Ca2+ signalling plays a role in celastrol-mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats

Publication type:
Journal article
Metadata:
Autoren
  • 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 Liu
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000475816900007&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1111/bph.14718
eISSN
1476-5381
Externe Identifier
  • Clarivate Analytics Document Solution ID: IJ3PN
  • PubMed Identifier: 31124139
ISSN
0007-1188
Ausgabe der Veröffentlichung
16
Zeitschrift
BRITISH JOURNAL OF PHARMACOLOGY
Paginierung
2922 - 2944
Datum der Veröffentlichung
2019
Status
Published
Titel
Ca<SUP>2+</SUP> signalling plays a role in celastrol-mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
Sub types
  • Article
Ausgabe der Zeitschrift
176

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:sec><jats:title>Background and Purpose</jats:title><jats:p>Celastrol exhibits anti‐arthritic effects in rheumatoid arthritis (RA), but the role of celastrol‐mediated Ca<jats:sup>2+</jats:sup> mobilization in treatment of RA remains undefined. Here, we describe a regulatory role for celastrol‐induced Ca<jats:sup>2+</jats:sup> signalling in synovial fibroblasts of RA patients and adjuvant‐induced arthritis (AIA) in rats.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>We used computational docking, Ca<jats:sup>2+</jats:sup> dynamics and functional assays to study the sarcoplasmic/endoplasmic reticulum Ca<jats:sup>2+</jats:sup> ATPase pump (SERCA). In rheumatoid arthritis synovial fibroblasts (RASFs)/rheumatoid arthritis fibroblast‐like synoviocytes (RAFLS), mechanisms of Ca<jats:sup>2+</jats: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.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>Celastrol inhibited SERCA to induce autophagy‐dependent cytotoxicity in RASFs/RAFLS via Ca<jats:sup>2+</jats: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<jats:sup>2+</jats:sup> in celastrol‐regulated gene expression.</jats:p></jats:sec><jats:sec><jats:title>Conclusion and Implications</jats:title><jats:p>Celastrol triggered Ca<jats:sup>2+</jats: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<jats:sup>2+</jats:sup> signalling.</jats:p></jats:sec>
Autoren
  • 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 Liu
DOI
10.1111/bph.14718
eISSN
1476-5381
ISSN
0007-1188
Ausgabe der Veröffentlichung
16
Zeitschrift
British Journal of Pharmacology
Sprache
en
Online publication date
2019
Paginierung
2922 - 2944
Datum der Veröffentlichung
2019
Status
Published
Herausgeber
Wiley
Herausgeber URL
http://dx.doi.org/10.1111/bph.14718
Datum der Datenerfassung
2023
Titel
Ca<sup>2+</sup> signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
Ausgabe der Zeitschrift
176

Data source: Crossref

Abstract
<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>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.<h4>Key results</h4>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.<h4>Conclusion and implications</h4>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.
Addresses
  • State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
Autoren
  • 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 Liu
DOI
10.1111/bph.14718
eISSN
1476-5381
Externe Identifier
  • PubMed Identifier: 31124139
  • PubMed Central ID: PMC6637043
Funding acknowledgements
  • Fundo para o Desenvolvimento das Ciências e da Tecnologia: 084/2013/A3
  • Fundo para o Desenvolvimento das Ciências e da Tecnologia: 0022/2018/A1
Open access
true
ISSN
0007-1188
Ausgabe der Veröffentlichung
16
Zeitschrift
British journal of pharmacology
Schlüsselwörter
  • Synovial Membrane
  • Cells, Cultured
  • Fibroblasts
  • Animals
  • Mice, Knockout
  • Humans
  • Rats, Sprague-Dawley
  • Arthritis, Experimental
  • Arthritis, Rheumatoid
  • Triterpenes
  • Calcium Signaling
  • Gene Expression Regulation
  • Autophagy
  • Male
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Pentacyclic Triterpenes
Sprache
eng
Medium
Print-Electronic
Online publication date
2019
Open access status
Open Access
Paginierung
2922 - 2944
Datum der Veröffentlichung
2019
Status
Published
Publisher licence
CC BY-NC
Datum der Datenerfassung
2019
Titel
Ca<sup>2+</sup> signalling plays a role in celastrol-mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
176

Files

https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bph.14718 https://europepmc.org/articles/PMC6637043?pdf=render

Data source: Europe PubMed Central

Abstract
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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.
Date of acceptance
2019
Autoren
  • 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 Liu
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/31124139
DOI
10.1111/bph.14718
eISSN
1476-5381
Externe Identifier
  • PubMed Central ID: PMC6637043
Ausgabe der Veröffentlichung
16
Zeitschrift
Br J Pharmacol
Schlüsselwörter
  • Animals
  • Arthritis, Experimental
  • Arthritis, Rheumatoid
  • Autophagy
  • Calcium Signaling
  • Cells, Cultured
  • Fibroblasts
  • Gene Expression Regulation
  • Humans
  • Male
  • Mice, Knockout
  • Pentacyclic Triterpenes
  • Rats, Sprague-Dawley
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Synovial Membrane
  • Triterpenes
Sprache
eng
Country
England
Paginierung
2922 - 2944
Datum der Veröffentlichung
2019
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2020
Titel
Ca2+ signalling plays a role in celastrol-mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
176

Data source: PubMed

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