name><affiliation><nlm:aff id="bph14718-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Dias, Ivo Ricardo De Seabra Rodrigues" sort="Dias, Ivo Ricardo De Seabra Rodrigues" uniqKey="Dias I" first="Ivo Ricardo De Seabra Rodrigues" last="Dias">Ivo Ricardo De Seabra Rodrigues Dias</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Qu, Yuan Qing" sort="Qu, Yuan Qing" uniqKey="Qu Y" first="Yuan Qing" last="Qu">Yuan Qing Qu</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Chan, Tsz Wai" sort="Chan, Tsz Wai" uniqKey="Chan T" first="Tsz Wai" last="Chan">Tsz Wai Chan</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Han, Yu" sort="Han, Yu" uniqKey="Han Y" first="Yu" last="Han">Yu Han</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Ni" sort="Zhang, Ni" uniqKey="Zhang N" first="Ni" last="Zhang">Ni Zhang</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Mok, Simon Wing Fai" sort="Mok, Simon Wing Fai" uniqKey="Mok S" first="Simon Wing Fai" last="Mok">Simon Wing Fai Mok</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Chen, Xi" sort="Chen, Xi" uniqKey="Chen X" first="Xi" last="Chen">Xi Chen</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Yu, Lu" sort="Yu, Lu" uniqKey="Yu L" first="Lu" last="Yu">Lu Yu</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Pan, Hudan" sort="Pan, Hudan" uniqKey="Pan H" first="Hudan" last="Pan">Hudan Pan</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Hamdoun, Sami" sort="Hamdoun, Sami" uniqKey="Hamdoun S" first="Sami" last="Hamdoun">Sami Hamdoun</name><affiliation><nlm:aff id="bph14718-aff-0003"></nlm:aff></affiliation></author><author><name sortKey="Efferth, Thomas" sort="Efferth, Thomas" uniqKey="Efferth T" first="Thomas" last="Efferth">Thomas Efferth</name><affiliation><nlm:aff id="bph14718-aff-0003"></nlm:aff></affiliation></author><author><name sortKey="Yu, Wen Jing" sort="Yu, Wen Jing" uniqKey="Yu W" first="Wen Jing" last="Yu">Wen Jing Yu</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Wei" sort="Zhang, Wei" uniqKey="Zhang W" first="Wei" last="Zhang">Wei Zhang</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Li, Zheng" sort="Li, Zheng" uniqKey="Li Z" first="Zheng" last="Li">Zheng Li</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Xie, Yuesheng" sort="Xie, Yuesheng" uniqKey="Xie Y" first="Yuesheng" last="Xie">Yuesheng Xie</name><affiliation><nlm:aff id="bph14718-aff-0004"></nlm:aff></affiliation></author><author><name sortKey="Luo, Riqiang" sort="Luo, Riqiang" uniqKey="Luo R" first="Riqiang" last="Luo">Riqiang Luo</name><affiliation><nlm:aff id="bph14718-aff-0004"></nlm:aff></affiliation></author><author><name sortKey="Jiang, Quan" sort="Jiang, Quan" uniqKey="Jiang Q" first="Quan" last="Jiang">Quan Jiang</name><affiliation><nlm:aff id="bph14718-aff-0005"></nlm:aff></affiliation></author><author><name sortKey="Liu, Liang" sort="Liu, Liang" uniqKey="Liu L" first="Liang" last="Liu">Liang Liu</name><affiliation><nlm:aff id="bph14718-aff-0001"></nlm:aff></affiliation></author></analytic><series><title level="j">British Journal of Pharmacology</title><idno type="ISSN">0007-1188</idno><idno type="eISSN">1476-5381</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="bph14718-sec-0001"><title>Background and Purpose</title><p>Celastrol exhibits anti‐arthritic effects in rheumatoid arthritis (RA), but the role of celastrol‐mediated Ca<sup>2+</sup> mobilization in treatment of RA remains undefined. Here, we describe a regulatory role for celastrol‐induced Ca<sup>2+</sup> signalling in synovial fibroblasts of RA patients and adjuvant‐induced arthritis (AIA) in rats.</p></sec><sec id="bph14718-sec-0002"><title>Experimental Approach</title><p>We used computational docking, Ca<sup>2+</sup> dynamics and functional assays to study the sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup> ATPase pump (SERCA). In rheumatoid arthritis synovial fibroblasts (RASFs)/rheumatoid arthritis fibroblast‐like synoviocytes (RAFLS), mechanisms of Ca<sup>2+</sup>‐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.</p></sec><sec id="bph14718-sec-0003"><title>Key Results</title><p>Celastrol inhibited SERCA to induce autophagy‐dependent cytotoxicity in RASFs/RAFLS via Ca<sup>2+</sup>/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<sup>2+</sup> in celastrol‐regulated gene expression.</p></sec><sec id="bph14718-sec-0004"><title>Conclusion and Implications</title><p>Celastrol triggered Ca<sup>2+</sup> 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<sup>2+</sup> signalling.</p></sec></div></front><back><div1 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sortKey="Chan, Tsz Wai" sort="Chan, Tsz Wai" uniqKey="Chan T" first="Tsz Wai" last="Chan">Tsz Wai Chan</name><name sortKey="Chen, Xi" sort="Chen, Xi" uniqKey="Chen X" first="Xi" last="Chen">Xi Chen</name><name sortKey="Dias, Ivo Ricardo De Seabra Rodrigues" sort="Dias, Ivo Ricardo De Seabra Rodrigues" uniqKey="Dias I" first="Ivo Ricardo De Seabra Rodrigues" last="Dias">Ivo Ricardo De Seabra Rodrigues Dias</name><name sortKey="Efferth, Thomas" sort="Efferth, Thomas" uniqKey="Efferth T" first="Thomas" last="Efferth">Thomas Efferth</name><name sortKey="Hamdoun, Sami" sort="Hamdoun, Sami" uniqKey="Hamdoun S" first="Sami" last="Hamdoun">Sami Hamdoun</name><name sortKey="Han, Yu" sort="Han, Yu" uniqKey="Han Y" first="Yu" last="Han">Yu Han</name><name sortKey="Jiang, Quan" sort="Jiang, Quan" uniqKey="Jiang Q" first="Quan" last="Jiang">Quan Jiang</name><name sortKey="Law, Betty Yuen Kwan" sort="Law, Betty Yuen Kwan" uniqKey="Law B" first="Betty Yuen Kwan" last="Law">Betty Yuen Kwan Law</name><name sortKey="Li, Zheng" sort="Li, Zheng" uniqKey="Li Z" first="Zheng" last="Li">Zheng Li</name><name sortKey="Liu, Liang" sort="Liu, Liang" uniqKey="Liu L" first="Liang" last="Liu">Liang Liu</name><name sortKey="Luo, Riqiang" sort="Luo, Riqiang" uniqKey="Luo R" first="Riqiang" last="Luo">Riqiang Luo</name><name sortKey="Michelangeli, Francesco" sort="Michelangeli, Francesco" uniqKey="Michelangeli F" first="Francesco" last="Michelangeli">Francesco Michelangeli</name><name sortKey="Mok, Simon Wing Fai" sort="Mok, Simon Wing Fai" uniqKey="Mok S" first="Simon Wing Fai" last="Mok">Simon Wing Fai Mok</name><name sortKey="Pan, Hudan" sort="Pan, Hudan" uniqKey="Pan H" first="Hudan" last="Pan">Hudan Pan</name><name sortKey="Qiu, Congling" sort="Qiu, Congling" uniqKey="Qiu C" first="Congling" last="Qiu">Congling Qiu</name><name sortKey="Qu, Yuan Qing" sort="Qu, Yuan Qing" uniqKey="Qu Y" first="Yuan Qing" last="Qu">Yuan Qing Qu</name><name sortKey="Wang, Hui" sort="Wang, Hui" uniqKey="Wang H" first="Hui" last="Wang">Hui Wang</name><name sortKey="Wong, Vincent Kam Wai" sort="Wong, Vincent Kam Wai" uniqKey="Wong V" first="Vincent Kam Wai" last="Wong">Vincent Kam Wai Wong</name><name sortKey="Xie, Yuesheng" sort="Xie, Yuesheng" uniqKey="Xie Y" first="Yuesheng" last="Xie">Yuesheng Xie</name><name sortKey="Xu, Su Ei" sort="Xu, Su Ei" uniqKey="Xu S" first="Su-Wei" last="Xu">Su-Wei Xu</name><name sortKey="Yu, Lu" sort="Yu, Lu" uniqKey="Yu L" first="Lu" last="Yu">Lu Yu</name><name sortKey="Yu, Wen Jing" sort="Yu, Wen Jing" uniqKey="Yu W" first="Wen Jing" last="Yu">Wen Jing Yu</name><name sortKey="Zeng, Wu" sort="Zeng, Wu" uniqKey="Zeng W" first="Wu" last="Zeng">Wu Zeng</name><name sortKey="Zhang, Ni" sort="Zhang, Ni" uniqKey="Zhang N" first="Ni" last="Zhang">Ni Zhang</name><name sortKey="Zhang, Wei" sort="Zhang, Wei" uniqKey="Zhang W" first="Wei" last="Zhang">Wei Zhang</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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