High dose 1,25(OH)2D3 inhibits osteoblast mineralization in vitro.
Vitamin D is essential for optimal calcium absorption needed for maintaining             normal bone mineral density (BMD). Consequently, vitamin D-deficiency leads to             poorly mineralized bone with diminished strength and load bearing capacity. Surprisingly,             several animal and clinical studies have identified suppressive effects of high             dose vitamin D supplementation on bone formation. These data suggest that while             vitamin D is necessary for basal bone homeostasis, excessive concentrations may             be detrimental to the skeleton. To further examine the direct effects of high             dose vitamin D on the function of osteoblasts we differentiated primary osteoblast             precursors and MC3T3 preosteoblastic cells, in the presence of supraphysiological             doses of the active metabolite, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. In vitro             osteoblast mineralization was potently suppressed by high dose 1,25(OH)2D3. To             investigate the mechanism we used a bioassay to examine nuclear factor-κB (NF-κB)             activation in MC3T3 cells. Although NF-κB agonists are generally potent inhibitors             of osteoblast differentiation, surprisingly, 1,25(OH)2D3 dose-dependently suppressed,             rather than stimulated, NF-κB activation. Interestingly, 1,25(OH)2D3 also suppressed             Smad activation induced by the osteoblast commitment and differentiation factors             transforming growth factor-β (TGF-β) and bone morphogenetic protein 2 (BMP2),             which may account for the inhibitory activities of 1,25(OH)2D3 on mineralization.             Our data suggest that vitamin D has complex pleiotropic effects on osteoblast             signal transduction. As the net balance of high dose 1,25(OH)2D3 appears to be             an inhibitory action on osteoblasts, our data suggest that the therapeutic value             of vitamin D to maximize bone mass through indirect actions on calcium absorption             may need to be carefully balanced with potential inhibitory direct effects on             mineralizing cells. Our data suggest that indiscriminate over-dosing may be detrimental             to bone formation and optimal concentrations need to be established for humans             in vivo.
Division of Endocrinology and Metabolism and Lipids, Department                     of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Masayoshi
M
Yamaguchi
M Neale
MN
Weitzmann
D016475:3T3 Cells; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects*; D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D050071:Bone Density Conservation Agents; D055396:Bone Morphogenetic Protein 2; D016328:NF-kappa B; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D002117:Calcitriol