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Cited by 48Wnt/β-catenin signaling in development and cancerLiver physiology and pathologyTGF-β signaling in diseases

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

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Zhang, Mingjun, Haughey, Michael, Wang, Nai-Yu, Blease, Kate, Kapoun, Ann M., Couto, Suzana, Belka, Igor, Hoey, Timothy +16 more·2020·PLOS ONE
DOI 10.1371/journal.pone.0229445PMC PMC7065809
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Abstract

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 (CCl4)-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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  • Deletion of Rspo3 in HSCs or inhibition of RSPO3 by blocking antibodies inhibits CCl4-induced fibrosis in mice.

    “Deletion of Rspo3 in HSCs or inhibition of RSPO3 by blocking antibodies51 inhibited CCl4-induced fibrosis in mice, but P450-activated toxins like APAP are not considered clinically relevant causes of CLD and liver fibrosis as they usually trigger only acute liver disease.”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [51]

    The Results section (page not provided) reports that an anti-RSPO3 antibody significantly protected mice from developing CCl4-induced liver fibrosis. The paper does not report deletion of Rspo3 in hepatic stellate cells, so it supports only the antibody-inhibition part of the claim. (LLM, conf=0.88)

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Authors
Zhang, M., Haughey, M., Wang, N.-Y., Blease, K., Kapoun, A. M., Couto, S., Belka, I., Hoey, T., Groza, M., Hartke, J., Bennett, B., Cain, J., Gurney, A., Benish, B., Castiglioni, P., Drew, C., Lachowicz, J., Carayannopoulos, L., Nathan, S. D., Distler, J., Brenner, D. A., Hariharan, K., Cho, H., & Xie, W.
Affiliations
  • OncoMed (United States) (US)
  • Celgene (United States) (US)
  • Inova Fairfax Hospital (US)
  • University of California San Diego (US)
Corresponding author
Xie, Weilin
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2020-03-11
Volume
15
Issue
3
Pages
e0229445
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0229445
PMC
PMC7065809
OpenAlex
W3012558710
Cited by
48
References
3
Citations by year
2026: 4 · 2025: 9 · 2024: 11 · 2023: 9 · 2022: 8 · 2021: 6 · 2020: 1
FWCI
1.95
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OPUS Repository (Kooperativer Bibliotheksverbund Berlin-Brandenburg) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
RSPO3, Wnt/β-catenin signaling, organ fibrosis, antifibrotic therapy, monoclonal antibodies, liver fibrosis, pulmonary fibrosis, skin fibrosis, idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis, Kupffer cells, hepatocytes, cytokines and chemokines, β-catenin activation
MeSH terms
R-Spondins, Animals, Antibodies, Cells, Cultured, Humans, Male, Mice, Inbred DBA, Thrombospondins, Mice, Idiopathic Pulmonary Fibrosis, Wnt Signaling Pathway, Non-alcoholic Fatty Liver Disease

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