Paclitaxel modulates TGFbeta signaling in scleroderma skin grafts in immunodeficient mice

Area of Science:

• Dermatology
• Immunology
• Pharmacology

Background:

• Systemic sclerosis (SSc) involves excessive fibrosis and vascular damage, with abnormal TGFbeta activation playing a key role.
• Aberrant TGFbeta/Smad signaling, a hallmark of SSc, can potentially be modulated by paclitaxel through microtubule stabilization.

Purpose of the Study:

• To investigate the effect of low-dose paclitaxel on TGFbeta signaling, fibrosis, and neovessel formation in SSc skin grafts.
• To determine if paclitaxel can prevent the SSc phenotype in transplanted skin grafts.

Main Methods:

• Human SSc and healthy skin biopsies were treated with or without paclitaxel and transplanted into immunodeficient mice.
• Quantitative RT-PCR and immunohistochemical staining were used to assess TGFbeta signaling, collagen deposition, and neovessel formation.

Main Results:

• Paclitaxel significantly suppressed Smad2/3 phosphorylation and collagen deposition in SSc grafts, preventing SSc phenotype maintenance.
• SSc grafts exhibited a two-fold increase in neovessel formation compared to normal grafts, irrespective of paclitaxel treatment.
• Increased angiogenesis in SSc grafts was linked to elevated mouse PECAM-1 expression, indicating mouse-derived neovascular cells.

Conclusions:

• Low-dose paclitaxel effectively suppresses TGFbeta/Smad activity and reduces fibrosis in SSc mouse models.
• Paclitaxel treatment did not affect the pronounced angiogenesis observed in SSc skin grafts.
• Findings suggest low-dose paclitaxel may offer therapeutic benefits for SSc by modulating TGFbeta signaling, despite potential dose-dependent pro-fibrotic effects at higher concentrations.