| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥300,000)
Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2010: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
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.
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