Besides serving as an intermediate in retinoic acid formation, retinal has been shown to be present at biologically active concentrations in fat tissue, where it antagonizes PPAR activity, inhibits adipogenesis, and improves insulin sensitivity (49). 1960 Mar; 87:9–12. There are fewer studies on the effects of vitamin A on bone formation than on resorption. Vitamin A deficiency is still a problem in developing countries, and supplementation with vitamin A has had an enormous worldwide impact, improving vision and immune functions and saving countless lives at a minimal cost per patient (52). 1978. Multinucleated osteoclasts are formed by proliferation, differentiation, and fusion of mononuclear progenitor cells of myeloid hematopoietic origin (Figure 4A). 1. Hepatocytes take up the remnants by receptor-mediated endocytosis, and the retinyl esters are hydrolyzed (18). Furthermore, an association between low vitamin D and high serum retinol levels leading to an increased risk of osteoporosis has been reported recently in a cross-sectional study of 232 postmenopausal Spanish women (116). At the endosteal surface of cortical bone, it seems as if vitamin A decreases osteoclasts, which may be due to decreased numbers of microvessels in bone marrow due to hypoxia. Canon E, Cosgaya JM, Scsucova S, Aranda A. Aggarwal S, Kim SW, Cheon K, Tabassam FH, Yoon JH, Koo JS. The breakdown (resorption) of bone is initiated by dissolution of bone mineral crystals by a lowered pH (approximately 4.5). ATRA and BMP-2 have also been found to act synergistically to stimulate alkaline phosphatase activity in 3T3-F442A cells. Oxford University Press is a department of the University of Oxford. The in vivo physiological level of ATRA in human serum is approximately 2–20 nmol/L (150-fold lower than retinol) (142). ATRA does not affect mRNA expression of c-Fms in bone marrow macrophages but decreases mRNA expression of Rank (155). Differences were also noted in the number of osteoclasts. Although there was no association between osteoporosis and retinol or total serum vitamin A (retinol plus retinyl esters), retinyl esters as a percentage of total vitamin A tended to be associated (P = .070) with osteoporosis (99). 2017 May 21;6(2):37. doi: 10.3390/antiox6020037. Furthermore, ATRA caused a transient decrease of Opg mRNA with no effect on OPG protein. Increased osteoclastic resorption of periosteal bone is a well-documented in vitro consequence of excess vitamin A. Calvarial bone is considered to be a good model of periosteal resorption of cortical bone, and it has been established that ATRA is a good in vitro stimulator of RANKL, osteoclastogenesis, and resorption in cultured calvarial bones. HUANG HS, GOODMAN DS. Few foods are naturally rich in vitamin D. It was observed that the medullary area was increased and cortical thickness decreased in young rats, but no such effects could be seen in middle-aged rats. Reduced bone formation was observed (173). In the fasting state, most retinoid in the circulation (>95%) is suggested to exist as retinol-RBP; however, in the postprandial state, chylomicron retinyl esters can account for a significant proportion of the total circulating retinoid (22). Nongenomic effects of ATRA include cytoplasmic regulation of translation and activation of signaling pathways causing phosphorylation of CREB and transcription of genes containing CRE. One is vision, because vitamin A is the precursor for the formation of 11-cis-retinal (2, 3). These experiments suggest that RARα is responsible for the inhibition of osteoclastogenesis stimulated by RANKL. Thus, the possibility exists that ATRA might increase RANKL and bone resorption by indirect mechanisms, perhaps mediated by cytokines capable of stimulating RANKL and bone resorption. Absorption can be reduced when there is a high amount of intracellular glucose (interferes with ascorbate transporters). TREM-2, triggering receptor expressed on myeloid cells 2. Importantly, only 99% of ingested cobalamin requires IF for absorption. Of this, about 70–75% is thought to be due to the intake of preformed vitamin A. Dietary retinyl esters are hydrolyzed by pancreatic and intestinal enzymes, and the free retinol is taken up by intestinal mucosal cells (ie, enterocytes; Figure 2) (14, 15). These vitamins tend to be abundant in fatty foods and you can enhance their absorption by adding fat or oil to an otherwise low-fat meal. Osteoblasts control differentiation of mononuclear progenitor cells to mature, multinucleated osteoclasts by expressing M-CSF and RANKL, which expand the number of myeloid progenitor cells and promote their differentiation, respectively. . In the cytosol, the dimeric transcription factor NF-κB is bound to its inhibitor, IκBα; activation of IKKβ by RANK signaling leads to phosphorylation of IκBα and dissociation from NF-κB, which then translocates to the nucleus and binds NF-κB response elements in DNA. Effects of vitamin A on bone formation have not been studied in as great a detail and are not as well characterized as effects on bone resorption. Animal studies using state-of-the-art techniques to access site-specific effects of vitamin A on bone resorption and formation, BMD, and bone fragility also seem clearly warranted, as do studies in mice with cell-specific deletions of different RARs and RXRs. No data on bone formation at trabecular sites were provided, but it seems reasonable to assume that bone formation may have been decreased in trabecular bone because bone mass was not increased, despite the absence of trabecular osteoclasts. Importantly, only 99% of ingested cobalamin requires IF for absorption. Conversion of β-carotene into vitamin A, Mechanisms involved in the intestinal digestion and absorption of dietary vitamin A, The Retinoids, Biology, Chemistry and Medicine, Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone, Biochemical basis for depressed serum retinol levels in transthyretin-deficient mice, Retinoid uptake, metabolism and transport, Handbook of Experimental Pharmacology, The Retinoids, Uptake of postprandial lipoproteins into bone in vivo: impact on osteoblast function, A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A, Plasma delivery of retinoic acid to tissues in the rat, Nuclear retinoid receptors and the transcription of retinoid-target genes, Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis, Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion, Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase, SMRT isoforms mediate repression and anti-repression of nuclear receptor heterodimers, Active repression by unliganded retinoid receptors in development: less is sometimes more, Requirement for RAR-mediated gene repression in skeletal progenitor differentiation, Endogenous retinoids in mammalian growth plate cartilage: analysis and roles in matrix homeostasis and turnover, Mechanisms of transcriptional activation by retinoic acid receptors, The RXR heterodimers and orphan receptors, PPARs: transcription factors controlling lipid and lipoprotein metabolism, The PPARs: from orphan receptors to drug discovery, Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors, Retinoic acid as cause of cell proliferation or cell growth inhibition depending on activation of one of two different nuclear receptors, All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR β, Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism, Examination of nuclear receptor expression in osteoblasts reveals Rorβ as an important regulator of osteogenesis, Rapid effects of retinoic acid on CREB and ERK phosphorylation in neuronal cells, Nonclassical action of retinoic acid on the activation of the cAMP response element-binding protein in normal human bronchial epithelial cells, All-trans-retinoic acid stimulates translation and induces spine formation in hippocampal neurons through a membrane-associated RARα, The nuclear transcription factor RARα associates with neuronal RNA granules and suppresses translation, Retinoic acid-gated sequence-specific translational control by RARα, Retinaldehyde represses adipogenesis and diet-induced obesity, Overview of retinoid metabolism and function, Retinoic acid in development: towards an integrated view, Vitamin A deficiency and attributable mortality among under-5-year-olds, Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid, Vitamin A concentrations in liver determined by isotope dilution assay with tetradeuterated vitamin A and by biopsy in generally healthy adult humans, Serum retinol distributions in residents of the United States: third National Health and Nutrition Examination Survey, 1988–1994, Intraindividual variation in serum retinol concentrations among participants in the third National Health and Nutrition Examination Survey, 1988–1994, Effects of dietary vitamin A deficiency, retinoic acid and protein quantity and quality on serially obtained plasma and liver levels of vitamin A in rats, Assessing vitamin A status: past, present and future, Vitamin A: biomarkers of nutrition for development, The acute and chronic toxic effects of vitamin A, Hepatic hyper-vitaminosis A: importance of retinyl ester level determination, Relationship of vitamin A and vitamin E intake to fasting plasma retinol, retinol-binding protein, retinyl esters, carotene, α-tocopherol, and cholesterol among elderly people and young adults: increased plasma retinyl esters among vitamin A-supplement users, Serum retinyl esters are not associated with biochemical markers of liver dysfunction in adult participants in the third National Health and Nutrition Examination Survey (NHANES III), 1988–1994, Postprandial plasma retinyl ester response is greater in older subjects compared with younger subjects. the absorption, uptake, transport (Figure 1 ... Our data highlight a mechanism by which an enzyme involved in vitamin A metabolism can improve B cell resistance to oncogenesis. 2019 Jul;57(7-8):e23303. Clinical studies have used primarily retinol or retinyl esters to determine vitamin A status; however, in ex vivo and in vitro studies discussed in Sections VIII and IX, the active metabolite ATRA is normally used to study effects of retinoids. Mata-Granados JM, Cuenca-Acevedo JR, Luque de Castro MD, Holick MF, Quesada-Gomez JM. . On the other hand, in C3H10T1/2 cells overexpressing BMP-9, both retinoids have been observed to synergistically potentiate alkaline phosphatase, as well as late mineralization. The serum level of retinol is not associated with hepatic vitamin A storage over a wide range of liver values, and alternative methods, including dose-response tests and isotope dilution assays, have been developed that are better indicators of liver vitamin A reserves (55, 58–60). Extra- and intracellular regulation of osteoclast formation. Information on the effects of vitamin A on bone formation in vitro is still very sparse, and it is not possible to reach a firm conclusion regarding vitamin A action at this time. Inside the hepatocytes, retinyl esters are hydrolyzed to retinol and bound to RBP. To evaluate which of the RARs were required for inhibition of osteoclast differentiation by ATRA, purified macrophages were incubated with RANKL with or without different retinoids. However, there was a drastic reduction in the number of mature osteoclasts at endosteal surfaces, and it was suggested that 8 days of hypervitaminosis A kills endosteal osteoclasts because of hypoxia caused by reduction of blood vessels in the bone marrow close to endosteal surfaces. Stimulation of total TRAP activity by RANKL was abolished by ATRA concentrations at and above 0.04 nm. Solon FS, Solon MS, Mehansho H, et al. One possibility is that osteoclast progenitor cells in the periosteum are different from those in the bone marrow and circulation. The authors ruled out the possibility that the decrease in mineralizing surfaces was a consequence of increased resorption by demonstrating that identical responses were seen when resorption was inhibited by alendronate. Intestinal β-carotene bioconversion in humans is determined by a new single-sample, plasma isotope ratio method and compared with traditional and modified area-under-the-curve methods. Serum levels of osteocalcin were measured at 0 and 6 weeks, and serum bone-specific alkaline phosphatase and N-telopeptide of type 1 collagen were measured at 0, 2, 4, and 6 weeks (103). View. Excessive intake of preformed vitamin A or retinoid derivatives can cause hypervitaminosis A; however, hypervitaminosis A does not occur after increased intake of provitamin A carotenoids such as β-carotene. In the preadipocyte cell line 3T3-F442A, ATRA has been shown to act synergistically with BMP-2 to inhibit insulin-induced adipocyte differentiation, as assessed by Oil Red O staining of lipids and mRNA expression of PPARγ (169). . Vitamin A (retinol) is ingested as either retinyl esters or carotenoids and metabolized to active compounds such as 11- cis -retinal, which is important for vision, and all- trans -retinoic acid, which is the primary mediator of biological actions of vitamin A. Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. The increased fracture risk was attributed to increased retinol intake, with no significantly increased risk of fracture noted for β-carotene intake. Where it is possible to increase dietary fat, this will likely improve the absorption of vitamin A activity from the diet. Dietary uptake and transport of vitamin A. Vitamin A is obtained from the diet as preformed vitamin A (retinyl esters) or as provitamin A (carotenoids, mainly β-carotene). The fatty acid binding protein (FABP) 5 can shuttle ATRA to the nucleus, where it activates PPAR β/δ that bind to PPAR response elements (PPREs) (39, 40). Target cell uptake and intracellular signaling. In cultured neonatal, mouse calvarial bones, we have observed that 0.1 μm ATRA inhibits mRNA expression of the osteoblastic genes Osteocalcin, Akp1, Runx2, and Procollagen α(1) I (89). It appears that the roles retinoids play in osteoblast differentiation and activity in different parts of the skeleton are still elusive, and more studies are needed to assess how these compounds affect the anabolic side of bone remodeling. In Europe, mean vitamin D intake in Scandinavia has been reported to be 200–400 IU/d (118). We seek to define the mechanism(s) of intestinal absorption of dietary carotenoids and their distribution into blood cells. However, increased immunohistochemical staining for osteocalcin was noted at the endosteal surfaces. Furthermore, it was determined that inhibition with ATRA was not due to cell toxicity or inhibition of cell proliferation. In the absence of ligand, the RARs actively repress transcription. Vitamin D 3 is made in the skin from 7-dehydrocholesterol under the influence of UV light. . The authors concluded that ATRA stimulates formation of osteoclasts lacking bone-resorbing activity. Levels of serum retinyl ester (retinyl palmitate), together with serum retinol and β-carotene, were evaluated to determine whether they were predictors of osteoporotic fractures, including hip fracture, in a nested case-control study (312 cases and 934 controls) from a cohort of 2606 women more than 75 years of age in the United Kingdom (107). Medications that you are at least one intact molecule of retinol were found on trabecular bone remain... 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