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A potential new approach for treating systemic sclerosis: Dedifferentiation of SSc fibroblasts and change in the microenvironment by blocking store-operated Ca(2+) entry

Transforming growth factor-β (TGF-β) is an important target for treating systemic sclerosis (SSc). However, our study revealed three levels of TGF-β1 expression in SSc patients, indicating that inhibiting TGF-β is not sufficient to treat SSc. A previous clinical trial also displayed disappointing re...

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Autores principales: Wu, Ching-Ying, Hsu, Wen-Li, Tsai, Ming-Hsien, Chai, Chee-Yin, Yen, Chia-Jung, Chen, Chu-Huang, Lu, Jian-He, Yu, Hsin-Su, Yoshioka, Tohru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417669/
https://www.ncbi.nlm.nih.gov/pubmed/30870448
http://dx.doi.org/10.1371/journal.pone.0213400
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author Wu, Ching-Ying
Hsu, Wen-Li
Tsai, Ming-Hsien
Chai, Chee-Yin
Yen, Chia-Jung
Chen, Chu-Huang
Lu, Jian-He
Yu, Hsin-Su
Yoshioka, Tohru
author_facet Wu, Ching-Ying
Hsu, Wen-Li
Tsai, Ming-Hsien
Chai, Chee-Yin
Yen, Chia-Jung
Chen, Chu-Huang
Lu, Jian-He
Yu, Hsin-Su
Yoshioka, Tohru
author_sort Wu, Ching-Ying
collection PubMed
description Transforming growth factor-β (TGF-β) is an important target for treating systemic sclerosis (SSc). However, our study revealed three levels of TGF-β1 expression in SSc patients, indicating that inhibiting TGF-β is not sufficient to treat SSc. A previous clinical trial also displayed disappointing results. Thus, our study attempted to search for a potential novel approach. Ingenuity Pathway Analysis (IPA) indicated that the SSc pathological pathways were closely associated with store-operated Ca(2+) entry (SOCE)-regulated signals, and SOCE activity was found to be increased in SSc fibroblasts. Further treatment of SSc fibroblasts with SOCE inhibitors, 2APB, and associated calcium channel inhibitors SKF96365, and indomethacin, showed that the SOCE inhibitors selectively decreased fibrosis markers and altered the cell morphology. Consequently, SOCE inhibitors, especially 2APB and indomethacin, caused the dedifferentiation of SSc fibroblasts via cytoskeleton remodeling and altered collagen secretion and restored the cell mobility. We further explained SSc pathogenesis as fibroblast differentiation with SOCE. Treatment with exogenous factors, gelatin-1, FAM20A and human albumin, which were identified from the conditioned medium of SSc fibroblasts, was important for regulating the differentiation of fibroblasts with higher levels of SOCE and α-SMA. Conclusively, to treat SSc, blockage of the increased SOCE activity in SSc induces the dedifferentiation of SSc fibroblasts and simultaneously changes the extracellular matrix (ECM) structure to limit SSc pathogenesis.
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spelling pubmed-64176692019-04-01 A potential new approach for treating systemic sclerosis: Dedifferentiation of SSc fibroblasts and change in the microenvironment by blocking store-operated Ca(2+) entry Wu, Ching-Ying Hsu, Wen-Li Tsai, Ming-Hsien Chai, Chee-Yin Yen, Chia-Jung Chen, Chu-Huang Lu, Jian-He Yu, Hsin-Su Yoshioka, Tohru PLoS One Research Article Transforming growth factor-β (TGF-β) is an important target for treating systemic sclerosis (SSc). However, our study revealed three levels of TGF-β1 expression in SSc patients, indicating that inhibiting TGF-β is not sufficient to treat SSc. A previous clinical trial also displayed disappointing results. Thus, our study attempted to search for a potential novel approach. Ingenuity Pathway Analysis (IPA) indicated that the SSc pathological pathways were closely associated with store-operated Ca(2+) entry (SOCE)-regulated signals, and SOCE activity was found to be increased in SSc fibroblasts. Further treatment of SSc fibroblasts with SOCE inhibitors, 2APB, and associated calcium channel inhibitors SKF96365, and indomethacin, showed that the SOCE inhibitors selectively decreased fibrosis markers and altered the cell morphology. Consequently, SOCE inhibitors, especially 2APB and indomethacin, caused the dedifferentiation of SSc fibroblasts via cytoskeleton remodeling and altered collagen secretion and restored the cell mobility. We further explained SSc pathogenesis as fibroblast differentiation with SOCE. Treatment with exogenous factors, gelatin-1, FAM20A and human albumin, which were identified from the conditioned medium of SSc fibroblasts, was important for regulating the differentiation of fibroblasts with higher levels of SOCE and α-SMA. Conclusively, to treat SSc, blockage of the increased SOCE activity in SSc induces the dedifferentiation of SSc fibroblasts and simultaneously changes the extracellular matrix (ECM) structure to limit SSc pathogenesis. Public Library of Science 2019-03-14 /pmc/articles/PMC6417669/ /pubmed/30870448 http://dx.doi.org/10.1371/journal.pone.0213400 Text en © 2019 Wu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wu, Ching-Ying
Hsu, Wen-Li
Tsai, Ming-Hsien
Chai, Chee-Yin
Yen, Chia-Jung
Chen, Chu-Huang
Lu, Jian-He
Yu, Hsin-Su
Yoshioka, Tohru
A potential new approach for treating systemic sclerosis: Dedifferentiation of SSc fibroblasts and change in the microenvironment by blocking store-operated Ca(2+) entry
title A potential new approach for treating systemic sclerosis: Dedifferentiation of SSc fibroblasts and change in the microenvironment by blocking store-operated Ca(2+) entry
title_full A potential new approach for treating systemic sclerosis: Dedifferentiation of SSc fibroblasts and change in the microenvironment by blocking store-operated Ca(2+) entry
title_fullStr A potential new approach for treating systemic sclerosis: Dedifferentiation of SSc fibroblasts and change in the microenvironment by blocking store-operated Ca(2+) entry
title_full_unstemmed A potential new approach for treating systemic sclerosis: Dedifferentiation of SSc fibroblasts and change in the microenvironment by blocking store-operated Ca(2+) entry
title_short A potential new approach for treating systemic sclerosis: Dedifferentiation of SSc fibroblasts and change in the microenvironment by blocking store-operated Ca(2+) entry
title_sort potential new approach for treating systemic sclerosis: dedifferentiation of ssc fibroblasts and change in the microenvironment by blocking store-operated ca(2+) entry
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417669/
https://www.ncbi.nlm.nih.gov/pubmed/30870448
http://dx.doi.org/10.1371/journal.pone.0213400
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