Osteoblast‐Specific γ‐Glutamyl Carboxylase‐Deficient Mice Display Enhanced Bone Formation With Aberrant Mineralization. (July 2015)

• Record Type: Journal Article
• Authors: Azuma, Kotaro; Shiba, Sachiko; Hasegawa, Tomoka; Ikeda, Kazuhiro; Urano, Tomohiko; Horie‐Inoue, Kuniko; Ouchi, Yasuyoshi; Amizuka, Norio; Inoue, Satoshi
• Is Part Of: Journal of bone and mineral research. Volume 30:Number 7(2015:Jul.)
• Page Start: 1245
• Page End: 1254
• Publication Date: 2015-07
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2463
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2463-sec-0001" sec-type="section"> <p>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 <italic>Pxr</italic>‐knockout mice displayed osteopenia. Because systemic <italic>Ggcx</italic>‐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 <italic>Ggcx</italic>‐floxed mice to generate osteoblast‐specific GGCX‐deficient (<italic>Ggcx<sup>Δobl/Δobl</sup></italic>) mice by crossing them with Col1‐Cre mice. The bone mineral density (BMD) of <italic>Ggcx<sup>Δobl/Δobl</sup></italic> mice was significantly higher than that of control Col1‐Cre (<italic>Ggcx<sup>+/+</sup></italic>) mice. Histomorphometrical analysis of trabecular bones in the proximal tibia showed increased osteoid volume and a higher rate of bone formation in <italic>Ggcx<sup>Δobl/Δobl</sup></italic> mice. Histomorphometrical analysis of cortical bones revealed a thicker cortical width and a higher rate of bone formation in <italic>Ggcx<sup>Δobl/Δobl</sup></italic> mice. Electron microscopic examination revealed disassembly of mineralized nodules and aberrant calcification of collagen fibers in <italic>Ggcx<sup>Δobl/Δobl</sup></italic> mice. The mechanical properties of bones from <italic>Ggcx<sup>Δobl/Δobl</sup></italic> mice tended to be stronger than those from control <italic>Ggcx<sup>+/+</sup></italic> 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. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.</p> </sec> </abstract>