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

  1. Zhang, Mingjun
  2. Haughey, Michael
  3. Wang, Nai-Yu
  4. Blease, Kate
  5. Kapoun, Ann M.
  6. Couto, Suzana
  7. Belka, Igor
  8. Hoey, Timothy
  9. Groza, Matthew
  10. Hartke, James
  11. Bennett, Brydon
  12. Cain, Jennifer
  13. Gurney, Austin
  14. Benish, Brent
  15. Castiglioni, Paola
  16. Drew, Clifton
  17. Lachowicz, Jean
  18. Carayannopoulos, Leon
  19. Nathan, Steven D.
  20. Distler, Jorg
  21. Brenner, David A.
  22. Hariharan, Kandasamy
  23. Cho, Ho
  24. Xie, Weilin ORCID logo

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1000 Titel
  • Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs
1000 Autor/in
  1. Zhang, Mingjun |
  2. Haughey, Michael |
  3. Wang, Nai-Yu |
  4. Blease, Kate |
  5. Kapoun, Ann M. |
  6. Couto, Suzana |
  7. Belka, Igor |
  8. Hoey, Timothy |
  9. Groza, Matthew |
  10. Hartke, James |
  11. Bennett, Brydon |
  12. Cain, Jennifer |
  13. Gurney, Austin |
  14. Benish, Brent |
  15. Castiglioni, Paola |
  16. Drew, Clifton |
  17. Lachowicz, Jean |
  18. Carayannopoulos, Leon |
  19. Nathan, Steven D. |
  20. Distler, Jorg |
  21. Brenner, David A. |
  22. Hariharan, Kandasamy |
  23. Cho, Ho |
  24. Xie, Weilin |
1000 Erscheinungsjahr 2020
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2020-03-11
1000 Erschienen in
1000 Quellenangabe
  • 15(3):e0229445
1000 Copyrightjahr
  • 2020
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1371/journal.pone.0229445 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065809/ |
1000 Ergänzendes Material
  • https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229445#sec022 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • 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.
1000 Sacherschließung
lokal Collagens
lokal Liver fibrosis
lokal Immunohistochemistry techniques
lokal Antibody therapy
lokal Mouse models
lokal Epitjhelial cells
lokal Fibrosis
lokal Hepatocytes
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
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1000 (Academic) Editor
1000 Label
1000 Förderer
  1. Celgene Corporation |
  2. OncoMed Pharmaceutical |
1000 Fördernummer
  1. -
  2. -
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  1. -
  2. -
1000 Dateien
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  1. 1000 joinedFunding-child
    1000 Förderer Celgene Corporation |
    1000 Förderprogramm -
    1000 Fördernummer -
  2. 1000 joinedFunding-child
    1000 Förderer OncoMed Pharmaceutical |
    1000 Förderprogramm -
    1000 Fördernummer -
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1000 Erstellt am 2023-07-13T09:50:54.304+0200
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