Syntaxin 4a Regulates Matrix Vesicle-Mediated Bone Matrix Production by Osteoblasts
Syntaxin 4a Regulates Matrix Vesicle-Mediated Bone Matrix Production by Osteoblasts
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DOI：
10.1002/jbmr.3056
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发表时间：
2017-03-01
影响因子：
6.2
通讯作者：
Wakisaka, Satoshi
中科院分区：
文献类型：
--
作者：
Kawai, Shinji;Michikami, Ikumi;Wakisaka, Satoshi
成骨细胞分泌基质囊泡和蛋白质到骨表面，但这种分泌系统的分子机制尚不清楚。本研究结果揭示了成骨细胞中参与细胞外基质分泌调控的重要基因的作用。我们特别关注“可溶性N-乙基马来酰亚胺敏感因子（NSF）附着蛋白受体”（SNARE）基因，并确定了成骨细胞质膜基底外侧显著的突触融合蛋白4a（Stx 4a）表达。此外，发现Stx 4a过表达增加成骨细胞的矿化，而Stx 4a敲低降低矿化水平。此外，BMP-4和IGF-1诱导Stx 4a定位到细胞的基底外侧。为了研究Stx 4a在成骨细胞中的功能，我们产生了成骨细胞特异性Stx 4a条件性敲除小鼠，其表现出由于基质分泌减少而导致的骨质减少表型。外周定量计算机断层扫描（pQCT）显示的骨密度在Stx 4a成骨细胞特异性缺陷小鼠的股骨干骺端和骨干区域降低，而微计算机断层扫描（mu CT）和骨组织形态计量学分析显示的骨参数在小梁骨中也降低。此外，这些小鼠的原代颅骨细胞显示矿化减少和基质囊泡分泌减少。我们的研究结果表明，Stx 4a在成骨细胞产生骨基质中起着关键作用。(C)2016年美国骨与矿物质研究学会。
Osteoblasts secrete matrix vesicles and proteins to bone surfaces, but the molecular mechanisms of this secretion system remain unclear. The present findings reveal the roles of important genes in osteoblasts involved in regulation of extracellular matrix secretion. We especially focused on "soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor" (SNARE) genes and identified notable Syntaxin 4a (Stx4a) expression on the basolateral side of the plasma membrane of osteoblasts. Furthermore, Stx4a overexpression was found to increase mineralization by osteoblastic cells, whereas Stx4a knockdown reduced levels of mineralization. Also, BMP-4 and IGF-1 induced the localization of Stx4a to the basolateral side of the cells. To examine the function of Stx4a in osteoblasts, we generated osteoblast-specific Stx4a conditional knockout mice, which demonstrated an osteopenic phenotype due to reduced matrix secretion. Bone mineral density, shown by peripheral quantitative computed tomography (pQCT), was reduced in the femur metaphyseal and diaphyseal regions of Stx4a osteoblast-specific deficient mice, whereas bone parameters, shown by micro-computed tomography (mu CT) and bone histomorphometric analysis, were also decreased in trabecular bone. In addition, primary calvarial cells from those mice showed decreased mineralization and lower secretion of matrix vesicles. Our findings indicate that Stx4a plays a critical role in bone matrix production by osteoblasts. (C) 2016 American Society for Bone and Mineral Research.