Identification of Optimal Mouse Models of Systemic Sclerosis by Interspecies Comparative Genomics.

Area of Science:

• Immunology
• Dermatology
• Genomics

Background:

• Systemic sclerosis (SSc) pathogenesis is complex due to significant disease heterogeneity.
• Current animal models of SSc do not fully recapitulate distinct molecular subsets of the human disease.
• Identifying suitable animal models is crucial for advancing SSc research and developing targeted therapies.

Purpose of the Study:

• To compare gene expression profiles of various mouse models of SSc with human SSc molecular subsets.
• To determine which animal models best represent the intrinsic molecular heterogeneity observed in SSc patients.
• To identify potential molecular targets for SSc by analyzing gene expression patterns.

Main Methods:

• Interspecies comparative analysis of genomic data from multiple mouse models (sclerodermatous GVHD, bleomycin-induced fibrosis, Tsk1/+, Tsk2/+) and SSc patients.
• Gene expression profiling of skin biopsies.
• Assessment of transforming growth factor β (TGFβ) activation and tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression.

Main Results:

• Gene expression in sclerodermatous GVHD and bleomycin models aligned with the inflammatory SSc subset.
• Tsk2/+ mice exhibited gene expression patterns corresponding to the fibroproliferative SSc subset.
• Elevated TNFRSF12A expression was observed in fibroproliferative SSc patients and Tsk2/+ mice.

Conclusions:

• Distinct mouse models can effectively recapitulate specific molecular subsets of SSc.
• Key pathways like TGFβ, IL-13, and IL-4 are implicated in SSc pathogenesis.
• TNFRSF12A emerges as a novel potential therapeutic target for the fibroproliferative subset of SSc.