This article [Caire-Juvera et al., 2008: (http://www.ajcn.org/cgi/content/abstract/ajcn.2008.26451v1) (http://www.ncbi.nlm.nih.gov/pubmed/19056568?dopt=Abstract)] suggests that a "high" vitamin A intake, together with a low vitamin D intake, may increase the risk of fractures. This is interesting, and the article cites some of the past research that links excessive vitamin A intakes with an increased risk of fracture. But the intakes of vitamin A that supposedly increase the risk of osteoporosis or fractures, according to past research, are in the range of only 5,000 IU/d or more. A single carrot contains something like 3,000 IU of preformed vitamin A. I forget the amounts, but some vegetables contain large amounts. But this association with low vitamin D intakes and high vitamin A intakes is plausible, given that vitamin D tends to antagonize and oppose the cellular differentiation "programs" that vitamin A produces in cultured monocytic cell lines. A similar type of thing may occur in the bones, in which progenitor cells can differentiate into either osteoclasts or monocytes/macrophages. This article [Kaji et al. (2000): (http://www.ncbi.nlm.nih.gov/pubmed/10623885)] shows that hormonal vitamin D can induce differentiation of poorly-differentiated monocytic cells along the osteoclast lineage (implying that hormonal vitamin D would increase bone breakdown), but the osteoclast precursor cells were deficient in bone resorptive activity (implying that this effect of hormonal vitamin D would tend to inhibit bone breakdown or have a neutral effect, all other things being equal). Kaji et al. (2000) also showed that the differentiation produced by hormonal vitamin D was very dependent on the actions of other cytokines, such as interleukin-4. Vitamin D also influences osteoblast differentiation [van Driel et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15320744)], but the point is that vitamin A could promote osteoclast differentiation. Caire-Juvera et al. (2008) discuss effects of vitamin A on serum calcium, and that could play a role. But I'm sure a big part of it is antagonistic differentiation patterns on osteoclasts, osteoblasts, their progenitor cells, or all of the above. The research is so vast in that area that I'd have to read about it more to get the details, but there are countless articles that, in that vein, show interactions of retinoids with vitamin D in osteoclastic differentiation. In terms of monocyte vs. granulocyte differentiation, though, the research is fairly clear and shows that hormonal vitamin D tends to antagonize many of the pro-granulocytic-differentiating effects retinoids, derived from vitamin A, on poorly-differentiated, monocytic progenitor cells.
This article by Bastie et al. (2004) [Bastie et al., 2004: (http://mend.endojournals.org/cgi/content/full/18/11/2685) (http://www.ncbi.nlm.nih.gov/pubmed/15284334?dopt=Abstract)] shows that 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], the hormonal form of vitamin D3, generally promotes monocyte-macrophage differentiation in cultured monocytic cells (such as HL-60 cells) and, by producing this differentiation along the monocyte-macrophage lineage, opposes the granulocytic differentiation that all-trans-retinoic acid (ATRA) and other vitamin A-derived mediators produce. This is not always the case, and hormonal vitamin D can, in some cell types or cell contexts, enhance ATRA-induced granulocyte differentiation. One of many examples of that is in this article [Le et al., 1999: (http://www.jbc.org/cgi/content/full/274/31/21651) (http://www.ncbi.nlm.nih.gov/pubmed/10419474?dopt=Abstract)], in which both hormonal vitamin D and ATRA are shown to enhance AML2 expression in association with granulocytic differentiation of cultured HL-60 cells. That's a random example out of many others. But, in general, hormonal vitamin D, which can be produced locally by cells in the bone marrow from 25-hydroxyvitamin D, promotes the differentiation and maturation of undifferentiated bone marrow progenitor cells into monocytes and macrophages, and retinoids produce more of a granulocytic differentiation "program." That article by Bastie et al. (2004) is interesting and discusses the close analogy between HL-60 cells and CD34+ progenitor cells from the bone marrow. The authors note that HL-60 cells are likely to be more differentiated along the monocyte lineage than CD34+ cells are, and CD34+ cells can actually become red blood cells or megakaryocytes [Loo and Beguin, 1999: (http://bloodjournal.hematologylibrary.org/cgi/content/full/93/10/3286) (http://www.ncbi.nlm.nih.gov/pubmed/10233880?dopt=Abstract)], also.
This type of thing might be relevant to understanding the mysterious aspects of conditions such as intracranial hypertension. Iron deficiency has been associated with pseudotumor cerebri and "papilledema" (which is basically part and parcel of pseudotumor cerebri and idiopathic intracranial hypertension) [Tugal et al., 1994: (http://www.ncbi.nlm.nih.gov/pubmed/8037348)], and both folic acid and vitamin B12 deficiencies have been shown to be associated with elevations in intracranial pressure due to venous sinus thrombosis, etc. [Boncoraglio et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15171737); Hotoleanu et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/18333369); Nagaraja et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18617193); Sirdofsky et al., 1994: (http://www.ncbi.nlm.nih.gov/pubmed/8032485); van Gelder et al., 1991: (http://www.ncbi.nlm.nih.gov/pubmed/1665766); Yetgin et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16326411)]. Retinoids and excesses of vitamin A have a profound association with intracranial hypertension and papilledema [Jacobson et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10496276)], and the mechanisms underlying this condition are not well understood. It's generally explained in terms of being the result of anemia in general, but there's probably some more specific imbalance of hematopoietic cells that can lead to it or something. Given all the information about endothelial progenitor cells contributing to the maintenance and growth or replenishment of the endothelium, I wonder if it's anemia + depletion of some specific subtype of bone marrow-derived, endothelial progenitor cell. There may be an increase in turnover of CD34+-derived cells, leading to depletion of different subsets. A subset of CD34+ cells are endothelial progenitor cells [Shi et al., 1998: (http://bloodjournal.hematologylibrary.org/cgi/reprint/92/2/362.pdf)]. In the context of excess vitamin A, particularly in the absence of vitamin D, more of those progenitor cells might be driven into granulocytic differentiation, thereby producing worsening of inflammation from the accumulation of perivascular mast cells in combination with the anemia, etc.
This competition among CD34+ cells for differentiation along either the erythrocyte or megakaryocyte lineage is sensitive to iron availability, and iron repletion was shown to produce transient thrombocytopenia by increasing the erythroid differentiation of CD34+ cells, at the expense of their differentiation into megakaryocytes (as platelet precursors) (Loo and Beguin, 1999). Vitamin D has actually been used as an adjunct in the treatment of anemia in people with renal disease, and I think this article talks about that [Erturk et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12324918)]. Alon et al. (2002) [Alon et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12031646)] found that hormonal vitamin D promoted the erythroid differentiation of CD34+ bone-marrow cells, in a manner that was synergistic with the erythrocyte survival that erythropoietin had produced.
Vitamin A and the retinoids derived from it also have been shown to influence one-carbon metabolism and interact with the folate cycle and vitamin B12-dependent methionine synthase activity. Retinoids, such as those derived from vitamin A, can increase glycine N-methyltransferase expression in the liver [Ozias et al., 2003: (http://jn.nutrition.org/cgi/content/full/133/12/4090) (http://www.ncbi.nlm.nih.gov/pubmed/14652353?dopt=Abstract)], and maybe retinoids can derange one-carbon metabolism in other cell types. Even though the induction of GNMT lowers plasma homocysteine levels in animals (Ozias et al., 2003), this is not really beneficial. For example, Rowling et al. (2002) [Rowling et al., 2002: (http://jn.nutrition.org/cgi/content/full/132/3/365) (http://www.ncbi.nlm.nih.gov/pubmed/11880556?dopt=Abstract)] found that vitamin A and other retinoids produced an extreme degree of hypomethylation of DNA in the livers of rats, and this was at least partially a result of the increases in GNMT expression and activity. Given that folic acid and vitamin B12 tend to increase and normalize DNA methylation, albeit inconsistently in different cellular contexts [Stempak et al., 2005: (http://carcin.oxfordjournals.org/cgi/content/full/26/5/981) (http://www.ncbi.nlm.nih.gov/pubmed/15695236?dopt=Abstract)], and also to ameliorate some cases of intracranial hypertension, it's conceivable that the positive association of excessive vitamin A intakes with intracranial hypertension may be due to some vitamin A-induced changes in DNA methylation in, and differentiation of, endothelial progenitor cells or of endothelial cells by themselves (changes that would lead to thrombosis). That could be a starting point to try to detect some kind of unifying explanation for those more mysterious associations of intracranial hypertension with, on the one hand, iron and folate and vitamin B12 deficiencies and, on the other hand, vitamin A excesses.
It's also possible that vitamin A acts on choroid plexus epithelial cells to produce intracranial hypertension (or something like that). The effect is still pretty mysterious.
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