title: Vitamin a is a negative regulator of osteoblast mineralization.
abstract: An excessive intake of vitamin A has been associated with an increased risk of fractures in humans. In animals, a high vitamin A intake leads to a reduction of long bone diameter and spontaneous fractures. Studies in rodents indicate that the bone thinning is due to increased periosteal bone resorption and reduced radial growth. Whether the latter is a consequence of direct effects on bone or indirect effects on appetite and general growth is unknown. In this study we therefore used pair-feeding and dynamic histomorphometry to investigate the direct effect of a high intake of vitamin A on bone formation in rats. Although there were no differences in body weight or femur length compared to controls, there was an approximately halved bone formation and mineral apposition rate at the femur diaphysis of rats fed vitamin A. To try to clarify the mechanism(s) behind this reduction, we treated primary human osteoblasts and a murine preosteoblastic cell line (MC3T3-E1) with the active metabolite of vitamin A; retinoic acid (RA), a retinoic acid receptor (RAR) antagonist (AGN194310), and a Cyp26 inhibitor (R115866) which blocks endogenous RA catabolism. We found that RA, via RARs, suppressed in vitro mineralization. This was independent of a negative effect on osteoblast proliferation. Alkaline phosphatase and bone gamma carboxyglutamate protein (Bglap, Osteocalcin) were drastically reduced in RA treated cells and RA also reduced the protein levels of Runx2 and Osterix, key transcription factors for progression to a mature osteoblast. Normal osteoblast differentiation involved up regulation of Cyp26b1, the major enzyme responsible for RA degradation, suggesting that a drop in RA signaling is required for osteogenesis analogous to what has been found for chondrogenesis. In addition, RA decreased Phex, an osteoblast/osteocyte protein necessary for mineralization. Taken together, our data indicate that vitamin A is a negative regulator of osteoblast mineralization.
authors: Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University, Uppsala, Sweden.
authors: Thomas
authors: T
authors: Lind
authors: Anders
authors: A
authors: Sundqvist
authors: Lijuan
authors: L
authors: Hu
authors: Gunnar
authors: G
authors: Pejler
authors: Göran
authors: G
authors: Andersson
authors: Annica
authors: A
authors: Jacobson
authors: Håkan
authors: H
authors: Melhus
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D002113:Calcification, Physiologic / Q000187:drug effects*; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D005269:Femur / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction / Q000187:drug effects; D000076182:Sp7 Transcription Factor; D013876:Thiophenes / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014801:Vitamin A / Q000009:adverse effects* / Q000494:pharmacology; D014815:Vitamins / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: C121616:4-((4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl)ethynyl)benzoic acid; D001565:Benzoates; D052160:Benzothiazoles; D050659:Core Binding Factor Alpha 1 Subunit; D065607:Cytochrome P-450 Enzyme Inhibitors; C493709:RUNX2 protein, human; D018168:Receptors, Retinoic Acid; C493717:Runx2 protein, rat; D000076182:Sp7 Transcription Factor; C478163:SP7 protein, human; C495181:Sp7 protein, rat; D013876:Thiophenes; D014157:Transcription Factors; D014230:Triazoles; D014815:Vitamins; D014801:Vitamin A; D003577:Cytochrome P-450 Enzyme System; C000607079:CYP26B1 protein, human; C000607082:Cyp26b1 protein, rat; D000072516:Retinoic Acid 4-Hydroxylase; C406527:R 115866