title: Enhanced and suppressed mineralization by acetoacetate and β-hydroxybutyrate in osteoblast cultures.
abstract: It is known that diabetes aggravates alveolar bone loss associated with periodontitis. While insulin depletion increases the blood concentration of ketone bodies, i.e., acetoacetate and β-hydroxybutyrate, their roles in bone metabolism have not been much studied until today. We investigated the effects of acetoacetate and β-hydroxybutyrate on mineralization of extracellular matrix in cultures of mouse osteoblastic MC3T3-E1 cells and primary mouse osteoblasts in the presence and absence of bone morphogenetic protein-2. Acetoacetate potentiated alkaline phosphatase activity in MC3T3-E1 cells in a concentration-dependent manner, ranging from physiological to pathological concentrations (0.05-5 mmol/L). In contrast, β-hydroxybutyrate lowered it in the same experimental settings. Mineralization in cultures of these cells was also up-regulated by acetoacetate and down-regulated by β-hydroxybutyrate. Similar results were obtained in cultures of mouse primary osteoblasts. Neither alkaline phosphatase mRNA nor its protein expression in MC3T3-E1 cells was affected by acetoacetate or β-hydroxybutyrate, indicating that these ketone bodies control the enzyme activity of alkaline phosphatase in osteoblasts and hence their mineralization bi-directionally. Finally, either gene silencing of monocarboxylate transporter-1, a major transmembrate transporter for ketone bodies, nullified the effects of ketone bodies on alkaline phosphatase activity in MC3T3-E1 cells. Collectively, we found that ketone bodies bidirectionally modulates osteoblast functions, which suggests that ketone bodies are important endogenous factors that regulate bone metabolism in both physiological and pathological situations.
authors.affiliation: Department of Biochemistry, Showa University School of Dentistry, Tokyo 142-8555, Japan; Department of Periodontology, Showa University School of Dentistry, Tokyo 145-8515, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Biochemistry, Showa University School of Dentistry, Tokyo 142-8555, Japan. Electronic address: kyoshimura@dent.showa-u.ac.jp.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Biochemistry, Showa University School of Dentistry, Tokyo 142-8555, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Biochemistry, Showa University School of Dentistry, Tokyo 142-8555, Japan; Department of Oral and Maxillofacial Surgery, Tokyo Medical University, Tokyo 160-0023, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kaneko
authors.affiliation: Department of Oral and Maxillofacial Surgery, Tokyo Medical University, Tokyo 160-0023, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Chikazu
authors.affiliation: Department of Periodontology, Showa University School of Dentistry, Tokyo 145-8515, Japan.
authors.forename: Matsuo
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Biochemistry, Showa University School of Dentistry, Tokyo 142-8555, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Kamijo
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism*; D000090:Acetoacetates / Q000378:metabolism*; D000469:Alkaline Phosphatase / Q000378:metabolism*; D000818:Animals; D002113:Calcification, Physiologic; D002460:Cell Line; D002478:Cells, Cultured; D007657:Ketone Bodies / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*
chemical_list: D000090:Acetoacetates; D007657:Ketone Bodies; C016635:acetoacetic acid; D000469:Alkaline Phosphatase; D020155:3-Hydroxybutyric Acid
keywords: Alkaline phosphatase; Ketone bodies; Mineralization; Osteoblasts