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Selective proteolysis by matrix metalloproteinases of photo-oxidised dermal extracellular matrix proteins
Cellular Signalling ( IF 4.8 ) Pub Date : 2018-12-03 , DOI: 10.1016/j.cellsig.2018.11.024
Sarah A. Hibbert , Rachel E.B. Watson , Christopher E.M. Griffiths , Neil K. Gibbs , Michael J. Sherratt

Photodamage in chronically sun-exposed skin manifests clinically as deep wrinkles and histologically as extensive remodelling of the dermal extracellular matrix (ECM) and in particular, the elastic fibre system. We have shown previously that loss of fibrillin microfibrils, a key elastic fibre component, is a hallmark of early photodamage and that these ECM assemblies are susceptible in vitro to physiologically attainable doses of ultraviolet radiation (UVR). Here, we test the hypotheses that UVR-mediated photo-oxidation is the primary driver of fibrillin microfibril and fibronectin degradation and that prior UVR exposure will enhance the subsequent proteolytic activity of UVR-upregulated matrix metalloproteinases (MMPs).

We confirmed that UVB (280-315 nm) irradiation in vitro induced structural changes to both fibrillin microfibrils and fibronectin and these changes were largely reactive oxygen species (ROS)-driven, with increased ROS lifetime (D2O) enhancing protein damage and depleted O2 conditions abrogating it. Furthermore, we show that although exposure to UVR alone increased microfibril structural heterogeneity, exposure to purified MMPs (1, −3, −7 and − 9) alone had minimal effect on microfibril bead-to-bead periodicity; however, microfibril suspensions exposed to UVR and then MMPs were more structurally homogenous. In contrast, the susceptibly of fibronectin to proteases was unaffected by prior UVR exposure. These observations suggest that both direct photon absorption and indirect production of ROS are important mediators of ECM remodelling in photodamage. We also show that fibrillin microfibrils are relatively resistant to proteolysis by MMPs −1, −3, −7 and − 9 but that these MMPs may selectively remove damaged microfibril assemblies. These latter observations have implications for predicting the mechanisms of tissue remodelling and targeted repair.



中文翻译:

基质金属蛋白酶对光氧化的真皮细胞外基质蛋白的选择性蛋白水解

长期暴露在阳光下的皮肤中的光损伤在临床上表现为深层皱纹,在组织学上表现为真皮细胞外基质(ECM)尤其是弹性纤维系统的广泛重塑。先前我们已经表明,原纤维蛋白微纤维(一种关键的弹性纤维成分)的丧失是早期光损伤的标志,并且这些ECM组件在体外对生理学上可达到的剂量紫外线辐射(UVR)敏感。在这里,我们测试以下假设:UVR介导的光氧化是原纤维微纤蛋白和纤连蛋白降解的主要驱动力,并且先前的UVR暴露将增强UVR上调的基质金属蛋白酶(MMP)的后续蛋白水解活性。

我们证实,体外UVB(280-315 nm)辐射诱导了原纤维蛋白微纤维和纤连蛋白的结构变化,这些变化很大程度上是由活性氧(ROS)驱动的,并具有增加的ROS寿命(D 2 O),从而增强了蛋白质的破坏和耗竭。 Ø 2废除它的条件。此外,我们显示,尽管单独暴露于UVR会增加微纤维的结构异质性,但单独暴露于纯化的MMP(1、3,-7和-9)对微纤维微珠间的周期性影响却很小。但是,微纤维悬浮液暴露于UVR,然后暴露于MMP,在结构上更加均一。相反,纤连蛋白对蛋白酶的敏感性不受先前UVR暴露的影响。这些观察结果表明,直接光子吸收和间接产生ROS都是光损伤ECM重塑的重要介质。我们还表明,原纤维微纤维微纤维对MMPs -1,-3,-7和-9的蛋白水解具有相对的抵抗力,但是这些MMPs可以选择性地去除受损的微纤维蛋白组件。

更新日期:2018-12-03
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