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The virulence factor GroEL promotes gelatinase secretion from cells in the osteoblast lineage: Implication for direct crosstalk between bacteria and adult cells. In the bloodstream, chylomicron remnants containing retinyl esters are formed after hydrolysis of chylomicron triglyceride by lipoprotein lipase and addition of apolipoprotein E (13). In agreement with Lind et al (76), increasing vitamin A was associated with decreased trabecular BMD. Interestingly, the authors reported that ATRA could enhance the number of M-CSF-stimulated CD14+ cells in culture. Genes up-regulated at different stages of osteoclast differentiation are shown in squares. Like many malignant tumors, APL is associated with increased angiogenesis most likely due to vascular endothelial growth factor produced by the tumor cells. In addition, circulating levels of TRAP5b and carboxy-terminal collagen crosslinks were decreased, suggesting inhibition of bone resorption; supporting this view, serum RANKL was decreased with no change in OPG. In this investigation, BMD of total hip, femoral neck, and spine at baseline and after 4 years was measured in 570 women and 288 men. Mechanism of conversion of beta-carotene into vitamin A--central cleavage versus random cleavage. Solubility is the primary factor affecting absorption. In the United States, it is not unusual for foods such as cereals to be heavily fortified with vitamin A. Finally, activation by ATRA (1 μm) of mature osteoclasts from egg-laying hens, based on expression of integrin αvβ3 and activation of latent TGFβ, has been reported (165). Higher 25(OH) D levels are found in Canada, where 35% of the population is thought to have levels >75 nmol/L (119). Excessive intake of preformed vitamin A may have been a problem since ancient times (69). This idea was supported by the observation that the decrease in bone mass was reduced by the bisphosphonate, alendronate. Vitamin A is involved in immune function, vision, reproduction, and cellular communication [1,4,5]. The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed? 1 Intestinal absorption in health and disease: micronutrients Although these studies suggest that RARs are present in mature osteoclasts, it is not possible at this time to determine how the receptors might be regulating the bone-resorbing activity of the mature osteoclasts. Bone marrow macrophages express Fabp5 mRNA, and the possibility that ATRA might inhibit osteoclast differentiation by activation of PPARβ/δ was evaluated. The tissue concentrations of ATRA are generally higher than serum concentrations because ATRA is produced locally. Hepatocytes take up the remnants by receptor-mediated endocytosis, and the retinyl esters are hydrolyzed (18). This suggests that the number of bone-forming osteoblasts was reduced, but the activity of the remaining osteoblasts was unaffected, a finding in agreement with in vitro observations suggesting that retinoids inhibit osteoblast differentiation. • The reduction requires a reduced pyridine nucleotide (NADH/NADPH) as a cofactor. Inhibition of osteoclast formation and mRNA expression of Calcr, c-Fos, and Nfatc1 were found with retinoids that are recognized by the 3 RARs: ATRA, 9-cis RA, 13-cis RA, and TTNPB (4-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetra-methyl-2-naphthalenyl)-1-propenyl]benzoic acid). The RDA for vitamin D was increased in 2010 to 600 IU/d (15 μg/d) for individuals 1–70 years of age and 800 IU/d (20 μg/d) for older individuals (112). Acute hypervitaminosis A sickness, characterized by vertigo, vomiting, diarrhea, headache, convulsions, and peeling of the skin, also occurs. . Vitamin B9 is necessary for the cell growth, DNA formation and amino acid metabolism. Evaluation of different promoter usage and alternative splicing has shown that there are at least 2 different isoforms for each isotype (26). and goodmani}, year={2003} } 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). Weston AD, Chandraratna RA, Torchia J, Underhill TM. . The Rancho Bernardo Study, a study of retinol intake and BMD in the elderly, has presented additional evidence in support of bone fragility (94). Retinyl esters and carotenoids are incorporated into chylomicrons that are transported by the lymphatics. View. Macrophages and dendritic cells important for immune function arise from the same bone marrow progenitor pool of cells (131). It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. In another account, acute hypervitaminosis A developing after ingestion of Greenland Husky sled dog liver (also quite high in vitamin A) may have been responsible for the sickness and death that occurred in polar explorers of the Far Eastern Party, part of the 1911–1914 Australasian Antarctic Expedition (72). The development of hypervitaminosis A is rare today. 4, pp. Langlois K, Greene-Finestone L, Little J, Hidiroglou N, Whiting S. Cho DY, Frey RA, Guffy MM, Leipold HW. Treatment of these mice with CD1530 prevented the heterotopic bone formation at the site of adeno-Cre injections. If you contend with low energy or a slow metabolism because of a B12 deficiency, there is hope. Wolf RL, Cauley JA, Pettinger M, et al. When these cells were incubated with 3H-labeled bone particles, the osteoclasts were incapable of degrading the particles. Possible implications for retinoid uptake by cells, Studies on the intestinal absorption of radioactive β-carotene and vitamin A in man. The fusion process is not well understood, but dendritic cell-specific transmembrane protein (Dc-stamp) seems to be involved (135). The prevalence of high serum retinol levels (≥2.8 μmol/L) was 36.4%. In contrast to 1,25(OH)2 D3, ATRA did not induce expression of genes associated with osteoclast differentiation, such as those encoding the calcitonin receptor, TRAP, cathepsin K, Nfatc1, or c-Fos, indicating that ATRA was not able to initiate differentiation of osteoclast progenitor cells. Niemeier A, Niedzielska D, Secer R, et al. Ford JL, Green MH, Green JB, Oxley A, Lietz G. Arch Biochem Biophys. Ingestion of β-carotene is thought to account for over 75% of the provitamin A carotenoid intake in the United States. Mechanism of the biosynthesis of vitamin A from beta-carotene. 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). As regards the very interesting observation of decreased numbers of osteoclasts at the endosteal surfaces of cortical bone reported by Lind et al (76), no such observation was reported by Kneissel et al (75). Vitamin K is … The RARα antagonist, GR110, reversed inhibition by ATRA. Periosteal resorption of cortical bone has also been firmly established as an in vivo consequence of excess vitamin A in experimental animals, as well as in humans. In the Third National Health and Nutrition Examination Survey (NHANES III), the prevalence of serum samples with retinyl ester concentrations >10% of total vitamin A was substantially higher than expected (64). Local concentrations of ATRA in different bone compartments have not been investigated as thoroughly. Up to 1% of free cobalamin is absorbed passively in the terminal ileum. Itt is thus clear that, although a t the time of active absorption a certain proportion of the free vitamin is always present in the mucosac and muscles of the small intestine and in the mesenteric lymph fluid, it is transported from the intestine only as long-chain fatty acid ester, and through the lymphatic route alone. There is a need for stable isotope studies with enhanced sensitivity to expand knowledge of the bioavailability, absorption, disposition, and metabolism of different molecular forms of vitamin K. Another area for future research stems from evidence that common polymorphisms or haplotypes in certain key genes implicated in vitamin K metabolism might affect nutritional requirements. Absorption, Transport and Metabolism of Vitamin E. Free Radical Research Communications: Vol. Eating of animal livers, during a period of time when the dietary habit of Homo erectus was changing, was suggested to be responsible for the high intake of vitamin A. Abstract. Solubility is the primary factor affecting absorption. Subsequent, proximal events include activation of several kinases, including MAPKs, inhibitor of nuclear factor-κB (NF-κB) kinase β (IKKβ), phosphoinositide 3-kinase (PI3K), and Akt. The intracellular tail of RANK expresses several binding sites for TNF-related associated factors (TRAFs), of which TRAF6 seems to be most important (131, 132). Houtkooper LB, Ritenbaugh C, Aickin M, et al. . 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). Antioxidants (Basel). Some disorders, called malabsorption disorders, interfere with absorption of fats and thus of fat-soluble vitamins. Absorption of vitamin A I. A number of studies have suggested that increased osteoporosis and fracture may occur with “subclinical” levels of vitamin A. Melhus et al (91) observed an increase in hip fracture for dietary intakes of retinol >1500 μg/d vs ≤500 μg/d (odds ratio, 2.1) in a nested case-control study where 247 women with a first hip fracture were age-matched with 873 controls from a cohort of 66 651 Swedish women. Over a period of 7 days, control rats were fed with pellets containing 12 IU vitamin A/g pellet, and experimental rats were given 1700 IU vitamin A/g pellet as a mixture of retinyl palmitate and retinyl acetate. 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). VITAMIN A AND CAROTENOIDS. If you are at risk for vitamin A deficiency, speak to your healthcare provider about any medications that you are taking. 3. A 3-fold increased risk of osteoporosis was observed in the highest retinol quintile. 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). For osteoclastogenesis to occur, progenitor cells must be activated by macrophage colony-stimulating factor (M-CSF), which is needed for proliferation and survival of osteoclasts, and by receptor activator of nuclear factor-κB (RANK) ligand (RANKL), which is required for osteoclast differentiation. When these mice were treated with ATRA for 2 weeks, the amount of bone was reduced; when the animals were treated with the specific RAR-γ agonist, NRX204647, hardly any bone was formed. Some disorders impair the absorption of fats. Absorption of 14 C-labelled retinol was determined along the gastrointestinal tract of chicks, using 141 Cerium as a non-absorbed reference substance, as influenced by high dietary vitamin A and the addition of tocopherol to the diet.. 2. The efficiency of production and utilization of vitamin B 12 was studied with sheep given a cobalt-deficient diet with and without supplementary Co (1 mg/d). Vitamin B1, also called thiamine, plays a role in metabolism and brain function, helping the body metabolize carbohydrates, which are a significant source of energy. The in vivo data noting stimulation of cortical bone resorption by retinoids are in good agreement with in vitro observations showing increased periosteal bone resorption in organ-cultured bone. Myhre AM, Carlsen MH, Bohn SK, Wold HL, Laake P, Blomhoff R. Kneissel M, Studer A, Cortesi R, Susa M. Johansson S, Lind PM, Hakansson H, Oxlund H, Orberg J, Melhus H. Halkier-Sorensen L, Laurberg G, Andresen J. Cuny JF, Schmutz JL, Terver MN, et al. The vitamin most closely associated with protein metabolism is. However, 25–33% of dietary retinoid that is absorbed in the intestine is delivered to tissues other than the liver by chylomicrons (13). Furthermore, it has been observed that the hypercalcemia can be decreased by glucocorticoid treatment (84, 87, 88). Supplementation with vitamin A during growth has also been associated with decreased bone mass in peri- and premenopausal women. Retinol-RBP is combined with transthyretin and transported by the blood to target cells. I. Intestinal absorption and metabolism of 14 C-labeled vitamin A alcohol, and β-carotene in the rat. Hu L, Lind T, Sundqvist A, Jacobson A, Melhus H. Saneshige S, Mano H, Tezuka K, et al. Remodeling is initiated by formation of osteoclasts, mainly on endosteal surfaces of trabecular and cortical bone, or within the Haversian canals in cortical bone. Dectin-1-mediated suppression of RANKL-induced osteoclastogenesis by glucan from baker's yeast. Experiments with organ-cultured bones do not reveal how osteoclastogenic agents such as retinoids affect osteoclast formation and function. In contrast to mouse bone marrow macrophages, RANK mRNA and protein were not up-regulated by RANKL in the CD14+ human monocytes. In clinical studies, fracture risk is considered to be the best predictor of bone health, but measurement of bone mineral density (BMD) is also commonly employed for evaluating bone, and in a cross-sectional study of 175 randomly selected Swedish women 28–74 years of age, Melhus et al (91) showed that BMD was decreased 6–14% at skeletal sites (femoral neck, Wards triangle, trochanter region of proximal femur, lumbar spine, and total body) for retinol intake >1500 μg/d vs ≤500 μg/d. This site needs JavaScript to work properly. Serum levels of retinol increase with age and under normal conditions in adults are in the range of 1–3 μmol/L. Rothenberg AB, Berdon WE, Woodard JC, Cowles RA. During absorption from the intestine vitamin A and β -carotene become finely dispersed in the intestinal fluid in mixed lipid micelles formed with the aid of bile salts, lysolecithin, lower glycerides and cholesterol. These results are very similar to the observations with ATRA and 1,25(OH)2 D3 in mouse bone marrow cultures and suggest that the purified mononucleated cells used in the study by Thavarajah et al (156) contained stromal cells. I. INTESTINAL ABSORPTION AND METABOLISM OF 14C-LABELLED VITAMIN A ALCOHOL AND BETA-CAROTENE IN THE RAT. Bone mineral content of the radius, ulna, and humerus was measured every 6 months for 3 years in 17 premenopausal women at the University of Wisconsin. 1960 Mar; 87:9–12. Hypervitaminosis A decreased bone mineral content and density not only in cortical bone but also in trabecular bone (76). 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. ATRA induces a rapid phosphorylation of cAMP response element binding protein (CREB), which translocates to the nucleus, binds, and activates genes containing cAMP response elements (CREs) in their promoters (44) (Figure 3). Thus, whereas ATRA can stimulate RANKL and periosteal osteoclast formation in mouse organ cultures of parietal bones, in bone marrow cultures that are dependent on stromal cells for RANKL formation and osteoclastogenesis, evidence indicates that ATRA is ineffective. In contrast, mice lacking OPG exhibit early-onset osteoporosis (131, 132). Suggested Citation:"Vitamin B6: Chemistry, Absorption, Metabolism, Catabolism, and Toxicity. O'Neill RP, Jones SJ, Boyde A, Taylor ML, Arnett TR. Similarly, the synthetic acyclic retinoid, geranylgeranoic acid, also inhibited osteoclast formation stimulated by 1,25(OH)2 D3, although with less potency than ATRA. The hypercalcemia noted in hypervitaminosis A patients is thought to be due to a direct bone resorptive action of retinoids, suggesting that the mechanism by which glucocorticoids are decreasing hypercalcemia in patients exhibiting hypervitaminosis A may be mediated by the monomeric glucocorticoid receptor. These data suggest that RARβ and RARγ are not as important as RARα for inhibition of osteoclastogenesis stimulated by RANKL, but conclusive evidence for this awaits studies where RARβ and RARγ are knocked down by interference silencing or use of cells from mice in which these receptors have been deleted. Recently, it was demonstrated that ATRA stimulates mineral release and bone matrix degradation in neonatal mouse calvarial bones and that osteoclast inhibitors such as zoledronic acid and calcitonin blocked the bone-resorptive effects of ATRA (89). ATRA was also found to be a potent inhibitor of osteoclast formation when spleen cells were used as osteoclast precursors. Retinoids can also have rapid nongenomic/nonclassical actions. Importantly, only 99% of ingested cobalamin requires IF for absorption. . 4: Trainee in Metabolism and Endocrinology under grant T1-AM-5397 from the National Institutes of Health. Hata K, Kukita T, Akamine A, Kukita A, Kurisu K. Chiba M, Teitelbaum SL, Cao X, Ross FP. Increased bone fragility can be a consequence not only of increased bone resorption, but also of decreased bone formation. The observations in the studies by Kneissel et al (75) and Lind et al (76) both show decreased cortical bone and increased formation of periosteal osteoclasts, which is in agreement with several previous studies; however, Kneissel et al (75) found no change in trabecular bone density although the number of osteoclasts was decreased, whereas Lind et al (76) found that trabecular bone was decreased but there was no change in the number of osteoclasts. Alternatively, ATRA can be shuttled by FABP to bind PPARs in the nucleus. Although the reasons for the opposing effects of the active metabolites of vitamin A (ATRA) and vitamin D (1,25-dihydroxyvitamin D [1,25(OH)2 D3]) are not known, their nuclear receptors, RAR and vitamin D receptor, respectively, employ the same heterodimerization partner, RXR, for binding to response elements of target genes (126, 127). In rats exhibiting hypervitaminosis A with thin, weakened long bones and increased periosteal osteoclasts, reduced endosteal/marrow blood flow and pathological endosteal mineralization have also been reported (76). Few foods are naturally rich in vitamin D. After cellular uptake, retinol is oxidized first to all-trans retinal by cytosolic alcohol dehydrogenases and bound to CRBP. How are osteoclasts induced to resorb bone? In support of this idea, it was observed that withdrawal of ATRA from culture medium 6 hours after initial treatment with RANKL plus ATRA still caused profound inhibition of osteoclastogenesis. 1 A, B. COVID-19 is an emerging, rapidly evolving situation. Vitamin C is required for the biosynthesis of collagen, L-carnitine, and certain neurotransmitters; vitamin C is also involved in protein metabolism [1,2]. Collagen is an essential component of connective tissue, which plays a vital role in wound healing. Oxford University Press is a department of the University of Oxford. The hormone form calcitriol (vitamin D) acts with two other hormones. Please enable it to take advantage of the complete set of features! It was observed that NRX204647 and 2 structurally different RARγ agonists, CD1530 and R667, were potent inhibitors of the heterotopic ossification. Vitamin D: A steroid vitamin which promotes absorption and metabolism of calcium and phosphorus. Extra- and intracellular regulation of osteoclast formation. Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. Subsequent, more convincing evidence that vitamin A directly affected bone was presented by Fell and Mellanby (140) at Strangeways Laboratories in Cambridge, United Kingdom. Our own work discussed in this manuscript was supported by the Swedish Research Council for Medicine (project no. Under normal conditions of sunlight exposure, no dietary supplementation is necessary because sunlight promotes adequate vitamin D synthesis in the skin. In all cases, much more bone was formed after the addition of transplanted cells compared to when no cells were added; however, the study lacked transplanted control cells not incubated with ATRA and/or BMP-2, which would have helped assess the importance of these agents. Hough et al (153) reported that hypervitaminosis A in male rats (10 000 to 25 000 IU vitamin A administered as retinyl palmitate by stomach tube daily for 21 d) causes increased bone resorption, increased numbers of tibial osteoclasts, and increased urinary hydroxyproline, while having no effect on plasma calcium or circulating levels of PTH or 25(OH) D. Kneissel et al (75) performed an extensive study on female rats given the retinoid Ro 13–6298 sc (125 μg/kg) for 4 days. Kini AR, Peterson LA, Tallman MS, Lingen MW. In cultured calvarial bones, ATRA was additionally found to robustly increase the mRNA and protein expression of RANKL, with no effect on Rank mRNA expression (89). Copyright © 2013 by The Endocrine Society, Making, Cloning and Expression of Human Insulin Genes in Bacteria: The Path to Humulin@, Revisiting the complexity of GLP-1 action-from sites of synthesis to receptor activation, Multiple Endocrine Neoplasia Type 1: Latest Insights, Metabolic Consequences of Solid Organ Transplantation, Progress in Translational Regulatory T Cell Therapies for Type 1 Diabetes and Islet Transplantation, The Journal of Clinical Endocrinology & Metabolism, II Necessity of Vitamin A for Vision and Cellular Functions, III Dietary Sources, Absorption, Hepatic Storage, and Transport of Vitamin A to Tissues, IV Target Cell Uptake, Intracellular Metabolism, Cytoplasmic and Nuclear Receptors Mediating Vitamin A Effects, VI Human Studies Evaluating Whether Current Intake of Vitamin A Is Associated With Osteoporosis and Fracture, VII Bone Remodeling and Modeling at the Cellular Level, VIII Retinoids, Osteoclast Differentiation, and Bone Resorption in Organ-Cultured Intact Bones, IX Retinoids and Osteoclast Differentiation and Activity in Cell Cultures, Receive exclusive offers and updates from Oxford Academic, Transforming Growth Factor-β1 to the Bone, Osteoclast Activity and Subtypes as a Function of Physiology and Pathology—Implications for Future Treatments of Osteoporosis, Chick Ovalbumin Upstream Promoter-Transcription Factors (COUP-TFs): Coming of Age, Retinoic Acid Receptors and Cellular Retinoid Binding Proteins: Complex Interplay in Retinoid Signaling. TREM-2, triggering receptor expressed on myeloid cells 2. I. INTESTINAL ABSORPTION AND METABOLISM OF 14C-LABELLED VITAMIN A ALCOHOL AND BETA-CAROTENE IN THE RAT. BMD for the femoral neck, trochanter, intertrochanter, and total hip was measured in 5709 participants aged 20 to 90+ years. Dietary sources include various fruits, vegetables and meat. Hip fracture was significantly elevated in both the lowest (≤46.1 μg/dL) and highest (≥73.3 μg/dL) vitamin A quintiles, with individuals in the highest quintile having more than twice the risk of a hip fracture than those in the middle quintile. The presence of fat in the diet greatly aids vitamin A absorption. It was also observed that 1,25(OH)2 D3, but not ATRA, can stimulate Rankl mRNA in the mouse ST-2 stromal cell line (our unpublished observations). 2. Bonewald LF, Oreffo RO, Lee CH, Park-Snyder S, Twardzik D, Mundy GR. Get the latest public health information from CDC:, Get the latest research information from NIH:, Find NCBI SARS-CoV-2 literature, sequence, and clinical content:, NLM 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. The efficiency of production and utilization of vitamin B 12 was studied with sheep given a cobalt-deficient diet with and without supplementary Co (1 mg/d). Mechanisms involved in the digestion and absorption of dietary vitamin A require the participation of several proteins. The studies also demonstrate a remarkable heterogeneity in the cortical and trabecular responses to vitamin A in long bones. High serum retinyl levels have been suggested to be a marker for excessive vitamin A intake. ATRA and BMP-2 have also been found to act synergistically to stimulate alkaline phosphatase activity in 3T3-F442A cells. These medications can reduce calcium absorption and impair vitamin D metabolism . In contrast to retinol, ATRA is partially soluble in water (210 nm), can diffuse through water-soluble phases and hydrophobic membranes, and may have paracrine effects. J Clin Invest. Food and supplemental vitamin A intake were also evaluated in a longitudinal study conducted on 891 women aged 45–55 at baseline and 50–59 after follow-up 5–7 years later (98). is split at least one intact molecule of retinol, retinal, or retinoic acid can be obtained. The hypothesis that RA can have opposing effects depending on CRABPII/RAR or FABP5/PPAR β/δ binding has been proposed for keratinocytes and carcinomas, but so far it has not been tested in bone cells. Epub 2018 Jun 27. The evidence from different ex vivo bone cultures indicates that vitamin A has the capacity to stimulate bone resorption (Table 2). "National Research Council. These vitamins are essential for a fully functioning metabolism. Cobalamin is involved in brain function maintenance, DNA synthesis… Vitamin C has a role in neurological functions, formation of red blood cells, organism defence. Shimono et al (175) have recently reported that retinoids inhibit heterotopic bone formation. Wan DC, Shi YY, Nacamuli RP, Quarto N, Lyons KM, Longaker MT. J Biol Chem 240:2839–2844 PubMed Google Scholar In their experiments, plasma with vitamin A added or plasma from fowl treated with high doses of vitamin A was added to explant cultures of either chicken embryonic limb buds obtained from eggs or to fetal mouse long bones. Estimates of vitamin D status indicate widespread insufficiency. One in vivo study using dynamic histomorphometry indicates that vitamin A decreases the number of bone-forming osteoblasts on periosteal surfaces with no effect on the activity of the remaining osteoblasts, which suggests that vitamin A has an inhibitory effect on periosteal bone formation. Mononucleated osteoclasts fuse to latent multinucleated osteoclasts, which subsequently become activated and attach to mineralized bone surfaces. 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. Nongenomic effects of ATRA include cytoplasmic regulation of translation and activation of signaling pathways causing phosphorylation of CREB and transcription of genes containing CRE. After normalization of high vitamin A intake, human radiographs have shown new subperiosteal bone formation in affected areas, such as the shafts of tibias and fibulas (83). Yellowing of the skin, carotenemia, can occur with high intake of carotenes, but this is reversible when intake is decreased (68). Esterification of vitamin A by an acetone powder from pancreas. Decreased mRNA expressions of the NF-κB inhibitor, inhibitory κBα (IκBα), and of the NF-κB subunits, p52 and RelB, stimulated by RANKL were also noted after ATRA exposure, indicating that the NF-κB pathway is inhibited by ATRA as well.

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