Extracellular matrix stiffness aggravates urethral stricture through Igfbp3/Smad pathway

Area of Science:

• Urology
• Biomaterials Science
• Cell Biology

Background:

• Urethral stricture, a narrowing of the urethra, is often initiated by inflammation, but its progression mechanisms are poorly understood.
• Previous research suggests a role for inflammation, but the physical and molecular factors driving urethral fibrosis remain unclear.

Purpose of the Study:

• To investigate the role of matrix stiffness in the progression of urethral stricture.
• To identify molecular pathways involved in stiffness-induced fibroblast-to-myofibroblast transition (FMT) in urethral stricture.

Main Methods:

• Atomic Force Microscopy (AFM) was used to measure urethral matrix stiffness in human and rat models.
• Polyacrylamide hydrogels mimicked varying matrix stiffness to study rat urethral fibroblasts.
• RNA sequencing (RNA-seq) analyzed gene expression changes, focusing on the Igfbp3/Smad pathway.

Main Results:

• Urethral stricture tissue exhibited significantly higher matrix stiffness (41.59 kPa) compared to normal tissue (5.23 kPa).
• Increased matrix stiffness promoted fibroblast-to-myofibroblast transition (FMT), evidenced by enhanced α-SMA and Collagen I expression.
• Inhibition of Igfbp3 blocked stiffness-induced FMT and reduced p-Smad2/3 levels, while Igfbp3 overexpression promoted FMT.

Conclusions:

• Matrix stiffness is a critical factor in the progression of urethral stricture.
• The Igfbp3/Smad pathway is implicated in regulating stiffness-driven FMT and urethral fibrosis.
• Targeting the Igfbp3/Smad pathway presents a promising therapeutic strategy for urethral stricture.