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Molecular mechanism of osteocyte lacunar canalicular system on PTH and bone quality

骨细胞腔隙微管系统对PTH和骨质量影响的分子机制

基本信息

批准号：
18390487
负责人：
AMIZUKA Norio
金额：
$ 11.17万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390487/
关键词：
anatomy cell biology animal model bone parathyroid hormone

项目摘要

The aim of this research project is to clarify 1) osteocytic function of mineral regulation in bone, 2) effects of osteocytelacunar canalicular system onto bone quality, and 3) PTH action on the transport of bone mineral. (1) We generated a transgenic mouse expressing osteocytes-specific diphtheria toxin (DT) receptor. Following a injection of DT, 70%-80% of the osteocytes were dead, resulting in loss of bone minerals, intracortical porosity and microfractures (bone mineral regulation). This transgenic mouse was also resistant to unloading-induced bone loss, suggesting the osteocytic mechanotransduction. Both of bone mineral regulation and mechanotransduction by osteocytes appears to affect bone quality. (2) Using Schoen's silver staining, we have examined the distribution of the osteocytic lacunar canalicular system (OLCS) in mouse bones. Trabecular bones with high bone turnover displayed osteocytic cytoplasmic processes without any perceptible alignment. Also, many plump osteocytes w … More ere embedded in the mineralized bone in a disorderly manner. However, well-remodeled bone (epiphyseal trabecules and cortical bone), showed osteocytes with their spindle shape, organized so as to parallel the longitudinal axis of trabecular bone. Given the data gathered, the OLCS appears to assume an organized, probably function-related spatial distribution as normal bone remodeling goes on. OLCS seems to be a cellular factor to affect bone quality. (3) Finally, we have examined whether osteocytic osteolysis would occur after PTH administration. When injecting PTH, the size of osteocytic lacunae enlarged and the expression of sclerostin was reduced in the wild-type mice, but no such changes in the c-fos-/- mice in which osetoclastogenesis is totally inhibited. C-fos-/- mice showed disrupted OCLS, while wild-type mice had well-organized, functional OLCS, as described above. Thus, PTH signaling appears to be transduced from PTH receptor-bearing osteoblasts into osteocytes by means of functional OLCS, resulting in osteocytic ostelysis. Less

该研究项目的目的是阐明 1) 骨中矿物质调节的骨细胞功能，2) 骨细胞腔小管系统对骨质量的影响，以及 3) PTH 对骨矿物质运输的作用。 (1)我们产生了表达骨细胞特异性白喉毒素（DT）受体的转基因小鼠。注射 DT 后，70%-80% 的骨细胞死亡，导致骨矿物质流失、皮质内孔隙和微骨折（骨矿物质调节）。这种转基因小鼠还能够抵抗卸载引起的骨质流失，这表明骨细胞的机械传导作用。骨矿物质调节和骨细胞的机械传导似乎都会影响骨质量。 (2)利用Schoen银染法，我们检查了小鼠骨骼中骨细胞腔隙小管系统(OLCS)的分布。具有高骨转换率的骨小梁显示出骨细胞的细胞质过程，没有任何可察觉的排列。此外，许多饱满的骨细胞以无序的方式嵌入矿化骨中。然而，重塑良好的骨（骨骺小梁和皮质骨）显示出具有纺锤形的骨细胞，其组织方式与骨小梁的纵轴平行。根据收集到的数据，随着正常骨重塑的进行，OLCS 似乎呈现出一种有组织的、可能与功能相关的空间分布。 OLCS 似乎是影响骨质量的细胞因素。 (3)最后，我们检查了PTH给药后是否会发生骨细胞骨质溶解。注射PTH后，野生型小鼠骨细胞腔隙增大，硬化蛋白表达减少，而破骨细胞生成完全受到抑制的c-fos-/-小鼠则没有这种变化。如上所述，C-fos-/- 小鼠表现出破坏的 OCLS，而野生型小鼠则具有组织良好、功能齐全的 OLCS。因此，PTH 信号似乎通过功能性 OLCS 从携带 PTH 受体的成骨细胞转导至骨细胞，导致骨细胞骨溶解。较少的