Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs
| Autor: | Weilin Xie, Jean Lachowicz, Timothy Hoey, Igor Belka, Paola Castiglioni, James Hartke, Steven D. Nathan, Leon Carayannopoulos, David A. Brenner, Matthew C. Groza, Ann M. Kapoun, Cho Ho, Nai-Yu Wang, Austin L. Gurney, Mingjun Zhang, Brent Benish, Jörg H W Distler, Michael Haughey, Jennifer Cain, Kate Blease, Suzana Couto, Brydon L. Bennett, Hariharan Kandasamy, Clifton Drew |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Chemokine Biochemistry Epithelium Idiopathic pulmonary fibrosis Mice 0302 clinical medicine Medizinische Fakultät Fibrosis Animal Cells Non-alcoholic Fatty Liver Disease Medicine and Health Sciences Wnt Signaling Pathway Cells Cultured Connective Tissue Cells Multidisciplinary biology Liver Diseases Wnt signaling pathway Animal Models Experimental Organism Systems Liver Connective Tissue Mice Inbred DBA 030220 oncology & carcinogenesis Medicine Liver Fibrosis Signal transduction Cellular Types Anatomy Research Article Science Mouse Models Gastroenterology and Hepatology Research and Analysis Methods Antibodies 03 medical and health sciences Model Organisms In vivo medicine Animals Humans ddc:610 RSPO1 Immunohistochemistry Techniques RSPO3 business.industry Biology and Life Sciences Proteins Epithelial Cells Cell Biology Fibroblasts medicine.disease Idiopathic Pulmonary Fibrosis Histochemistry and Cytochemistry Techniques 030104 developmental biology Biological Tissue Cancer research biology.protein Immunologic Techniques Animal Studies Hepatocytes business Thrombospondins Collagens Developmental Biology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 15, Iss 3, p e0229445 (2020) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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