Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 30, Issue 7, Pages 1245-1254Publisher
WILEY-BLACKWELL
DOI: 10.1002/jbmr.2463
Keywords
VITAMIN K; GGCX; BONE FORMATION; OSTEOBLASTS
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology
- Japan Society for the Promotion of Science
- Ministry of Health, Labor, and Welfare
- Novartis Foundation for Gerontological Research
- Grants-in-Aid for Scientific Research [26670797, 25293214, 23249040] Funding Source: KAKEN
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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 -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(obl/obl)) mice by crossing them with Col1-Cre mice. The bone mineral density (BMD) of Ggcx(obl/obl) 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(obl/obl) mice. Histomorphometrical analysis of cortical bones revealed a thicker cortical width and a higher rate of bone formation in Ggcx(obl/obl) mice. Electron microscopic examination revealed disassembly of mineralized nodules and aberrant calcification of collagen fibers in Ggcx(obl/obl) mice. The mechanical properties of bones from Ggcx(obl/obl) 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. (c) 2015 American Society for Bone and Mineral Research. (c) 2015 American Society for Bone and Mineral Research.
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