Reduced SPAG17 Expression in Systemic Sclerosis Triggers Myofibroblast Transition and Drives Fibrosis.

Area of Science:

• Fibrosis research
• Molecular biology
• Dermatology

Background:

• Systemic sclerosis (SSc) is a fibrotic disease with poorly understood drivers of myofibroblast activation.
• Myofibroblasts are key to fibrosis in SSc, impacting skin and internal organs.

Purpose of the Study:

• To investigate the role of SPAG17 in the pathogenesis of Systemic Sclerosis.
• To identify novel therapeutic targets for SSc and other fibrotic conditions.

Main Methods:

• Unbiased transcriptome analysis of SSc patient skin biopsies.
• Orthogonal approaches to correlate SPAG17 expression with fibrotic markers.
• Analysis of chromatin accessibility in SSc fibroblasts and endothelial cells.
• Spag17 knockout mouse models and SPAG17 knockdown in human/mouse cells.

Main Results:

• SPAG17 was downregulated in multiple SSc patient cohorts, negatively correlating with fibrotic gene expression.
• Reduced chromatin accessibility at the SPAG17 locus was observed in SSc cells.
• Spag17-deficient mice exhibited spontaneous skin fibrosis.
• SPAG17 knockdown induced myofibroblast transformation and heightened profibrotic responses, linked to constitutive TGF-β pathway activation.

Conclusions:

• Impaired SPAG17 expression is a feature of SSc.
• SPAG17 plays a cell-intrinsic role in negatively regulating fibrotic responses.
• SPAG17 signaling represents a potential therapeutic avenue for SSc and other fibrotic diseases.