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

本研究旨在阐明骨细胞在骨矿物质调节中的作用，骨细胞-骨腔隙小管系统对骨质量的影响，以及PTH在骨矿物质转运中的作用。（1）建立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，导致骨矿物质损失、皮质内孔隙和微骨折（骨矿物质调节）。该转基因小鼠也抵抗卸载诱导的骨丢失，提示骨细胞的机械转导。骨矿物质调节和骨细胞的机械传导似乎都影响骨质量。(2)用Schoen银染色法观察了骨细胞腔隙性小管系统（OLCS）在小鼠骨中的分布。高骨转换的松质骨显示骨细胞胞质突起，没有任何可感知的对齐。此外，许多丰满的骨细胞， ...更多信息 以无序的方式嵌入矿化骨中。然而，重塑良好的骨（骨骺骨小梁和皮质骨）显示梭形骨细胞，其组织平行于骨小梁的纵轴。根据所收集的数据，OLCS似乎呈现有组织的，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子。(3)最后，我们研究了PTH给药后是否会发生骨细胞性骨质溶解。当注射PTH时，野生型小鼠骨细胞陷窝的大小扩大，sclerostin的表达减少，但在c-fos-/-小鼠中没有这样的变化，其中破骨细胞生成被完全抑制。如上所述，C-fos-/-小鼠显示出破坏的OCLS，而野生型小鼠具有组织良好的功能性OLCS。因此，PTH信号似乎从PTH受体承载成骨细胞通过功能性OLCS转导到骨细胞中，导致骨细胞溶骨。少

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