title: Pyruvate dehydrogenase kinase 4 induces bone loss at unloading by promoting osteoclastogenesis.
abstract: Disuse osteoporosis, which occurs commonly in prolonged bed rest and immobilization, is becoming a major problem in modern societies; however, the molecular mechanisms underlying unloading-driven bone loss have not been fully elucidated. The osteocyte network is considered to be an ideal mechanosensor and mechanotransduction system. We searched for the molecules responsible for disuse osteoporosis using BCL2 transgenic mice, in which the osteocyte network was disrupted. Pyruvate dehydrogenase kinase 4 (Pdk4), which inactivates pyruvate dehydrogenase complex (PDC), was upregulated in femurs and tibiae of wild-type mice but not of BCL2 transgenic mice after tail suspension. 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.
authors.affiliation: Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Wang
authors.forename: Wenguang
authors.initials: W
authors.lastname: Liu
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Masuyama
authors.forename: Ryo
authors.initials: R
authors.lastname: Fukuyama
authors.forename: Masako
authors.initials: M
authors.lastname: Ito
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hisato
authors.initials: H
authors.lastname: Komori
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Murakami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Moriishi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Riko
authors.initials: R
authors.lastname: Kitazawa
authors.forename: Carolina A
authors.initials: CA
authors.lastname: Yoshida
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawai
authors.forename: Shinichi
authors.initials: S
authors.lastname: Izumi
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Komori
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D002454:Cell Differentiation; D015870:Gene Expression; D019417:Hindlimb Suspension; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046228:Microarray Analysis; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D010024:Osteoporosis / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D053245:RANK Ligand; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4