Wareing Nancy, Mills Tingting W, Collum Scott, Wu Minghua, Revercomb Lucy, Girard Rene, Lyons Marka, Skaug Brian, Bi Weizhen, Ali Meer A, Koochak Haniyeh, Flores Anthony R, Yang Yuntao, Zheng W Jim, Swindell William R, Assassi Shervin, Karmouty-Quintana Harry
Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth Houston), TX, USA.
Division of Rheumatology, Department of Internal Medicine, McGovern Medical School, UTHealth Houston, Houston TX, USA.
bioRxiv. 2024 Jul 19:2024.05.22.595271. doi: 10.1101/2024.05.22.595271.
Dermal fibrosis is a cardinal feature of systemic sclerosis (SSc) for which there are limited treatment strategies. This is in part due to our fragmented understanding of how dermal white adipose tissue (DWAT) contributes to skin fibrosis. We identified elevated sine oculis homeobox homolog 1 (SIX1) expression in SSc skin samples from the GENISOS and PRESS cohorts, the expression of which correlated with adipose-associated genes and molecular pathways. SIX1 localization studies identified increased signals in the DWAT area in SSc and in experimental models of skin fibrosis. Global and adipocyte specific Six1 deletion abrogated end-stage fibrotic gene expression and dermal adipocyte shrinkage induced by SQ bleomycin treatment. Further studies revealed a link between elevated SIX1 and increased expression of SERPINE1 and its protein PAI-1 which are known pro-fibrotic mediators. However, SIX1 deletion did not appear to affect cellular trans differentiation. Taken together these results point at SIX1 as a potential target for dermal fibrosis in SSc.
皮肤纤维化是系统性硬化症（SSc）的主要特征，针对这一病症的治疗策略有限。部分原因在于我们对真皮白色脂肪组织（DWAT）如何导致皮肤纤维化的理解较为零散。我们在GENISOS和PRESS队列的SSc皮肤样本中发现眼无同源盒1（SIX1）表达升高，其表达与脂肪相关基因和分子途径相关。SIX1定位研究发现，在SSc的DWAT区域以及皮肤纤维化实验模型中信号增强。全身性和脂肪细胞特异性Six1缺失消除了博来霉素治疗诱导的终末期纤维化基因表达和真皮脂肪细胞萎缩。进一步研究揭示了SIX1升高与丝氨酸蛋白酶抑制剂E1（SERPINE1）及其蛋白纤溶酶原激活物抑制剂1（PAI-1）表达增加之间的联系，而PAI-1是已知的促纤维化介质。然而，Six1缺失似乎并未影响细胞转分化。综合这些结果表明，SIX1是SSc皮肤纤维化的一个潜在靶点。
