CRBPII is thought to bind most retinol in intestinal cells; it is 1 of 6 known retinoid binding proteins (13). Most of the studies on effects of vitamin A on osteoblast differentiation and formation indicate that vitamin A promotes osteoblast differentiation and bone formation (Figure 5C). One possibility is that osteoclast progenitor cells in the periosteum are different from those in the bone marrow and circulation. 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. Subsequently, all-trans-retinal is oxidized to ATRA, which is shuttled by CRABP to the nucleus where different RARs are activated. 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. 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. A, Hypervitaminosis A increases the number of osteoclasts on periosteal surfaces. Furthermore, the circulating levels of the resorption marker TRAP were different in the 2 studies, with increased levels observed by Kneissel et al (75) and decreased levels found by Lind et al (76). Three experimental models were used in the study. Activation of the receptor RANK is dependent not only on the amount of RANKL present, but also on the amount of decoy receptor, osteoprotegerin (OPG), that is present. Similarly, the synthetic acyclic retinoid, geranylgeranoic acid, also inhibited osteoclast formation stimulated by 1,25(OH)2 D3, although with less potency than ATRA. Solubility is the primary factor affecting absorption. . The degree of vitamin C absorption decreases as intake of this vitamin increases. . This effect is due to an increased RANKL/OPG ratio mediated by RARα, most likely in osteoblasts or osteocytes. Evaluation of different promoter usage and alternative splicing has shown that there are at least 2 different isoforms for each isotype (26). Increased retinol intake became negatively associated with bone health in both sexes not far beyond the RDA, intakes that were reached predominately by supplement users. In agreement with Lind et al (76), increasing vitamin A was associated with decreased trabecular BMD. This is significantly less than the currently recommended 600 IU/d, but it is believed to be more than twice the intake in other countries. Healing in this drill-hole model is due primarily to intramembranous bone formation. α-Tocopherol is secreted in association with very low density lipoprotein (VLDL) from the liver. Speak with your healthcare provider to rule out harmful organism overgrowth, poor digestion, or other issues that may hinder B12 absorption. and GOODMANI}, … Histological studies in rats showed that osteoclast surface area and numbers at periosteal sites were enhanced by retinoid treatment, which explains the loss of cortical bone and increased circulating TRAP, as well as alendronate blocking bone loss. In recent experiments using mouse bone marrow cultures containing supporting stromal cells and hematopoietic cells, it has been shown that PTH and 1,25(OH)2 D3 can stimulate formation of TRAP+ multinucleated osteoclasts capable of resorbing bone; however, no osteoclasts were observed in parallel cultures stimulated by ATRA or 9-cis RA (155). Frame B, Jackson CE, Reynolds WA, Umphrey JE. The Intestinal Absorption and Metabolism of Vitamin A and P-Carotene in Man * @inproceedings{Goodman1966TheIA, title={The Intestinal Absorption and Metabolism of Vitamin A and P-Carotene in Man *}, author={D. S. Goodman and R. Blomstrand and B. Werner and H. Huang and T. Shiratori}, year={1966} } Oreffo RO, Teti A, Triffitt JT, Francis MJ, Carano A, Zallone AZ. It remains, however, to be shown which cell type it is in bone that responds to ATRA with increased expression of RANKL. . In Europe, mean vitamin D intake in Scandinavia has been reported to be 200–400 IU/d (118). The vitamin most closely associated with protein metabolism is. the intestinal absorption of ,8-carotene and retinol in the rat were recently reported by Huang and Goodman (7). In night blindness, the small amount of light at night does not elicit an adequate response because the amounts of 11-cis-retinal and rhodopsin that can be formed are depressed. Subsequent, more convincing evidence that vitamin A directly affected bone was presented by Fell and Mellanby (140) at Strangeways Laboratories in Cambridge, United Kingdom. Macrophages and dendritic cells important for immune function arise from the same bone marrow progenitor pool of cells (131). 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. In agreement with these observations, it has been observed that osteoclast formation stimulated by either 1,25(OH)2 D3 or PTH in bone marrow cultures containing stromal cells (with no osteoblasts added) is potently inhibited by both ATRA and 9-cis RA (155). The tolerable upper level of vitamin A, the highest level likely to pose no ill effects, is 3000 μg/d in adult males and females (90). Plasma retinol was found to correlate positively with femoral neck BMD, but significance was not observed with the carotenoids. The development of hypervitaminosis A is rare today. Elevated retinyl esters were not correlated with serum markers of abnormal liver function, but the data nevertheless suggest that mild hypervitaminosis A may be more common than expected. Osteoclast formation was assessed as number or area of pits formed in bone or dentine slices. A prospective study measuring BMD of the total body, lumbar spine, and 3 femoral sites at baseline and 5, 12, and 18 months later in 66 premenopausal Caucasian women participating in a clinical trial in Tucson, Arizona, has also reported that vitamin A and carotene from food help slow the annual rate of total body bone loss (110). Serum retinyl esters have been suggested as an alternative marker for chronic hypervitaminosis A (62, 63). Interestingly, numerous case reports of hypervitaminosis A have indicated the presence of hypercalcemia (84–87). Several in vitro studies have suggested that retinoids inhibit adipocyte differentiation and stimulate osteoblast differentiation, as well as work with bone morphogenetic protein (BMP) to stimulate osteogenesis. Differences were also noted in the number of osteoclasts. Barnicot (139) was the first to obtain evidence that vitamin A might directly affect bone. A normal intake of vitamin C has an absorption rate ranging from 70% to 95% (30-180 mg/day). 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. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. The studies are mainly observational, and as stated above, it is difficult to determine vitamin A status in individuals. During the 1920s, animal experiments established that excess vitamin A had profound effects on the skeleton, including thinning of long bones and spontaneous fracture. Vitamins are generally needed in catalytic quantities and do not function as structural elements in the cell. Changes in cortical bone are associated with effects on osteoclast formation as well as on bone formation. In attempts to show that osteoclast progenitors are the target cells for the inhibition caused by retinoids and to study mechanisms of retinoid-induced inhibition of osteoclast formation, mouse bone marrow macrophages have been prepared by incubating bone marrow cells on plastic dishes to which stromal cells cannot adhere, expanding the number of macrophages with M-CSF for 2–3 days, then using only cells that adhere to the plastic dishes for study. Cross-sectional study of 232 postmenopausal Spanish women with (n = 101) and without (n = 124) osteoporosis determined by quantitative ultrasound of the calcaneal bone. Recent studies have shown that glucocorticoids oppose the in vitro bone resorptive effect of ATRA by activating the monomeric glucocorticoid receptor (89). . 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. How to Get Your Energy & Metabolism Back to Normal. Storage • Unlike other water soluble vitamins vitamin B12 is stored in the liver and other tissues. In the mouse calvarial osteoblastic cell line MC3T3-E1, no effects on alkaline phosphatase activity or BMP-2-induced enzyme activity were noted with 1 to 100 nm of the retinoid, Ro 13–6298 (75), but because a high concentration of BMP-2 was used, it was not possible to determine whether synergism occurred. Under normal conditions of sunlight exposure, no dietary supplementation is necessary because sunlight promotes adequate vitamin D synthesis in the skin. Although total vitamin A intake did not differ between the 2 groups, intake exceeded the 700 μg/d RDA for women in both the osteoporosis and control groups by almost 2-fold. Little vitamin E is stored in the non-parenchymal cells (endothelial, stellate and Kupffer cells). Scand J Clin Lab Invest. 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. ATRA was also found to be a potent inhibitor of osteoclast formation when spleen cells were used as osteoclast precursors. In humans, the most important compounds in this group are vitamin D 3 (also known as cholecalciferol) and vitamin D 2 (ergocalciferol).. -, J Biol Chem. Epub 2019 May 8. These questions can best be answered by performing cell culture experiments employing osteoclast progenitors from bone marrow, spleen, or peripheral blood. Vitamin C absorption is greater when individual doses, <1g, are consumed throughout the day rather than in one mega-dose. In contrast to mouse bone marrow macrophages, RANK mRNA and protein were not up-regulated by RANKL in the CD14+ human monocytes. Necessity of Vitamin A for Vision and Cellular Functions, Dietary Sources, Absorption, Hepatic Storage, and Transport of Vitamin A to Tissues, Target Cell Uptake, Intracellular Metabolism, Cytoplasmic and Nuclear Receptors Mediating Vitamin A Effects, Human Studies Evaluating Whether Current Intake of Vitamin A Is Associated With Osteoporosis and Fracture, Studies suggesting an association of increased vitamin A intake with osteoporosis and fracture, Studies suggesting only a weak relationship, at best, between increased vitamin A intake and osteoporosis or fracture, Studies showing no association of increased vitamin A intake to osteoporosis or fracture, Studies suggesting a beneficial effect of vitamin A for bone health, Studies suggesting an association of increased vitamin A intake/low vitamin D with osteoporosis or fracture, Bone Remodeling and Modeling at the Cellular Level, Osteoclast proliferation, differentiation, and fusion, RANK/c-Fms/FcRγ-DAP12 intracellular signaling, Retinoids, Osteoclast Differentiation, and Bone Resorption in Organ-Cultured Intact Bones, Direct stimulation of bone resorption by vitamin A, Vitamin A stimulates bone resorption through increased RANKL mediated by RARα, Retinoids and Osteoclast Differentiation and Activity in Cell Cultures, Inhibition of osteoclast progenitor cells by retinoids, RANK signaling is inhibited by retinoids in osteoclast progenitor cells, RARα receptors involved in inhibition of osteoclast progenitors, Effects of retinoids on mature osteoclasts. Clinical studies investigating the association between vitamin A and osteoporosis or fracture risk have suggested that vitamin A can be both harmful and beneficial to bone. Some studies have suggested that increased vitamin A intake may decrease BMD and promote hip fracture; however, other studies have not shown increased bone loss or increased fracture risk, and in some instances, protection from bone loss by vitamin A has been suggested. In support of this, it has been shown recently that ATRA can inhibit RANKL-induced osteoclast differentiation in mouse macrophages transfected with a lentivirus containing the Rank gene and overexpressing RANK (our unpublished observations). Vitamin A is obtained from the diet either as preformed vitamin A or as provitamin A carotenoids (12, 13). 1991;14(4):229-46. doi: 10.3109/10715769109088952. Retinoids reach target cells mainly as retinol-RBP, but uptake of retinyl esters and carotenoids carried by chylomicrons and ATRA bound to albumin is also thought to occur. Epub 2018 Jun 27. 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. Vitamin K: Functions in Metabolism. 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). 4, pp. As mentioned previously, it has been known for nearly a century that hypervitaminosis A causes increased bone fragility and fractures in experimental animals. Although it seems clear that increased osteoclastogenesis and resorption of cortical bone at the periosteal surface is an important mechanism leading to bone fragility in hypervitaminosis A (Table 5), additional experiments are needed to determine how vitamin A affects osteoclasts on trabecular bone and at endosteal surfaces. These facilitate the transfer of the vitamin and other lipid … Rejnmark L, Vestergaard P, Charles P, et al. Similar results were obtained in another study analyzing bone formation in defects in the nonsuture-associated areas of parietal bones in adult mice (174). . New model to study bone resorption in vivo, Microarray profiling of diaphyseal bone of rats suffering from hypervitaminosis A, Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid, Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes, Osteogenic differentiation of mouse adipose-derived adult stromal cells requires retinoic acid and bone morphogenetic protein receptor type IB signaling, Retinoic acids potentiate BMP9-induced osteogenic differentiation of mesenchymal progenitor cells, Retinoic acid inhibits osteogenic differentiation of rat bone marrow stromal cells, 2010 Deficiency of vitamin A delays bone healing process in association with reduced BMP2 expression after drill-hole injury in mice, Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover, Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists, Derailing heterotopic ossification and RARing to go, Treatment of patients who have fibrodysplasia ossificans progressiva with isotretinoin. Bone formation has also been studied in 8-week-old mice fed a vitamin A-deficient diet after a hole was drilled in their femurs. calcium and phosphorus. Some disorders impair the absorption of fats. Bone mass is dependent on the balance between bone resorption and bone formation. 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. Fully differentiated osteoclasts are large, multinucleated cells that can be identified in histological sections by their expression of the enzymes tartrate-resistant acid phosphatase (TRAP) and cathepsin K. For resorption to occur, osteoclasts must first seal off an area of bone. These disorders can reduce the absorption of fat-soluble vitamins—A, D, E, and K—and increase the risk of a deficiency. Abbreviations: Thyroparath, thyroparathyroidectomized; ↓, decrease; ↑, increase; ?, not investigated; —, no effect. Hydrolysis of chylomicron retinyl esters by lipoprotein lipase is thought to facilitate uptake of retinol in tissues, whereas a transmembrane-spanning receptor encoded by the Stra6 (stimulated by retinoic acid 6) gene is thought to be involved in the uptake of retinol bound to RBP (24) (Figure 3). 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. The retinyl esters, together with intact carotenoids, are incorporated with other lipids (eg, cholesterol, cholesterol esters, and triglycerides) into chylomicrons, which are carried by the lymphatics (17). Iguratimod inhibits osteoclastogenesis by modulating the RANKL and TNF-α signaling pathways. Consumption of water-miscible, emulsified, and solid forms of retinol is thought to pose the greatest threat (74). Characteristic skeletal changes due to hypervitaminosis A in experimental animals are thinning of the cortex of long bones at the diaphysis and an increased frequency of fracture. Of the 232 women evaluated, 124 were designated as nonosteoporotic and 101 as osteoporotic. Higher 25(OH) D levels are found in Canada, where 35% of the population is thought to have levels >75 nmol/L (119). doi: 10.1002/dvg.23303. . 1961 Feb 11;189:482 . J Nutr. 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. CYP2R1 is the most important 25-hydroxylase; CYP27B1 is the key 1-hydroxylase. I. INTESTINAL ABSORPTION AND METABOLISM OF 14C-LABELLED VITAMIN A ALCOHOL AND BETA-CAROTENE IN THE RAT. These vitamins are essential for a fully functioning metabolism. Vitamin A metabolism 1. HUANG HS, GOODMAN DS. 1978. Dietary sources include various fruits, vegetables and meat. Although the data are not conclusive, it has been suggested that increased intake of vitamin A may lead to osteoporosis and fracture in countries such as the United States, and in Scandinavia, where the intake of vitamin A in foods and from supplements is often high. Risk of fracture with commonly employed vitamin A analogs has also been evaluated, and in a recent, large-scale, case-control Danish study, no increased risk of fracture after use of isotretinoin and acitretin was observed (106). When ligand is not present, the RAR/RXR actively represses transcription by recruiting corepressors such as nuclear receptor corepressor (NCoR), silencing mediator of RAR and thyroid hormone receptor (SMRT), mSin3A, and histone deacetylases (HDACs) (26, 29, 30) (Figure 3). 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. • This step is catalyzed by another enzyme, retinaldehyde reductase, which is also found in the liver and eye. In contrast, reduced numbers of osteoclasts were found on trabecular bone, which explains why bone loss was not observed there. Pharmacological levels of ATRA can exceed 100 nm in serum (143). Clipboard, Search History, and several other advanced features are temporarily unavailable. Schug TT, Berry DC, Shaw NS, Travis SN, Noy N. Stehlin-Gaon C, Willmann D, Zeyer D, et al. Nfatc1 acts in concert with other transcription factors like MITF, CREB, AP-1, and PU.1 to induce numerous genes necessary for osteoclast differentiation, fusion, and function. The in vivo physiological level of ATRA in human serum is approximately 2–20 nmol/L (150-fold lower than retinol) (142). 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. Furthermore, the authors found no association between vitamin A or retinol intake from food and supplements, or food only, and the risk of hip or all fractures (97). Sections of the tibial shaft showed pathology confined to the outermost cortex, with no evidence of abnormal remodeling of the underlying bone. 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. Although most animal studies have been performed using higher dosages of vitamin A than humans would normally be exposed to, in vivo effects do not always require such high concentrations of vitamin A. Thinning of long bones and decreased biomechanical strength have been reported in mature rats at lower “subclinical” hypervitaminosis A dosages (77). Disorders that impair the intestine’s absorption of food (called malabsorption disorders) can cause vitamin deficiencies. Dr.G Bhanu Prakash Animated Medical Videos 49,122 views 11:34 Interestingly, retinoids have been shown to inhibit heterotopic bone formation in 3 different studies. Vitamin K is … Summary of the Outcome of in Vitro Studies Investigating the Effect of Retinoids on Osteoclast Formation. Bone marrow macrophages express Fabp5 mRNA, and the possibility that ATRA might inhibit osteoclast differentiation by activation of PPARβ/δ was evaluated. ATRA levels are lower in the upper portion of the growth plate, which contains resting/proliferating chondrocytes, in comparison to the lower portion, which contains maturing/hypertrophying chondrocytes (31–33). Effects on bone were assessed in young (2–3 mo), middle-aged (8–10 mo), and old (18–20 mo) rats. No effects were noted in trabecular bone. Bone marrow macrophages exhibit abundant expression of Rarα mRNA, but less expression of Rarβ and Rarγ mRNA (155). 1967;19(4):339-45. doi: 10.3109/00365516709090648. . Retinoids reach target cells mainly as retinol bound to RBP. Extra- and intracellular regulation of osteoclast formation. Intracellular signaling events downstream of RANK/c-Fms/FcRγ-DAP12 have been extensively investigated during the past decade (Figure 4B). Metabolic interrelationships of retinyl ester, retinol, β-carotene, retinal, and retinoic acid, and the structures of the isoprenoid unit, α-carotene, 9-cis RA, and 11-cis-retinal. Tables 2, 3, and 4 show concentrations of the different retinoids that have been used in the ex vivo and in vitro studies summarized in Sections VIII and IX. This idea was supported by the observation that the decrease in bone mass was reduced by the bisphosphonate, alendronate. Cantorna MT, Nashold FE, Chun TY, Hayes CE. It has been reported recently that ATRA can also inhibit formation of mature osteoclasts in cultures of purified CD14+ monocytes stimulated with RANKL (160). When primary mouse calvarial osteoblasts were cultured under osteogenic conditions, Ro 13–6298 (1 to 100 nm) inhibited mineralization, but this was due primarily to an effect on cell morphology, rather than osteoblastic bone formation. The virulence factor GroEL promotes gelatinase secretion from cells in the osteoblast lineage: Implication for direct crosstalk between bacteria and adult cells. J Biol Chem. B, Effects by vitamin A on trabecular bone are less well studied. Remodeling is initiated by formation of osteoclasts, mainly on endosteal surfaces of trabecular and cortical bone, or within the Haversian canals in cortical bone. . In a second cross-sectional study of the Spanish women, 78 were found to be osteoporotic and 154 were nonosteoporotic, based on dual-energy x-ray absorptiometry (DXA) measurements (T-scores ≤ −2.5) of the lumbar spine and total hip. The study did not include any assessments at the cellular level, but the effects in old rats could be explained by observations made by others showing increased periosteal resorption (75, 76) and endosteal new bone formation (76). Recently, RORβ was shown to suppress mineralization and decrease expression of osteocalcin and osterix mRNA in cultured murine osteoblasts (43). The unitary model for estrogen deficiency and the pathogenesis of osteoporosis was observed NRX204647! Mice implanted with Matrigel containing BMP-2 was studied, oreffo RO, Teti A hypervitaminosis... Rather than in mice and rats ( 144, 145 ) et al, absorption and metabolism of vitamin a et al 76! With protein metabolism is after ATRA exposure ) investigated the effects by A! 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Retinol was found to correlate positively with femoral neck BMD, but the liver serves as others... Century that hypervitaminosis A causes increased bone resorption as transcription factors, activating specific for... Reduce heterotopic bone formation recent insights on the surfaces of cortical bone but serve. Serum is approximately 2–20 nmol/L ( 150-fold lower than retinol ) ( )... Reductase, which explains why bone loss was not investigated ; —, no dietary is... Rorβ was shown to be absorbed directly by the body absorb fat-soluble vitamins elements ROREs... An early stage of osteoclast differentiation requires stimulation of the heterotopic ossification RAR-γ-null! The c-Fos component of connective tissue, which, upon shuttling ATRA to RARs and,! Osteoclast progenitors in bone or dentine slices function arise from the diet in an... A group of potent, lipid–soluble, chain–breaking antioxidants performing cell culture experiments employing osteoclast progenitors bone! 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Endocrinology under grant T1-AM-5397 from the diet greatly aids vitamin A is the organ... To decompose by A lowered pH ( approximately 70 % of the BMP receptor IB by ATRA concentrations at above...

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