This is a complex and difficult-to-understand area of research, for various reasons, but some of these articles have helped me to sort of understand the alkaline phosphatase issue. The authors of this article [Lomashvili et al., 2004: (http://jasn.asnjournals.org/cgi/content/full/15/6/1392)(http://www.ncbi.nlm.nih.gov/pubmed/15153550?dopt=Abstract)] discuss evidence that elevated alkaline phosphatase activity, either on the plasma membranes of smooth muscle cells or in soluble form, apparently, in the plasma, hydrolyzes pyrophosphate (P03-O-PO3)(4-) (PPi) and thereby prevents the inhibition of vascular calcification that PPi is thought to confer, even in the presence of elevated levels of free calcium Ca2+ and inorganic PO4(3-) (PO4). Vitamin B6 repletion/supplementation and vitamin D3 repletion generally decrease serum alkaline phosphatase (ALP) and may reduce calcification, in part, by those mechanisms (to the extent that reductions in free ALP activity reflect some changes at the sites of calcification). Matias et al. (2009) [Matias et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/18775809?dopt=Abstract)], for example, found that 25-hydroxyvitamin D concentrations correlated inversely with the extents of vascular calcification among patients with renal failure. The PPI is thought to bind to sites of existing calcification and block PO4 from binding and forming more hydroxyapatite crystals. I cited some of the articles showing the vitamin B6 associations and mechanisms, in relation to ALP, in some past postings [(http://hardcorephysiologyfun.blogspot.com/2009/01/another-article-mentioning-plp-in.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/pyridoxine-calcium-channels-and.html)].
This is a really confusing area of research, and it's still not clear to me what the origin of serum ALP is. Supposedly serum ALP decreases as bone turnover decreases, and Regidor et al. (2008) [Regidor et al., 2008: (http://www.asn-online.org/press/pdf/2008-Media/Kalantar-Zadeh-Bone%20Disease%20Study.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/18667733)] discussed the fact that extreme and pathological decreases in bone turnover (such as might result from some of the osteoclast-and-monocyte-macrophage-lineage-cell-cytotoxic approaches to treating bone demineralization) can decrease serum ALP to pathologically low levels. I don't think those kinds of decreases would occur in response to reasonable dosages of supplemental vitamin D, but the increases in serum calcium that tend to result from either excessive vitamin D or calcium supplementation could, in my opinion, promote thrombogenic effects (hypercoagulability, etc.) (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html). The article by Seelig (1990) is especially good, and here are two articles that discuss those issues and that are cited in that old posting [Ruttmann et al., 2007:(http://www.anesthesiaanalgesia.org/cgi/content/full/104/6/1475) (http://www.ncbi.nlm.nih.gov/pubmed/17513645); Seelig, 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2132751)]. Supposedly the actual serum ALP activity is partially a result of ALP, which acts extracellularly, on the plasma membranes of neutrophils, etc. I just read through an editorial and a couple of articles on ALP and calcification, and the researchers talk about the way no one really understands research on ALP. They don't say that, but they discuss the fact that it's not entirely clear if it's active on neutrophils or other cell types and then cleaved into a soluble form or what is even going on. It sounds like serum ALP is sort of like serum soluble transferrin receptor (sTfR), in the sense that serum ALP is normally produced, released upon cleavage of the membrane-anchored form during apoptosis (?), at some rate that correlates with the rate of turnover of osteoclasts and osteoblasts. But it can be elevated in cholestatic liver disease also (see 2nd old posting on vitamin B6 and ALP), etc. I guess this one article that I don't have time to cite right now says that serum ALP is enzymatically active but doesn't contribute to PPi cleavage. The authors also say that serum ALP don't correlate with serum PPi and that it's mainly the ALP expressed by smooth muscle cells that hydrolyzes PPi locally and is thought to thereby contribute to calcification (by forming PO4 locally, from PPi). The authors say no one knows why vascular calcification nonetheless seems to correlate with changes in bone turnover. I'm not sure what the correlation is that they're referring to, but presumably they're saying that increases in calcification accompany extremely low levels of bone turnover (presumably as a result of localized decreases in extracellular PPi at sites of vascular calcification, if one accepts the validity of these associations and mechanisms). They're saying they don't know how the expression and activity of smooth-muscle-cell ALP could be changed in association with changes in osteoblast apoptosis (and with the associated changes in serum ALP that do not contribute significantly to the localized cleavage of PPi, on the plasma membranes of the smooth muscle cells).
The research on vitamin B6 and ALP is just really confusing to everyone who reads it, seemingly, and to me. I can understand the basics--that plasma-membrane ALP cleaves albumin-bound pyridoxal-5'-phosphate (PLP) into pyridoxal, which then enters cells and is rephosphorylated, to PLP, by pyridoxal kinase. Humans and animals that have genetic mutations that decrease the activities of one or more of their alkaline phosphatase isoforms apparently have elevated serum PLP levels but have functional B6 deficiency, because ALP is required for the uptake of pyridoxal into cells (as discussed above). But it's not at all clear to me what the mechanism is by which an increase in B6 intake would decrease serum ALP. It's not an especially enjoyable topic to read about. I also think that excesses of B6 could produce neuropathy, in part, by decreasing ALP excessively, but that's just my opinion. And excesses of vitamin D intake could promote vascular calcification by elevating serum calcium, given that the traditional focus on the [Ca] x [PO4] product, as a factor whose elevation is associated with an increase in the extent calcification, shouldn't just be completely discounted or ignored. Everyone still seems to think taking a lot of calcium supplementation, beyond the RDA or whatever, is a good idea. I don't think it is, and I think people don't realize the manifold factors that can prevent the absorption or retention of dietary magnesium. I've discussed some of them in past postings and have discussed some of the dosage ranges that have been applied to extreme states, such as liver disease, in which magnesium absorption can become compromised. The dosage range for magnesium is fairly large, and I don't know what the right dosage is. That's the type of thing one would want to discuss with one's doctor.
No comments:
Post a Comment