title: Osteoblast-Specific γ-Glutamyl Carboxylase-Deficient Mice Display Enhanced Bone Formation With Aberrant Mineralization.
abstract: Vitamin K is a fat-soluble vitamin that is necessary for blood coagulation. In addition, it has bone-protective effects. Vitamin K functions as a cofactor of γ-glutamyl carboxylase (GGCX), which activates its substrates by carboxylation. These substrates are found throughout the body and examples include hepatic blood coagulation factors. Furthermore, vitamin K functions as a ligand of the nuclear receptor known as steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR). We have previously reported on the bone-protective role of SXR/PXR signaling by demonstrating that systemic Pxr-knockout mice displayed osteopenia. Because systemic Ggcx-knockout mice die shortly after birth from severe hemorrhage, the GGCX-mediated effect of vitamin K on bone metabolism has been difficult to evaluate. In this work, we utilized Ggcx-floxed mice to generate osteoblast-specific GGCX-deficient (Ggcx(Δobl/Δobl)) mice by crossing them with Col1-Cre mice. The bone mineral density (BMD) of Ggcx(Δobl/Δobl) mice was significantly higher than that of control Col1-Cre (Ggcx(+/+)) mice. Histomorphometrical analysis of trabecular bones in the proximal tibia showed increased osteoid volume and a higher rate of bone formation in Ggcx(Δobl/Δobl) mice. Histomorphometrical analysis of cortical bones revealed a thicker cortical width and a higher rate of bone formation in Ggcx(Δobl/Δobl) mice. Electron microscopic examination revealed disassembly of mineralized nodules and aberrant calcification of collagen fibers in Ggcx(Δobl/Δobl) mice. The mechanical properties of bones from Ggcx(Δobl/Δobl) mice tended to be stronger than those from control Ggcx(+/+) mice. These results suggest that GGCX in osteoblasts functions to prevent abnormal mineralization in bone formation, although this function may not be a prerequisite for the bone-protective effect of vitamin K.
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Azuma
authors.affiliation: Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Shiba
authors.affiliation: Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Urano
authors.affiliation: Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors.forename: Kuniko
authors.initials: K
authors.lastname: Horie-Inoue
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Toranomon Hospital, Tokyo, Japan.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ouchi
authors.affiliation: Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Amizuka
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.|Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D002113:Calcification, Physiologic; D019735:Carbon-Carbon Ligases / Q000172:deficiency* / Q000378:metabolism; D005269:Femur / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009928:Organ Specificity; D010006:Osteoblasts / Q000201:enzymology* / Q000473:pathology; D010012:Osteogenesis; D013977:Tibia / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure
chemical_list: D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase
keywords: BONE FORMATION; GGCX; OSTEOBLASTS; VITAMIN K