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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

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 patie...

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Autores principales: Wong, Vincent Kam Wai, Qiu, Congling, Xu, Su‐Wei, 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637043/
https://www.ncbi.nlm.nih.gov/pubmed/31124139
http://dx.doi.org/10.1111/bph.14718
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author Wong, Vincent Kam Wai
Qiu, Congling
Xu, Su‐Wei
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
author_facet Wong, Vincent Kam Wai
Qiu, Congling
Xu, Su‐Wei
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
author_sort Wong, Vincent Kam Wai
collection PubMed
description 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.
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spelling pubmed-66370432019-07-29 Ca(2+) signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats Wong, Vincent Kam Wai Qiu, Congling Xu, Su‐Wei 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 Br J Pharmacol Research Papers 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. John Wiley and Sons Inc. 2019-07-04 2019-08 /pmc/articles/PMC6637043/ /pubmed/31124139 http://dx.doi.org/10.1111/bph.14718 Text en © 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research Papers
Wong, Vincent Kam Wai
Qiu, Congling
Xu, Su‐Wei
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
Ca(2+) signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
title Ca(2+) signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
title_full Ca(2+) signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
title_fullStr Ca(2+) signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
title_full_unstemmed Ca(2+) signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
title_short Ca(2+) signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
title_sort ca(2+) signalling plays a role in celastrol‐mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637043/
https://www.ncbi.nlm.nih.gov/pubmed/31124139
http://dx.doi.org/10.1111/bph.14718
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