Endoglin haploinsufficiency is associated with differential regulation of extracellular matrix production during skin fibrosis and cartilage repair in mice
Endoglin haploinsufficiency is associated with differential regulation of extracellular matrix production during skin fibrosis and cartilage repair in mice
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DOI：
10.1007/s12079-018-0461-7
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发表时间：
2018-03-01
影响因子：
4.1
通讯作者：
Philip, Anie
中科院分区：
文献类型：
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作者：
Alzahrani, Anas;Chi, Yoon;Philip, Anie
转化生长因子 (TGF)-ss 是一种多功能生长因子，具有有效的促纤维化作用。内皮糖蛋白是一种 TGF-ss 共受体，可强烈调节多种细胞类型中的 TGF-ss 信号传导。尽管已知 TGF-β 信号传导的异常调节在硬皮病和软骨修复受损等纤维化疾病中发挥关键作用，但内皮糖蛋白功能在调节这些过程中的重要性却知之甚少。在这里，我们使用内皮糖蛋白杂合子（Eng+/-）小鼠和野生型（Eng+/+）同窝小鼠，检查了内皮糖蛋白单倍体不足是否在博莱霉素诱导的皮肤纤维化和手术诱导的骨关节炎期间调节细胞外（ECM）蛋白表达和纤维化反应。通过向小鼠皮内注射博来霉素或媒介物诱导皮肤纤维化。骨关节炎是通过内侧半月板不稳定而通过手术诱发的。然后测定真皮厚度、软骨完整性和 ECM 蛋白表达。与 Eng+/+ 小鼠相比，在基础和博莱霉素处理条件下，接受博来霉素攻击的 Eng+/- 小鼠显示真皮厚度显着降低 (P < 0.005)，胶原蛋白含量降低，胶原蛋白 I、纤连蛋白、α-平滑肌肌动蛋白水平降低。与Eng+/+小鼠相比，经历手术诱导的骨关节炎的Eng+/-小鼠在软骨退化程度方面没有差异，尽管从Eng(+/)-中分离的软骨细胞显示出胶原II水平显着增强。我们的研究结果表明，小鼠内皮糖蛋白单倍体不足可改善博来霉素诱导的皮肤纤维化，表明内皮糖蛋白代表小鼠皮肤中的促纤维化因子。然而，内皮糖蛋白单倍体不足并不能保护这些小鼠免受手术引起的软骨退化，这表明内皮糖蛋白在皮肤和软骨修复过程中的作用存在差异调节。
Transforming growth factor (TGF)-ss is a multifunctional growth factor with potent pro-fibrotic effects. Endoglin is a TGF-ss coreceptor that strongly regulates TGF-ss signaling in a variety of cell types. Although aberrant regulation of TGF-ss signaling is known to play a key role in fibrotic diseases such as scleroderma and impaired cartilage repair, the significance of endoglin function in regulating these processes is poorly understood. Here we examined whether endoglin haploinsufficiency regulates extracellular (ECM) protein expression and fibrotic responses during bleomycin induced skin fibrosis and surgically induced osteoarthritis, using endoglin-heterozygous (Eng+/-) mice and wild-type (Eng+/+) littermates. Skin fibrosis was induced by injecting mice intradermally with bleomycin or vehicle. Osteoarthritis was induced surgically by destabilization of medial meniscus. Dermal thickness, cartilage integrity and ECM protein expression were then determined. Eng+/-mice subjected to bleomycin challenge show a marked decrease in dermal thickness (P < 0.005) and reduced collagen content and decreased collagen I, fibronectin, alpha-smooth muscle actin levels as compared to Eng+/+ mice, both under basal and bleomycin treated conditions. Eng+/-mice undergoing surgically induced osteoarthritis show no differences in the degree of cartilage degradation, as compared to Eng+/+ mice, although chondrocytes isolated from Eng(+/)-display markedly enhanced collagen II levels. Our findings suggest that endoglin haploinsufficiency in mice ameliorates bleomycin-induced skin fibrosis suggesting that endoglin represents a pro-fibrotic factor in the mouse skin. However, endoglin haploinsufficiency does not protect these mice from surgically indiced cartilage degradation, demonstrating differential regulation of endoglin action during skin and cartilage repair.