ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts

Area of Science:

• Cell Biology
• Immunology
• Rheumatology

Background:

• Fibroblasts are crucial structural cells involved in both tissue homeostasis and disease pathogenesis.
• Pathogenic fibroblast phenotypes are observed across diverse diseases, including autoimmune arthritis, cancer, and inflammatory colitis.
• The molecular drivers of disease-associated fibroblast phenotypes remain largely unknown.

Purpose of the Study:

• To identify the key transcription factor responsible for pathological tissue-remodeling programs in fibroblasts.
• To elucidate the molecular mechanisms by which fibroblasts contribute to disease pathogenesis, particularly in arthritis.
• To investigate the therapeutic potential of targeting fibroblast-specific pathways.

Main Methods:

• Single-cell technologies and cross-tissue data analysis to identify shared fibroblast characteristics.
• Genetic loss-of-function experiments, including fibroblast-specific ETS1 deletion.
• Analysis of regulatory elements controlling key genes like receptor activator of nuclear factor-κB ligand (RANKL) and matrix metalloproteinases.

Main Results:

• ETS1 was identified as the central transcription factor governing pathological fibroblast activation.
• In arthritis, ETS1 orchestrates the expression of RANKL and matrix metalloproteinases, promoting tissue destruction.
• Fibroblast-specific deletion of ETS1 significantly ameliorated bone and cartilage damage in arthritis models.
• ETS1 appears to define a common pathogenic fibroblast signature across different diseases.

Conclusions:

• ETS1 is a critical regulator of pathogenic fibroblast polarization and tissue remodeling.
• Targeting ETS1 in fibroblasts presents a promising therapeutic strategy for diseases characterized by tissue destruction, such as arthritis.
• These findings provide a mechanistic understanding of fibroblast contributions to disease and highlight potential therapeutic targets.