Abstract
Excess vitamin A has been associated with decreased cortical bone thickness and increased fracture risk. While most studies in rodents have employed high dosages of vitamin A for short periods of time, we investigated the bone phenotype in mice after longer exposure to more clinically relevant doses. For 1, 4 and 10 weeks, mice were fed a control diet (4.5 µg retinyl acetate/g chow), a diet modeled from the human upper tolerable limit (UTL; 20 µg retinyl acetate/g chow) and a diet three times UTL (supplemented; 60 µg retinyl acetate/g chow). Time-dependent decreases in periosteal circumference and bone mineral content were noted with the supplemented dose. These reductions in cortical bone resulted in a significant time-dependent decrease of predicted strength and a non-significant trend toward reduced bone strength as analyzed by three-point bending. Trabecular bone in tibiae and vertebrae remained unaffected when vitamin A was increased in the diet. Dynamic histomorphometry demonstrated that bone formation was substantially decreased after 1 week of treatment at the periosteal site with the supplemental dose. Increasing amount of vitamin A decreased endocortical circumference, resulting in decreased marrow area, a response associated with enhanced endocortical bone formation. In the presence of bisphosphonate, vitamin A had no effect on cortical bone, suggesting that osteoclasts are important, even if effects on bone resorption were not detected by osteoclast counting, genes in cortical bone or analysis of serum TRAP5b and CTX. In conclusion, our results indicate that even clinically relevant doses of vitamin A have a negative impact on the amount of cortical bone.
Highlights
Vitamin A is an essential nutrient consumed in the diet in the form of retinyl esters or beta carotene
Mice fed control chow containing 4.5 μg retinyl acetate/g chow for 4 weeks had serum levels of 0.84 ± 0.03 μM retinol and 65 ± 17 nM retinyl esters, which is similar to what has been previously observed in C57BL/6 mice (Obrochta et al 2014)
(2) Increases in vitamin A levels time-dependently decreased cortical bone mass resulting in a trend toward decreased strength, (3) supplemental vitamin A diet did not significantly affect trabecular bone phenotype in the tibia or vertebra, (4) increased osteoclastic bone resorption, in combination with an early decrease in periosteal bone formation resulted in decreased periosteal circumference and (5) enhanced endocortical bone formation resulted in decreased marrow area and endocortical circumference
Summary
Vitamin A is an essential nutrient consumed in the diet in the form of retinyl esters or beta carotene. Retinyl esters are transported by chylomicrons to the liver where they are converted to retinol and bound to retinol-binding protein and released into the blood stream. Retinol is converted to all-trans retinoic acid (ATRA), which is the hormonally active form of vitamin A. 239:3 translocates to the nucleus where it ligates primarily to retinoic acid receptors, regulating gene transcription (reviewed in Tata 2002, Conaway et al 2013, Henning et al 2015, Green et al 2016). Vitamin A plays a crucial role in various physiological functions, including immune system regulation, vision and cell growth and differentiation (reviewed in Wiseman et al 2017)
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