The molecule mechanism of the bone mass regulation by a bone cell network

骨细胞网络调节骨量的分子机制

基本信息

批准号：
22659331
负责人：
KOMORI Toshihisa
金额：
$ 2.05万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Challenging Exploratory Research
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

项目摘要

Osteocytes form a network through processes and canaliculi throughout bone. Osteocytes have been reported to stimulate or inhibit bone formation and to inhibit bone resorption. As these functions have been estimated from the bone changes after osteocyte death, however, an inflammatory reaction in the microenvironment after necrosis has to be considered. The osteocyte network is thought to be a mechanosensor and mechanotransduction system due to its ideal anatomical feature. We established two lines of osteoblast-specific BCL2 transgenic mice. Unexpectedly, overexpression of BCL2 in osteoblasts eventually caused osteocyte apoptosis. Osteocytes, which had a reduced number of processes, gradually died with apoptotic structural alterations, and dead osteocytes reached 75% at 4 months of age. We identified a novel mechanical stress-responsible molecule, pyruvate dehydrogenase kinase 4(Pdk4), whose expression was upregulated in osteoblasts at the unloaded condition, using BCL2 transgenic mice with the disrupted osteocyte function. Bone in Pdk4^<-/-> mice developed normally and was maintained. At unloading, however, bone mass was reduced due to enhanced osteoclastogenesis and Rankl expression in wild-type mice but not in Pdk4^<-/-> mice. Osteoclast differentiation of Pdk4^<-/-> bone marrow-derived monocyte/ macrophage lineage cells(BMMs) in the presence of M-CSF and RANKL was suppressed, and osteoclastogenesis was impaired in the coculture of wild-type BMMs and Pdk4^<-/-> osteoblasts, in which Rankl expression and promoter activity were reduced. Further, introduction of Pdk4 into Pdk4^<-/-> BMMs and osteoblasts enhanced osteoclastogenesis and Rankl expression and activated Rankl promoter. These findings indicate that Pdk4 plays an important role in bone loss at unloading by promoting osteoclastogenesis.

骨细胞通过整个骨骼的过程和运河形成网络。据报道，骨细胞刺激或抑制骨骼形成并抑制骨吸收。但是，由于这些功能是从骨细胞死亡后的骨变化中估计的，但是必须考虑坏死后微环境的炎症反应。由于其理想的解剖学特征，骨细胞网络被认为是机械传感器和机械转移系统。我们建立了两条成骨细胞特异性BCL2转基因小鼠。出乎意料的是，成骨细胞中Bcl2的过表达最终会导致骨细胞凋亡。骨细胞的过程减少了，由于凋亡结构改变而逐渐死亡，而死骨细胞在4个月大时达到了75％。我们鉴定了一种新型的机械应激分子丙酮酸脱氢酶激酶4（PDK4），其表达在卸载条件下在成骨细胞中上调，使用BCL2转基因小鼠具有破坏的骨细胞功能。 Pdk4^< - / - >小鼠中的骨骼正常发育并保持维持。然而，在卸载时，由于野生型小鼠的破骨细胞生成和RANKL的表达增加而减少了骨骼量，但在Pdk4^< - / - >小鼠中没有减少。在M-CSF和RANKL存在下，PDK4^< - / - >骨髓衍生的单核细胞/巨噬细胞谱系细胞（BMM）的破骨细胞分化被抑制了，在野生型BMM和PDK4^<-/pdk4^<-/pdk4^<---> <---> <---> <---> s的共培养物中，骨化造成了骨化造成损害。减少。此外，将PDK4引入Pdk4^< - / - > BMM和成骨细胞增强了破骨质构成和RANKL表达以及激活的RANKL启动子。这些发现表明，PDK4通过促进破骨细胞生成而在卸载时起着重要作用。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of osteoblast differentiation and bone angiogenesis by RUNX2 and SP7.

RUNX2 和 SP7 对成骨细胞分化和骨血管生成的调节。

DOI：
发表时间：
2010
期刊：
影响因子：
0
作者：
Mikasa M;Rokutanda S;Komori H;Ito K;Tsang YS;Date Y;Yoshida CA;Komori T;Moriishi T;Wang Y;Komori T;Hisa I;Ann EJ;Mikasa M;Komori T;小守壽文;王宇英;小守壽文
通讯作者：
小守壽文

荷重感知遺伝子

负荷传感基因