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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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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. |
format | Online Article Text |
id | pubmed-6637043 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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