Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
Department of Biochemistry and Molecular Genetics, Biological Mass Spectrometry Facility, University of Colorado Denver, Aurora, CO 80045, USA.
Matrix Biol. 2019 Sep;82:71-85. doi: 10.1016/j.matbio.2019.03.002. Epub 2019 Mar 13.
Collagen fibrillogenesis and crosslinking have long been implicated in extracellular matrix (ECM)-dependent processes such as fibrosis and scarring. However, the extent to which matricellular proteins influence ECM protein production and fibrillar collagen crosslinking has yet to be determined. Here we show that thrombospondin 2 (TSP2), an anti-angiogenic matricellular protein, is an important modulator of ECM homeostasis. Specifically, through a fractionated quantitative proteomics approach, we show that loss of TSP2 leads to a unique ECM phenotype characterized by a significant decrease in fibrillar collagen, matricellular, and structural ECM protein production in the skin of TSP2 KO mice. Additionally, TSP2 KO skin displays decreased lysyl oxidase (LOX), which manifests as an increase in fibrillar collagen solubility and decreased levels of LOX-mediated fibrillar collagen crosslinking. We show that these changes are indirectly mediated by miR-29, a major regulator of ECM proteins and LOX, as miR-29 expression is increased in the TSP2 KO. Altogether, these findings indicate that TSP2 contributes to ECM production and assembly by regulating miR-29 and LOX.
胶原蛋白原纤维形成和交联长期以来一直与细胞外基质 (ECM) 相关过程有关，如纤维化和瘢痕形成。然而，细胞外基质蛋白对 ECM 蛋白产生和纤维胶原蛋白交联的影响程度尚未确定。在这里，我们表明，血小板反应蛋白 2（TSP2），一种抗血管生成细胞外基质蛋白，是 ECM 动态平衡的重要调节剂。具体来说，通过分馏定量蛋白质组学方法，我们表明 TSP2 的缺失导致 ECM 表型独特，其特征是皮肤中的纤维胶原蛋白、细胞外基质和结构性 ECM 蛋白产生显著减少 TSP2 KO 小鼠。此外，TSP2 KO 皮肤中的赖氨酰氧化酶 (LOX) 减少，表现为纤维胶原蛋白溶解度增加和 LOX 介导的纤维胶原蛋白交联水平降低。我们表明，这些变化是间接由 miR-29 介导的，miR-29 是 ECM 蛋白和 LOX 的主要调节剂，因为 TSP2 KO 中的 miR-29 表达增加。总的来说，这些发现表明 TSP2 通过调节 miR-29 和 LOX 来促进 ECM 的产生和组装。
