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.

中文翻译：

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血小板反应蛋白2通过下调miR-29调节细胞外基质的产生，LOX水平和交联。

长期以来，胶原原纤维形成和交联已牵连到细胞外基质（ECM）依赖性过程中，例如纤维化和瘢痕形成。然而，尚未确定基质细胞蛋白影响ECM蛋白产生和原纤维胶原交联的程度。在这里，我们显示血小板反应蛋白2（TSP2），一种抗血管生成的基质细胞蛋白，是ECM动态平衡的重要调节剂。具体而言，通过分级定量蛋白质组学方法，我们显示TSP2的丧失导致独特的ECM表型，其特征是TSP2 KO小鼠皮肤中的原纤维胶原蛋白，基质细胞和结构性ECM蛋白的产生显着减少。此外，TSP2 KO皮肤显示出赖氨酰氧化酶（LOX）减少，其表现为原纤维胶原蛋白溶解度的增加和LOX介导的原纤维胶原蛋白交联的水平降低。我们显示这些变化是由miR-29（ECM蛋白和LOX的主要调节剂）间接介导的，因为miR-29在TSP2 KO中的表达增加了。总而言之，这些发现表明TSP2通过调节miR-29和LOX促进了ECM的生产和组装。