Bone Gla Protein Increases HIF-1α-Dependent Glucose Metabolism and Induces Cartilage and Vascular Calcification
Bone Gla Protein Increases HIF-1α-Dependent Glucose Metabolism and Induces Cartilage and Vascular Calcification
复制标题
DOI：
10.1161/atvbaha.111.230904
复制
发表时间：
2011-09-01
影响因子：
8.7
通讯作者：
Monsonego-Ornan, Efrat
中科院分区：
文献类型：
--
作者：
Idelevich, Anna;Rais, Yoach;Monsonego-Ornan, Efrat
Objective-Bone Gla 蛋白（BGP，骨钙素）通常存在于钙化的脉管系统中，最近被证明是能量代谢调节激素。本研究探讨了 BGP 在软骨和脉管系统矿化中的作用。方法和结果-我们在软骨细胞 (ATDC5) 和血管平滑肌细胞 (MOVAS) 中建立了体外 BGP 过表达模型。 BGP 过表达上调软骨分化标记并强化矿物质染色。 BGP 过表达增强了葡萄糖摄取并增加了葡萄糖转运蛋白和糖酵解酶的表达，同时减少了糖异生酶。用纯化的 BGP 治疗可激活胰岛素信号通路并上调葡萄糖转运和利用的基因。 BGP 过表达和纯化 BGP 处理都会导致软骨细胞和血管平滑肌细胞中缺氧诱导因子 1 α (HIF-1 α) 的稳定，这对于介导 BGP 的直接代谢作用至关重要。 1,25(OH)(2)D-3 诱导大鼠血管钙化的体内模型揭示了钙化、BGP 水平升高以及主动脉和骨生长板中 HIF-1 α 表达增加之间的相关性。体内引入 BGP siRNA，与 1,25(OH)(2)D-3 共同给药，可防止 1,25(OH)(2)D-3 诱导的 HIF-1 α 稳定，并减少主动脉的骨软骨分化和矿化。结论 - 这项研究证明了 BGP 局部将细胞转向糖酵解分解的新机制。 葡萄糖以 HIF-1 α 依赖性方式刺激软骨和脉管系统的钙化。 （动脉硬化血栓 Vasc Biol.2011；31：e55-e71。）
Objective-Bone Gla Protein (BGP, osteocalcin) is commonly present in the calcified vasculature and was recently shown as energy metabolism-regulating hormone. This study investigates the role of BGP in cartilage and vasculature mineralization.Methods and Results-We established an in vitro BGP-overexpression model in chondrocytes (ATDC5) and vascular smooth muscle cells (MOVAS). BGP overexpression upregulated markers of chondrogenic differentiation and intensified staining for minerals. BGP overexpression enhanced glucose uptake and increased expression of glucose transporters and glycolysis enzymes while decreasing gluconeogenesis enzymes. Treatment with purified BGP activated insulin signaling pathway and upregulated genes of glucose transport and utilization. Both BGP overexpression and treatment with purified BGP resulted in stabilization of hypoxia-inducible factor 1 alpha (HIF-1 alpha) in chondrocytes and vascular smooth muscle cells, shown essential in mediating the direct metabolic effect of BGP. The in vivo model of 1,25(OH)(2)D-3-induced vascular calcification in rats revealed a correlation between calcification, elevated BGP levels, and increased HIF-1 alpha expression in aortas and bone growth plates. The in vivo introduction of BGP siRNA, coadministered with 1,25(OH)(2)D-3, prevented 1,25(OH)(2)D-3-induced HIF-1 alpha stabilization, and diminished osteochon-drogenic differentiation and mineralization of aortas.Conclusion-This study demonstrates novel mechanism by which BGP locally shifts cells toward glycolytic breakdown of glucose, in a HIF-1 alpha-dependent manner, and stimulates calcification of cartilage and vasculature. (Arterioscler Thromb Vasc Biol. 2011;31:e55-e71.)