Notch Signaling Activity Determines Uptake and Biological Effect of Imatinib in Systemic Sclerosis Dermal Fibroblasts

Area of Science:

• Pharmacology
• Fibrosis Research
• Rheumatology

Background:

• Tyrosine kinase inhibitors (TKIs) show promise for rheumatic diseases like systemic sclerosis (SSc).
• Fibroblast activation and fibrosis in SSc involve tyrosine kinases, leading to imatinib as a potential treatment.
• Organic cation transporters influence TKI uptake and efficacy, but their role in SSc is unclear.

Purpose of the Study:

• Investigate the role of organic cation transporters in imatinib uptake in SSc.
• Examine how SSc pathogenetic factors, PDGF and Notch signaling, affect imatinib transport.

Main Methods:

• Assessed expression of organic cation transporters (OCT1-3, OCTN1/2, MATE1) in healthy and SSc dermal fibroblasts.
• Utilized small interfering RNA to determine MATE1's role in imatinib uptake and effect.
• Studied the impact of PDGF and Notch pathway activation on transporter expression and imatinib uptake.

Main Results:

• MATE1, OCT1-3, and OCTN1/2 transporters are expressed in both healthy and SSc fibroblasts.
• SSc fibroblasts exhibit reduced MATE1 expression and imatinib uptake compared to healthy ones.
• MATE1 is identified as the key transporter for imatinib's uptake and biological effect.
• PDGF decreases imatinib uptake in SSc fibroblasts by reducing MATE1 expression.
• Notch pathway inhibition increases MATE1 expression and imatinib uptake in SSc fibroblasts.

Conclusions:

• MATE1-mediated transport is a critical determinant of imatinib's therapeutic efficacy in SSc.
• Altered MATE1 expression in SSc fibroblasts contributes to reduced imatinib uptake and effectiveness.
• Targeting MATE1 or modulating PDGF and Notch pathways may enhance imatinib therapy for SSc.