Osteoclast differentiation also requires down-regulation of genes such as Irf8, MafB, and Bcl6 associated with the macrophage phenotype. Vitamin A requirement can be met from dietary preformed vitamin A or provitamin A carotenoids, the most important of which is β -carotene. Vitamin A is critical for vision as an essential component of rhodopsin, a protein that absorbs light in the retinal receptors, and because it supports the normal differentiation and functioning of the conjunctival membranes and cornea . ITAM, immunoreceptor tyrosine-based activation motif. 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. intestinal absorption and metabolism of 14 c-labeled vitamin a alcohol and p-carotene in the rat * @inproceedings{huangt2003intestinalaa, title={intestinal absorption and metabolism of 14 c-labeled vitamin a alcohol and p-carotene in the rat *}, author={helen s. huangt and and and dewitt and {\vs}. In contrast to mouse bone marrow macrophages, RANK mRNA and protein were not up-regulated by RANKL in the CD14+ human monocytes. The studies also demonstrate a remarkable heterogeneity in the cortical and trabecular responses to vitamin A in long bones. Korycka M, Bialek T, Miler M, Chabrowski K, Berger S. Eur J Clin Nutr. In a study by Thavarajah et al (156), where gradient centrifugation was used to purify mononuclear cells from human rib bone marrow, no effect of ATRA was reported after 3–4 weeks of culture, but enhanced osteoclastogenesis was noted with 1,25(OH)2 D3. With regard to in vivo studies, we are aware of only 1 study where dynamic bone formation was assessed using double injections of alizarin and calcein (75). Vitamin D deficiency is common, and some studies have suggested that the risk of osteoporosis and fracture may increase when increased vitamin A intake occurs in individuals with low vitamin D levels. Increased pit number and increased mRNA expression of Ctsk have been observed after ATRA (≥1 pm) treatment of rabbit osteoclasts cultured on dentin slices (161). The authors also noted that vitamin A deficiency reduced the mRNA expression of Bmp2, Collagen α1 type I, and Osteocalcin. During the 1920s, animal experiments established that excess vitamin A had profound effects on the skeleton, including thinning of long bones and spontaneous fracture. Mouse liver, kidney, brain, and testis all have higher ATRA concentrations than serum (7–11 pmol/g tissue compared to approximately 2 pmol/g serum) (145). When the risk of fracture among subjects with an estimated dietary intake >1500 μg/d was compared to those with estimated intakes <500 μg/d, it was found that the risk of fracture was increased by a factor of approximately 2 among subjects in the highest category of vitamin A intake. Interestingly, retinoids have been shown to inhibit heterotopic bone formation in 3 different studies. ATRA does not affect mRNA expression of c-Fms in bone marrow macrophages but decreases mRNA expression of Rank (155). Please enable it to take advantage of the complete set of features! 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. A cross-sectional study measuring BMD of the total body, spine, and total hip (with subregions) on 11 068 women 50–79 years of age enrolled in the Women's Health Initiative Observational Study and Clinical Trial at 3 clinics in the United States (Pittsburgh, Pennsylvania; Birmingham, Alabama; and Tucson, Arizona) found no relationship of retinol or retinol plus provitamin A carotenoids from foods or foods and supplements to BMD (100). . These observations suggest that the inhibitory action of ATRA occurs at an early stage of osteoclast differentiation. This is in agreement with the study of Kneissel et al (75), which showed decreased periosteal mineralizing surfaces (independent of increased resorption), but an unaffected periosteal mineral apposition rate in rats treated with Ro 13–6298. 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). Increased vitamin D has been reported to protect the dog (121), chick (122), and human (74) against vitamin A toxicity, whereas excess vitamin A has been shown to reduce the effects of hypervitaminosis D in rats (123) and young broiler chickens (124). One possibility is that osteoclast progenitor cells in the periosteum are different from those in the bone marrow and circulation. Retinoids can also have rapid nongenomic/nonclassical actions. Domina Petric, MD Vitamin A: metabolism 2. Absorption and metabolism of vitamin B6 The phosphorylated vitamers are dephosphorylated by membrane-bound alkaline phosphatase in the intestinal mucosa; pyridoxal, pyridoxamine, and pyri-doxine are all absorbed rapidly by passive diffusion. Cross-sectional study of 232 postmenopausal Spanish women with (n = 101) and without (n = 124) osteoporosis determined by quantitative ultrasound of the calcaneal bone. In its inactive form, Nfatc1 is phosphorylated, and activation is caused by dephosphorylation mediated by calcineurin, which is activated by signaling from FcRγ and/or DAP12 linked to Ig-like receptors expressed on the surface of osteoclasts. 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). HUANG HS, GOODMAN DS. Furthermore, the reliability of the bone particle assay for use in measuring resorptive activity of mature osteoclasts has not been demonstrated. It is still not clear whether 9-cis RA is formed physiologically in bone cells and what role this isomer may play as a specific ligand for RXR (27); however, it was shown recently that 9-cis RA can be produced in vivo in the mouse pancreas (28), which suggests that the isomer may be physiologically relevant. Human Studies Evaluating the Risk of Fractures and BMD to Determine the Impact of Increased Vitamin A Intake on Bone Health. 3. 7525), the Swedish Rheumatism Association, the Royal 80 Year Fund of King Gustav V, Combine, the County Council of Västerbotten, ALF/TUA at Sahlgrenska University Hospital, and the Medical Faculty, Umeå University. The studies are mainly observational, and as stated above, it is difficult to determine vitamin A status in individuals. RAR-mediated repression has been shown to be essential for chondroblast differentiation during skeletal development. The binding of ATRA to the RAR/RXR complex induces a conformational change in the ligand binding domain of the receptor, which causes replacement of corepressors by coactivators, such as members of the steroid receptor coactivator (SRC)/p160 family and p300/CREB-binding protein (CBP) (26, 34). Evaluation of different promoter usage and alternative splicing has shown that there are at least 2 different isoforms for each isotype (26). Elsevier Inc. 2008. Scand J Clin Lab Invest. These experiments suggest that RARα is responsible for the inhibition of osteoclastogenesis stimulated by RANKL. As mentioned in Section IX.A., ATRA also inhibits osteoclast formation in RANKL-stimulated cultures of human CD14+ monocytes (160). Esterification of vitamin A by an acetone powder from pancreas. Goodman DS, Blomstrand R, Werner B, Huang HS, Shiratori T. Women in the highest quintile of vitamin A intake (≥3000 μg/d) had a significantly increased relative risk of 1.48 for hip fracture in comparison to women in the lowest quintile of intake (≤1250 μg/d). This suggestion was supported not only by morphological observations but also by increased expression of hypoxia-related genes like Hifα and downstream genes such as Twist1 and Mmp2 in bone marrow from humeri in rats fed with pellets containing high concentrations of retinyl palmitate and retinyl acetate for 8 days (76). In contrast, mice lacking OPG exhibit early-onset osteoporosis (131, 132). Increased numbers of resorption pits accompanied by altered microfilament morphology have also been demonstrated with the retinoid isotretinoin (13-cis RA; 1 μm) in rat osteoclasts incubated on bovine cortical bone slices (162). INTESTINAL ABSORPTION AND METABOLISM OF 14 C-LABELED VITAMIN A ALCOHOL AND P-CAROTENE IN THE RAT * @inproceedings{HUANGt2003INTESTINALAA, title={INTESTINAL ABSORPTION AND METABOLISM OF 14 C-LABELED VITAMIN A ALCOHOL AND P-CAROTENE IN THE RAT *}, author={HELEN S. HUANGt and And and Dewitt and {\vS}. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/, NLM 4, pp. 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). 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. [Influence of dietary fat-level on the carotene and vitamin A utilization]. Roforth MM, Liu G, Khosla S, Monroe DG. Similarly, a microarray analysis of the samples showed increased expression of other hypoxia-related genes such as Entpd3, Nt5e, Bhlhe41, and Loxl2 (167). Experiments employing different RAR agonists and antagonists have also demonstrated that inhibition of osteoclast formation in RANKL-stimulated human CD14+ cells is mediated by RARα (our unpublished observations). Esterification of vitamin A by an acetone powder from pancreas. Absorption, Metabolism, and Excretion of Vitamin D Vitamin D (vitamin D without a subscript represents either vitamin D2 or D3) is fat soluble and, therefore, once ingested vitamin D2 and vitamin D3 are incorporated into the chylomicron fraction and absorbed in the small intestine into the lymphatic system. Biosynthesis of Vitamin B6 3. J Clin Invest. A slowing of the rate of humerus bone loss was attributed to vitamin A intake. In the past, DXA has been employed to measure BMD and has proven to be valuable clinically, especially in the postmenopausal female, but DXA does not distinguish between cortical and trabecular bone. In recent experiments, however, no evidence has been found for ATRA to affect mRNA expression of Il1β, Il6, or Tnfα in calvarial bones or of Cox2 mRNA being affected (89). Remodeling is the process by which new bone replaces old bone. Treatment of these mice with CD1530 prevented the heterotopic bone formation at the site of adeno-Cre injections. Vitamin B12. 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. 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. This was explained by showing that ATRA, unlike 1,25(OH)2 D3, did not induce the mRNA expression of Rankl. In addition, several transcription factors, including v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MafB), interferon regulatory factor-8 (IRF-8), and B-cell lymphoma 6 (Bcl6), negatively regulate osteoclastogenesis (136), and the expression of these factors is repressed during osteoclast differentiation. dendritic cell-specific transmembrane protein, v-maf musculoaponeurotic fibrosarcoma oncogene homolog B, microphthalmia-associated transcription factor, peroxisome proliferator-activated receptor. . Macdonald HM, New SA, Golden MH, Campbell MK, Reid DM. Effects on bone were assessed in young (2–3 mo), middle-aged (8–10 mo), and old (18–20 mo) rats. The prevalence of vitamin D deficiency [25(OH) D < 50 nmol/L] was 70.1%. Corpus ID: 27651673. 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. Genetic experiments have shown that mice overexpressing OPG, or with a deletion of RANKL, RANK, or c-Fms, or double knockout of FcRγ/DAP12, lack osteoclasts and exhibit osteopetrosis. He noted erosion of bones after adding fragments of crystalline vitamin A acetate to parietal bones from newborn mice and transplanting them to cerebral hemispheres of littermates (139). 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. 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). 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. It has been reported that bone is the second most important organ for clearance of chylomicron remnants and that vitamins can be delivered to osteoblasts in vivo via chylomicrons (23). Effects of β-Carotene and Its Cleavage Products in Primary Pneumocyte Type II Cells. 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. Vitamin D deficiency is currently defined as 25(OH) D < 50 nmol/L (113). Later, Wang et al (158) used a coculture system containing mouse bone marrow cells to which primary calvarial osteoblasts from newborn mice were added, and they reported that ATRA (10−6 to 10−9m) inhibited osteoclast formation induced by 1,25(OH)2 D3. Toxic effects may be local, but the toxicant must be dissolved and absorbed to some extent to affect the cell. Toxic effects may be local, but the toxicant must be dissolved and absorbed to some extent to affect the cell. In humans, the most important compounds in this group are vitamin D 3 (also known as cholecalciferol) and vitamin D 2 (ergocalciferol).. . National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error, American Society for Clinical Investigation. Acute hypervitaminosis A sickness, characterized by vertigo, vomiting, diarrhea, headache, convulsions, and peeling of the skin, also occurs. During remodeling, bone cells called osteoblasts form new bone at specific sites after old bone is resorbed by large, multinucleated cells termed osteoclasts. • This step is catalyzed by another enzyme, retinaldehyde reductase, which is also found in the liver and eye. Goodman DS, Blomstrand R, Werner B, Huang HS, Shiratori T. This review aims to investigate the impact of high-fat feeding on functions of lipophilic vitamins. ADH, alcohol dehydrogenase; Stra6, stimulated by retinoic acid 6; RALDH, retinal dehydrogenase. Hepatocytes take up the remnants by receptor-mediated endocytosis, and the retinyl esters are hydrolyzed (18). . RAR-retinoid X receptor heterodimers function as transcription factors, binding RAR-responsive elements in promoters of different genes. Reduced bone formation was observed (173). 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). Sections of the tibial shaft showed pathology confined to the outermost cortex, with no evidence of abnormal remodeling of the underlying bone. Another example of nongenomic effects of retinoids is mediated by RARα. Retinyl esters and carotenoids are incorporated into chylomicrons that are transported by the lymphatics. 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). Huang H, Goodman DS (1965) Vitamin A and carotenoids. 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. 2017 May 21;6(2):37. doi: 10.3390/antiox6020037. Cantorna MT, Nashold FE, Chun TY, Hayes CE. A recent study employing pooled data from 11 double-blind, randomized, controlled trials of oral vitamin D supplementation offers a degree of validation to these recommendations. . 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. A, Osteoblasts on the surfaces of cortical and trabecular bone originate from pluripotent stromal cells present in bone marrow. Furthermore, a longitudinal, population-based, prospective study of 2322 men in Uppsala, Sweden, with 30 years of follow-up has suggested that the risk of fracture, including hip fracture, is higher among men with the highest levels of serum retinol (92). . Short-term studies in rodents treated with increased concentrations of retinoids (ATRA or Ro 13–6298) suggest that cortical bone thinning is due primarily to stimulation of subperiosteal resorption (75). . BMD of the lumbar spine and femoral neck showed that although dietary vitamin A (or retinol) appeared to worsen bone loss at the femoral neck, there was no relationship of BMD loss to either retinol or vitamin A intake when the vitamin A from supplements (mostly cod liver oil) was added. Bergman SM, O'Mailia J, Krane NK, Wallin JD. Vitamin D 2 (ergocalciferol) is derived from the plant sterol ergosterol. How to Get Your Energy & Metabolism Back to Normal. No stromal cells are present with adherent cells in these preparations, the adherent cells do not form osteoclasts when treated with 1,25(OH)2 D3 or PTH, and amplification of Akp1 (gene encoding alkaline phosphatase) and Rankl transcripts does not occur. The most potent inhibition occurred when ATRA was added with RANKL to the cultures; when ATRA was added 24 or 48 hours after RANKL, inhibition gradually decreased. Rothenberg AB, Berdon WE, Woodard JC, Cowles RA. How are osteoclasts induced to resorb bone? J … After combining with RBP, the retinol-RBP complex can enter the circulation, where it combines with transthyretin, a larger protein that is also synthesized in the liver (20). In adult life, 2 processes are responsible for changes in the skeleton: remodeling and modeling (128). You simply need to take in more vitamin B12. Alternatively, ATRA can be shuttled by FABP to bind PPARs in the nucleus. Mata-Granados JM, Cuenca-Acevedo JR, Luque de Castro MD, Holick MF, Quesada-Gomez JM. . It has been reported that mature osteoclasts exhibit more phenotypic variation than realized previously, suggesting that progenitor cells from different sites might exhibit significant differences also (137). O'Neill RP, Jones SJ, Boyde A, Taylor ML, Arnett TR. 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). Summary of the Effects by Retinoids on Bone Resorption and Osteoclast Formation in Vivo. Studies on the intestinal absorption of radioactive beta-carotene and vitamin A in man. 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. Vitamin A is obtained as retinol (preformed) from animal sources, or as provitamin A carotenoids from plant sources. -, Biochem J. Where it is possible to increase dietary fat, this will likely improve the absorption of vitamin A activity from the diet. FcRγ/DAP12 signaling causes activation of phospholipase Cγ (PLCγ), a rise of intracellular calcium, and subsequent activation of the phosphatase calcineurin. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. 4: Trainee in Metabolism and Endocrinology under grant T1-AM-5397 from the National Institutes of Health. This early inhibition suggests that ATRA inhibits osteoclastogenesis primarily by interfering with signal transduction pathways downstream of RANK, rather than by inhibiting RANK expression. Kurlandsky SB, Gamble MV, Ramakrishnan R, Blaner WS. 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. Absorption may occur through the alimentary tract, skin, lungs, via the eye, mammary gland, or uterus, as well as from sites of injection. Supplementation with vitamin A during growth has also been associated with decreased bone mass in peri- and premenopausal women. This is often referred to as coupling, and the sites where it occurs are called bone multicellular units. However, the changes in cortical and trabecular bone did not affect the resistance to fractures. J Nutr. In humans, increased vitamin A intake is suggested to diminish the ability of vitamin D to increase calcium absorption (125). After intestinal absorption and transport with chylomicrons α-tocopherol is mostly transferred to parenchymal cells of the liver were most of the fat-soluble vitamin is stored. VITAMIN A AND CAROTENOIDS. The prevalence of high serum retinol levels (≥2.8 μmol/L) was 36.4%; that of vitamin D deficiency, 70.1%; for individuals with vitamin D deficiency (n = 152), 60.4% (n = 92) had serum retinol levels higher than 2.8 μmol/L; in women with vitamin D deficiency, risk of osteoporosis in the highest retinol quintile was 5 times greater than risk in the lowest retinol quintile, Cross-sectional study of 232 postmenopausal Spanish women with (n = 78) and without (n = 154) osteoporosis determined by DXA of the lumbar spine and total hip, The prevalence of high serum retinol levels (>80 μg/dL) was 36.4%; that of vitamin D deficiency, 70.1%; for individuals with vitamin D deficiency (n = 152), 60.4% (n = 92) had serum retinol levels higher than 80 μg/dL; in women with vitamin D deficiency, risk of osteoporosis was approximately 8 times higher in women with the highest retinol levels in comparison to women with the lowest retinol levels, Egg-laying hen mononuclear bone marrow cells, Mouse bone marrow cells + mouse calvarial cells, Rabbit bone marrow osteoclasts on dentine, Chicken bone marrow osteoclasts on either bone or dentine. In neuronal cells, RARα has been shown to be actively transported from the nucleus to the cytoplasm, where it functions as an RNA-binding protein, inhibiting translation of other proteins (46–48). Abbreviations: Thyroparath, thyroparathyroidectomized; ↓, decrease; ↑, increase; ?, not investigated; —, no effect. It has been reported recently that ATRA can also inhibit formation of mature osteoclasts in cultures of purified CD14+ monocytes stimulated with RANKL (160). Vitamin A is a fat-soluble vitamin and depends on micellar solubilization for dispersion into the small intestine, which results in poor use of vitamin A from low-fat diets. Less clear balance between bone resorption primarily by enhancing the differentiation of osteoclast differentiation, Khosla S Welch... An RARα specific agonist, GR104 from cells in bone marrow, spleen, or as provitamin A is! Absorption decreases as intake of preformed vitamin A absorption, storage and mobilization, Chandraratna RA, J. 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