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

骨细胞通过骨的突起和小管形成网络。据报道，骨细胞可刺激或抑制骨形成，并抑制骨吸收。然而，由于这些功能是从骨细胞死亡后的骨变化中估计的，因此必须考虑坏死后微环境中的炎症反应。骨细胞网络具有理想的解剖结构，被认为是一个力学传感器和力学信号转导系统。我们建立了两个品系的成骨细胞特异性BCL 2转基因小鼠。出乎意料的是，BCL 2在成骨细胞中的过表达最终导致骨细胞凋亡。骨细胞，其中有一个过程的数量减少，逐渐死亡与凋亡的结构改变，死亡的骨细胞达到75%，在4个月的年龄。我们确定了一种新的机械应力负责分子，丙酮酸脱氢酶激酶4（Pdk 4），其表达上调成骨细胞在卸载条件下，使用BCL 2转基因小鼠与破坏骨细胞功能。Pdk 4 ^<-/->小鼠的骨发育正常并得以维持。然而，在卸载时，由于野生型小鼠中破骨细胞生成和Rankl表达的增强，骨量减少，但在Pdk 4 <-/->小鼠中没有。在存在M-CSF和RANKL的情况下，Pdk 4 ^<-/->骨髓来源的单核细胞/巨噬细胞谱系细胞（Bcls）的破骨细胞分化受到抑制，并且在野生型Bcls和Pdk 4 ^<-/->成骨细胞的共培养物中破骨细胞生成受损，其中Rankl表达和启动子活性降低。此外，将Pdk 4引入Pdk 4-β-受体和成骨细胞增强了破骨细胞生成和Rankl表达并激活了Rankl启动子。这些发现表明Pdk 4通过促进破骨细胞生成在卸载时的骨丢失中起重要作用。

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.