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

Area of Science:

• Cell biology
• Immunology
• Pathology

Background:

• The Wnt/β-catenin signaling pathway is crucial in cell proliferation and implicated in fibrotic diseases.
• While β-catenin's role in fibrosis is studied, R-spondin proteins (RSPOs), which enhance this pathway, are less understood in this context.
• Targeted interventional strategies for fibrosis involving this pathway are needed.

Purpose of the Study:

• To investigate the role of R-spondin proteins (RSPOs) in fibrosis.
• To develop and test monoclonal antibodies targeting RSPO family members for anti-fibrotic potential.
• To evaluate RSPO3 as a therapeutic target for fibrotic conditions.

Main Methods:

• Development of monoclonal antibodies against RSPO1, RSPO2, and RSPO3.
• In vivo testing of an anti-RSPO3 antibody (OMP-131R10) in carbon tetrachloride-induced liver fibrosis and bleomycin-induced pulmonary and skin fibrosis models.
• Analysis of RSPO3's mechanism, including its effect on pro-fibrotic factors and β-catenin activation.
• Quantification of RSPO3 levels in fibrotic tissues from mouse models and human patients (IPF, NASH).

Main Results:

• RSPO3 was identified as a critical factor in the development of multi-organ fibrosis.
• Therapeutic administration of OMP-131R10 significantly attenuated fibrosis in multiple preclinical models.
• RSPO3 was shown to stimulate pro-fibrotic chemokines and cytokines via Kupffer cells and hepatocytes.
• OMP-131R10's anti-fibrotic effect correlated with the inhibition of β-catenin activation.
• Elevated RSPO3 levels were observed in active fibrotic lesions in mouse models and human fibrotic diseases (IPF, NASH).

Conclusions:

• RSPO3 blockade represents a viable anti-fibrotic strategy by targeting the Wnt/β-catenin pathway.
• The anti-RSPO3 antibody OMP-131R10 demonstrates significant therapeutic potential for treating various fibrotic diseases.
• Targeting RSPO3 offers a novel approach for managing conditions like idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis.