title: Nongenomic effects of 1α,25-dihydroxyvitamin D3on cartilage formation deduced from comparisons between Cyp27b1 and Vdr knockout mice.
abstract: The active form of vitamin D, 1α,25-dihydroxyvitamin D3(1α,25D3), plays an important role in the maintenance of calcium (Ca) homeostasis, bone formation, and cell proliferation and differentiation via nuclear vitamin D receptor (VDR). It is formed by the hydroxylation of vitamin D at the 1α position by 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) in the kidney. However, Cyp27b1-/-mice, deficient in CYP27B1, and VDR-deficient mice (Vdr-/-) have not been extensively examined, particularly in a comparative framework. To clarify the physiological significance of 1α,25D3and VDR, we produced Cyp27b1-/-mice and compared their phenotypes with those of Vdr-/-mice. Cyp27b1-/-mice exhibited hypocalcemia, growth defects, and skeletogenesis dysfunction, similar to Vdr-/-mice. However, unlike Cyp27b1-/-mice, Vdr-/-mice developed alopecia. Cyp27b1-/-mice exhibited cartilage mass formation and had difficulty walking on hindlimbs. Furthermore, a phenotypic analysis was performed on Cyp27b1-/-mice provided a high Ca diet to correct for the Ca metabolic abnormality. In addition, the effects of 1α,25D3that are not mediated by Ca metabolic regulatory activity were investigated. Even when the blood Ca concentration was corrected, abnormalities in growth and cartilage tissue formation did not improve in Cyp27b1-/-mice. These results suggested that 1α,25D3directly controls chondrocyte proliferation and differentiation. Using Cyp27b1-/-mice produced in this study, we can analyze the physiological effects of novel vitamin D derivatives in the absence of endogenous 1α,25D3. Accordingly, this study provides a useful animal model for the development of novel vitamin D formulations that are effective for the treatment and prevention of osteoporosis.
authors.affiliation: Laboratory of Biochemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, 337-8570, Japan; Department of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan. Electronic address: hirotay@shibaura-it.ac.jp.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Hirota
authors.affiliation: Department of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan.
authors.forename: Shino
authors.initials: S
authors.lastname: Mimatsu
authors.affiliation: Department of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Sawada
authors.affiliation: Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, 939-0398, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaki
authors.affiliation: International Institute of Active Vitamin D Analogs, 35-6, Sankeidai, Mishima, Shizuoka, 411-0017, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Kubodera
authors.affiliation: Department of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Kamao
authors.affiliation: Department of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsugawa
authors.affiliation: Laboratory of Organic Synthesis and Medicinal Chemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama, 337-8570, Japan.
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Suhara
authors.affiliation: Department of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan. Electronic address: t-okano@kobepharma-u.ac.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Okano
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D000505:Alopecia / Q000235:genetics; D000818:Animals; D001835:Body Weight; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism; D002118:Calcium / Q000097:blood / Q000378:metabolism; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology; D005260:Female; D005269:Femur / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis; D010024:Osteoporosis / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism; D010641:Phenotype; D010758:Phosphorus / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism
chemical_list: D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; C076210:1 alpha-(hydroxymethyl)-25-hydroxyvitamin D3; D010758:Phosphorus; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium
keywords: Bone remodeling; CYP27B1; Genomic action; Knockout mice; VDR; Vitamin D