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Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs

The Wnt/β-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of β-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the...

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Autores principales: Zhang, Mingjun, Haughey, Michael, Wang, Nai-Yu, Blease, Kate, Kapoun, Ann M., Couto, Suzana, Belka, Igor, Hoey, Timothy, Groza, Matthew, Hartke, James, Bennett, Brydon, Cain, Jennifer, Gurney, Austin, Benish, Brent, Castiglioni, Paola, Drew, Clifton, Lachowicz, Jean, Carayannopoulos, Leon, Nathan, Steven D., Distler, Jorg, Brenner, David A., Hariharan, Kandasamy, Cho, Ho, Xie, Weilin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065809/
https://www.ncbi.nlm.nih.gov/pubmed/32160239
http://dx.doi.org/10.1371/journal.pone.0229445
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author Zhang, Mingjun
Haughey, Michael
Wang, Nai-Yu
Blease, Kate
Kapoun, Ann M.
Couto, Suzana
Belka, Igor
Hoey, Timothy
Groza, Matthew
Hartke, James
Bennett, Brydon
Cain, Jennifer
Gurney, Austin
Benish, Brent
Castiglioni, Paola
Drew, Clifton
Lachowicz, Jean
Carayannopoulos, Leon
Nathan, Steven D.
Distler, Jorg
Brenner, David A.
Hariharan, Kandasamy
Cho, Ho
Xie, Weilin
author_facet Zhang, Mingjun
Haughey, Michael
Wang, Nai-Yu
Blease, Kate
Kapoun, Ann M.
Couto, Suzana
Belka, Igor
Hoey, Timothy
Groza, Matthew
Hartke, James
Bennett, Brydon
Cain, Jennifer
Gurney, Austin
Benish, Brent
Castiglioni, Paola
Drew, Clifton
Lachowicz, Jean
Carayannopoulos, Leon
Nathan, Steven D.
Distler, Jorg
Brenner, David A.
Hariharan, Kandasamy
Cho, Ho
Xie, Weilin
author_sort Zhang, Mingjun
collection PubMed
description The Wnt/β-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of β-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the Wnt/β-catenin signaling, has not been described. A specific interventional strategy targeting this pathway for fibrosis remains to be defined. We developed monoclonal antibodies against members of the RSPO family (RSPO1, 2, and 3) and probed their potential function in fibrosis in vivo. We demonstrated that RSPO3 plays a critical role in the development of fibrosis in multiple organs. Specifically, an anti-RSPO3 antibody, OMP-131R10, when dosed therapeutically, attenuated fibrosis in carbon tetrachloride (CCl(4))-induced liver fibrosis, bleomycin-induced pulmonary and skin fibrosis models. Mechanistically, we showed that RSPO3 induces multiple pro-fibrotic chemokines and cytokines in Kupffer cells and hepatocytes. We found that the anti-fibrotic activity of OMP-131R10 is associated with its inhibition of β-catenin activation in vivo. Finally, RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in mouse models of fibrosis and in patients with idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Together these data provide an anti-fibrotic strategy for targeting the Wnt/β-catenin pathway through RSPO3 blockade and support that OMP-131R10 could be an important therapeutic agent for fibrosis.
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spelling pubmed-70658092020-03-23 Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs Zhang, Mingjun Haughey, Michael Wang, Nai-Yu Blease, Kate Kapoun, Ann M. Couto, Suzana Belka, Igor Hoey, Timothy Groza, Matthew Hartke, James Bennett, Brydon Cain, Jennifer Gurney, Austin Benish, Brent Castiglioni, Paola Drew, Clifton Lachowicz, Jean Carayannopoulos, Leon Nathan, Steven D. Distler, Jorg Brenner, David A. Hariharan, Kandasamy Cho, Ho Xie, Weilin PLoS One Research Article The Wnt/β-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of β-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the Wnt/β-catenin signaling, has not been described. A specific interventional strategy targeting this pathway for fibrosis remains to be defined. We developed monoclonal antibodies against members of the RSPO family (RSPO1, 2, and 3) and probed their potential function in fibrosis in vivo. We demonstrated that RSPO3 plays a critical role in the development of fibrosis in multiple organs. Specifically, an anti-RSPO3 antibody, OMP-131R10, when dosed therapeutically, attenuated fibrosis in carbon tetrachloride (CCl(4))-induced liver fibrosis, bleomycin-induced pulmonary and skin fibrosis models. Mechanistically, we showed that RSPO3 induces multiple pro-fibrotic chemokines and cytokines in Kupffer cells and hepatocytes. We found that the anti-fibrotic activity of OMP-131R10 is associated with its inhibition of β-catenin activation in vivo. Finally, RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in mouse models of fibrosis and in patients with idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Together these data provide an anti-fibrotic strategy for targeting the Wnt/β-catenin pathway through RSPO3 blockade and support that OMP-131R10 could be an important therapeutic agent for fibrosis. Public Library of Science 2020-03-11 /pmc/articles/PMC7065809/ /pubmed/32160239 http://dx.doi.org/10.1371/journal.pone.0229445 Text en © 2020 Zhang 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
Zhang, Mingjun
Haughey, Michael
Wang, Nai-Yu
Blease, Kate
Kapoun, Ann M.
Couto, Suzana
Belka, Igor
Hoey, Timothy
Groza, Matthew
Hartke, James
Bennett, Brydon
Cain, Jennifer
Gurney, Austin
Benish, Brent
Castiglioni, Paola
Drew, Clifton
Lachowicz, Jean
Carayannopoulos, Leon
Nathan, Steven D.
Distler, Jorg
Brenner, David A.
Hariharan, Kandasamy
Cho, Ho
Xie, Weilin
Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs
title Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs
title_full Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs
title_fullStr Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs
title_full_unstemmed Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs
title_short Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs
title_sort targeting the wnt signaling pathway through r-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065809/
https://www.ncbi.nlm.nih.gov/pubmed/32160239
http://dx.doi.org/10.1371/journal.pone.0229445
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