Role of iron in the collagen synthesis. 

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... and they form flattened lining cells on the bone surface until a new remodeling cycle is triggered or become osteocyte cells (as reviewed previously, osteocytes are cells derived from osteoblasts embedded in bone) [31]. Biochemical bone turnover markers are released during bone remodeling and provide a measure of the rate of bone metabolism. They comprise enzymes secreted by osteoblasts and osteoclasts during remodeling, degradation products formed during resorption, and precursors released during new bone formation. They reflect metabolic abnormalities such as accelerated bone turnover (Table 2) [46]. Iron participates in a variety of enzymatic systems in the body, including the enzymes involved in collagen synthesis. Collagen is the most abundant protein in animals, and the major component of connective tissue [47]. Regarding bone tissue, about 90% of total bone protein is composed of type I collagen [31]. For collagen synthesis, first, a three-dimensional stranded structure is assembled, with the amino acids glycine and proline as its principal components. This is not yet collagen but its precursor, procollagen. Procollagen is then modified by the addition of hydroxyl groups to the amino acids proline and lysine. This step is important for later glycosylation and the formation of the triple helix structure of collag en. This reaction requires α -ketoglutarate, molecular oxygen, ferrous iron, and a reducing agent [48,49]. In this regard, ascorbate reduces the inactive Fe 3+ state to the active Fe 2+ state [50]. During the reaction, α -ketoglutarate is decarboxylated oxidatively to produce succinate and CO 2 [48] (Figure 3). These hydroxylation reactions are catalyzed by two different enzymes: prolyl-4-hydroxylase [48] and lysyl-hydroxylase [49]. Another mechanism in which iron participates in bone metabolism is through vitamin D activation and deactivation. In this pathway, the cytochrome P450 superfamily, a large number of heme-containing monooxygenases, plays an important role [51]. Vitamin D undergoes two steps of hydroxylation for its activation. The first step occurs in the liver and as a result 25-hydroxyvitamin D (25OHD) is produced. This is the first and bounden step in the production of the active form of this vitamin [51,52]. This step occurs in the liver and is catalyzed by the cythocrome P-450 25-hydroxylase (CYP2R1) [51]. Mutations in CYP2R1 gene lead to low serum levels of 25OHD and are associated with rickets (softening and weakening of bones in children, ...

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... performed specific interventions in these women. Anemic women were treated with ferrous sulfate, and it was found that those who recovered normal hemoglobin levels exhibited a decrease in bone remodeling, as both P1NP and NTx were lower at the end of treatment compared to baseline [95]. Two nutritional interventions were carried out in iron-deficient women using functional foods. One of them studied the effects of consuming an iron-fortified fruit juice compared to placebo. This functional food was very efficacious in improving iron status [96]; however, iron formation and resorption markers did not change during the 16-week intervention period [90]. The other nutritional intervention investigated the effects of an iron- or iron and vitamin D-fortified dairy product on iron and bone metabolism. This product did not provide bioavailable iron and iron status did not improve [11]; the vitamin D fortification reduced both bone formation and resorption in these women, as expected, but the possible effect of iron on bone could not be seen [91]. It is difficult to explain why the bones of anemic women responded to the iron recovery, but no variation in bone remodeling was observed in the iron-deficient women who consumed the iron-fortified fruit juice, or why bones from iron-deficient women treated with vitamin D clearly improved. Therefore, further studies in this line are needed. Different mechanisms by which iron deficiency affects bone have been suggested. On the one hand, there is the role of iron as an essential cofactor for hydroxylation of prolyl and lysil residues of procollagen, as detailed before (Figure 2). On the other hand, there is its participation in vitamin D metabolism through the cytochromes P450 (Figure 3). A third mechanism to be considered is hypoxia. A state of hypoxia occurs when oxygen supply to tissues is reduced, as occurs in anemia. Hypoxia is a major stimulator of bone resorption, inducing osteoclastogenesis, which is later followed by osteoblastogenesis [97,98]. Interestingly, during normoxia, α -ketoglutarate and both molecular oxygen and iron are needed for the activity of a prolyl hydroxylase domain protein that acts on the hypoxia inducible factor α (HIF - 1α) for its degradation , preventing its action. The role of iron in HIF- 1α is similar to that involved in the collagen synthesis, as indicated previously (Figure 3). Under hypoxia conditions, HIF- 1α is not degraded and translocates to the nucleus where transcription of >100 genes is regulated [48]. Among these genes, erythropoietin (EPO), PDGF, and transferrin are of particular interest in exploring the link between iron deficiency anemia and bone health. In this regard, apart from the erythropoiesis function, several pleiotropic effects of EPO have been recognized. EPO acts ...

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... performed specific interventions in these women. Anemic women were treated with ferrous sulfate, and it was found that those who recovered normal hemoglobin levels exhibited a decrease in bone remodeling, as both P1NP and NTx were lower at the end of treatment compared to baseline [95]. Two nutritional interventions were carried out in iron-deficient women using functional foods. One of them studied the effects of consuming an iron-fortified fruit juice compared to placebo. This functional food was very efficacious in improving iron status [96]; however, iron formation and resorption markers did not change during the 16-week intervention period [90]. The other nutritional intervention investigated the effects of an iron- or iron and vitamin D-fortified dairy product on iron and bone metabolism. This product did not provide bioavailable iron and iron status did not improve [11]; the vitamin D fortification reduced both bone formation and resorption in these women, as expected, but the possible effect of iron on bone could not be seen [91]. It is difficult to explain why the bones of anemic women responded to the iron recovery, but no variation in bone remodeling was observed in the iron-deficient women who consumed the iron-fortified fruit juice, or why bones from iron-deficient women treated with vitamin D clearly improved. Therefore, further studies in this line are needed. Different mechanisms by which iron deficiency affects bone have been suggested. On the one hand, there is the role of iron as an essential cofactor for hydroxylation of prolyl and lysil residues of procollagen, as detailed before (Figure 2). On the other hand, there is its participation in vitamin D metabolism through the cytochromes P450 (Figure 3). A third mechanism to be considered is hypoxia. A state of hypoxia occurs when oxygen supply to tissues is reduced, as occurs in anemia. Hypoxia is a major stimulator of bone resorption, inducing osteoclastogenesis, which is later followed by osteoblastogenesis [97,98]. Interestingly, during normoxia, α -ketoglutarate and both molecular oxygen and iron are needed for the activity of a prolyl hydroxylase domain protein that acts on the hypoxia inducible factor α (HIF - 1α) for its degradation , preventing its action. The role of iron in HIF- 1α is similar to that involved in the collagen synthesis, as indicated previously (Figure 3). Under hypoxia conditions, HIF- 1α is not degraded and translocates to the nucleus where transcription of >100 genes is regulated [48]. Among these genes, erythropoietin (EPO), PDGF, and transferrin are of particular interest in exploring the link between iron deficiency anemia and bone health. In this regard, apart from the erythropoiesis function, several pleiotropic effects of EPO have been recognized. EPO acts ...