Skin Fibrosis and Recovery Is Dependent on Wnt Activation via DPP4

Area of Science:

• Dermatology
• Molecular Biology
• Biochemistry

Background:

• Fibrosis, characterized by excessive extracellular matrix accumulation, is a critical pathological process.
• Lipodystrophy, the loss of fat cells, often accompanies fibrosis in various organs.
• Understanding fibrosis mechanisms is crucial for developing effective therapeutic interventions.

Purpose of the Study:

• To investigate the role of Wnt signaling in fibrotic dermal remodeling and lipodystrophy.
• To identify key molecular targets for reversing established fibrosis.
• To explore the therapeutic potential of DPP4 inhibition in fibrosis reversal.

Main Methods:

• Development of a genetically inducible and reversible Wnt activation mouse model.
• Analysis of Wnt-induced fibrotic changes in mouse skin, including extracellular matrix deposition and adipocyte morphology.
• Investigation of CD26/DPP4 as a Wnt/β-catenin-responsive gene and its role in fibrotic transformation.
• Assessment of DPP4 inhibitors for their efficacy in reversing established Wnt-induced fibrosis.

Main Results:

• Wnt activation induced significant fibrotic dermal remodeling, extracellular matrix expansion, and dermal adipocyte shrinking.
• Reversible Wnt activation led to complete reversal of fibrosis and restoration of skin architecture upon withdrawal.
• CD26/DPP4 was identified as a Wnt/β-catenin-responsive gene and a functional mediator of fibrosis.
• Genetic evidence confirmed the Wnt/DPP4 axis is essential for fibrotic dermal remodeling and linked to human skin fibrosis severity.
• DPP4 inhibitors demonstrated efficacy in accelerating recovery from established Wnt-induced fibrosis.

Conclusions:

• The Wnt/DPP4 axis is a critical regulator of extracellular matrix homeostasis and dermal fat loss.
• Targeting the Wnt/DPP4 pathway offers promising therapeutic avenues for manipulating the onset and reversal of tissue fibrosis.
• DPP4 inhibitors represent a viable strategy for repurposing to treat fibrotic conditions.