Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma?
Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma?
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DOI：
10.1002/art.30312
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发表时间：
2011-06
影响因子：
--
通讯作者：
Varga J
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文献类型：
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作者：
Wei J;Melichian D;Komura K;Hinchcliff M;Lam AP;Lafyatis R;Gottardi CJ;MacDougald OA;Varga J
最近的研究发现了硬皮病和肺纤维化中异常的Wnt信号。本研究旨在探讨Wnt10b异位表达对fabp4定向表达Wnt10b转基因小鼠皮肤稳态和分化的影响。采用实时荧光定量pcr分析Wnt10b在博莱霉素诱导纤维化中的表达。测定了转基因和野生型FABP4-Wnt10b小鼠皮肤切片的真皮厚度和肌成纤维细胞。采用Sircol法、免疫印迹法和实时荧光定量pcr分析胶原蛋白的表达。在外植成纤维细胞和腺病毒感染的前脂肪细胞或成纤维细胞中检测了Wnt10b的作用。FABP4-Wnt10b转基因小鼠皮肤脂肪组织逐渐减少。真皮纤维化，胶原沉积增加，成纤维细胞活化，肌成纤维细胞积聚。在这些活组织检查中，典型Wnt信号的增加与胶原基因表达升高相关。转基因小鼠外植的成纤维细胞在体外表现出典型Wnt信号增加，I型胶原和α-平滑肌肌动蛋白基因表达升高。Wnt10b感染正常前脂肪细胞导致脂肪生成受阻，而在成纤维细胞中，Wnt10b诱导I型胶原蛋白显著上调。我们证明，体内异位的Wnt10b表达会导致脂肪组织的进行性损失，并伴有真皮的自发发育。这些发现表明，异位的Wnt10b在抑制脂肪形成的同时，通过诱导成纤维程序，驱动间充质细胞命运向肌成纤维细胞转变。因此，FABP4-Wnt10b转基因小鼠为研究Wnt信号在纤维化中的作用和机制提供了一种新的动物模型。
Recent studies identify aberrant Wnt signaling in scleroderma and pulmonary fibrosis. The aim of present study was to investigate the effect of ectopic Wnt10b expression on skin homeostasis and differentiation in transgenic mice with FABP4-directed Wnt10b expression. The expression of Wnt10b was analyzed by real-time qPCR in bleomycin-induced fibrosis. Dermal thickness and the myofibroblasts were determined in skin sections from FABP4-Wnt10b transgenic and wildtype mice. The expression of collagen was analyzed by Sircol assays, immunoblot and real-time qPCR. The effects of Wnt10b were examined in explanted fibroblasts and in adenovirus infected preadipocytes or fibroblasts. FABP4-Wnt10b transgenic mice showed progressive loss of adipose tissue in the skin. The dermis was fibrotic and showed increased collagen deposition, fibroblast activation and myofibroblast accumulation. Increased canonical Wnt signaling correlated with elevated collagen gene expression in these biopsies. Explanted fibroblasts from transgenic mice showed increased canonical Wnt signaling and elevated Type I collagen and α-smooth muscle actin gene expression in vitro. Infection of normal preadipocytes with Wnt10b resulted in blockade of adipogenesis, whereas in fibroblasts Wnt10b induced marked up-regulation of Type I collagen. We demonstrate that ectopic Wnt10b expression in vivo causes progressive loss of adipose tissue accompanied by the spontaneous development of dermal. These findings suggest that ectopic Wnt10b drives a switch in mesenchymal cell fate toward myofibroblasts by induction of a fibrogenic program while suppressing adipogenesis. Therefore FABP4-Wnt10b transgenic mice represent a novel animal model to study the role and mechanisms of Wnt signaling in fibrosis.