Identification of the Gene for Scleroderma in the Tsk/2 Mouse Strain: Implications for Human Scleroderma Pathogenesis and subset Distinctions.

摘要

This project is focused on an animal model of the human disease, system sclerosis (SSc), called Tsk2/+. The SSc-like traits in Tsk2/+ heterozygotes are highly penetrant. With their readily apparent skin fibrosis resulting from ECM anomalies, Tsk2/+ mice have signs that resemble human SSc features, making it useful as a pre-clinical model. In this report, we show a clear time dependence on the gene expression in the skin of the Tsk2/+ mice. We have pinpointed a mutation in Col3a1 that is the Tsk2 gene, and have confirmed the sequence difference between Tsk2/+ and the present strain, 101/H. We present results on the expression of TGF-beta mRNA from cells cultured from the Tsk2/+ and WT littermates that suggest a mechanism for the up-regulation of TGF-beta seen in the mutant strain. We show that elastin content in the skin, known to be controlled by TGF-beta and possibly up-regulated in SSc, is the earliest indicator of tight-skin in the tissue. Finally, we show that Tsk2/+ mice, and mouse fibroblasts transfected with Col3a1 from Tsk2/+, share a substantial fibrotic gene expression program compared to WT mice or transfectants, indicating that expression of the Col3a1 expn(Tsk2) gene alone accounts for the trait in Tsk2/+ mice.