Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, China.
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nat Commun. 2017 Jul 7;8:16003. doi: 10.1038/ncomms16003.
A specific bone vessel subtype, strongly positive for CD31 and endomucin (CD31Emcn), is identified as coupling angiogenesis and osteogenesis. The abundance of type CD31Emcn vessels decrease during ageing. Here we show that expression of the miR-497∼195 cluster is high in CD31Emcn endothelium but gradually decreases during ageing. Mice with depletion of miR-497∼195 in endothelial cells show fewer CD31Emcn vessels and lower bone mass. Conversely, transgenic overexpression of miR-497∼195 in murine endothelium alleviates age-related reduction of type CD31Emcn vessels and bone loss. miR-497∼195 cluster maintains the endothelial Notch activity and HIF-1α stability via targeting F-box and WD-40 domain protein (Fbxw7) and Prolyl 4-hydroxylase possessing a transmembrane domain (P4HTM) respectively. Notably, endothelialium-specific activation of miR-195 by intravenous injection of aptamer-agomiR-195 stimulates CD31Emcn vessel and bone formation in aged mice. Together, our study indicates that miR-497∼195 regulates angiogenesis coupled with osteogenesis and may represent a potential therapeutic target for age-related osteoporosis.
一种特定的骨血管亚型，强烈表达 CD31 和内粘蛋白（CD31Emcn），被鉴定为连接血管生成和骨生成。CD31Emcn 血管的数量在衰老过程中减少。在这里，我们表明 miR-497∼195 簇在 CD31Emcn 内皮细胞中的表达水平较高，但随着年龄的增长逐渐降低。内皮细胞中 miR-497∼195 耗竭的小鼠表现出较少的 CD31Emcn 血管和较低的骨量。相反，miR-497∼195 在鼠内皮细胞中的过表达可减轻与年龄相关的 CD31Emcn 血管减少和骨丢失。miR-497∼195 簇通过靶向 F -box 和 WD-40 结构域蛋白（Fbxw7）和具有跨膜结构域的脯氨酰 4-羟化酶（P4HTM）分别维持内皮细胞的 Notch 活性和 HIF-1α 的稳定性。值得注意的是，通过静脉注射适体-agomiR-195 对内皮细胞特异性激活 miR-195 可刺激老年小鼠的 CD31Emcn 血管和骨形成。总之，我们的研究表明，miR-497∼195 调节与骨生成偶联的血管生成，可能是与年龄相关的骨质疏松症的潜在治疗靶点。
Zotero 插件
