Wednesday, 9 December 2015

Vitamin D and remyelination

de la Fuente AG, Errea O, van Wijngaarden P, Gonzalez GA, Kerninon C, Jarjour AA, Lewis HJ, Jones CA, Nait-Oumesmar B, Zhao C, Huang JK, Ffrench-Constant C, Franklin RJ.Vitamin D receptor–retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiationJ Cell Biol. 2015 Dec 7;211(5):975-985

The mechanisms regulating differentiation of oligodendrocyte (OLG) progenitor cells (OPCs) into mature OLGs are key to understanding myelination and remyelination. Signaling via the retinoid X receptor γ (RXR-γ) has been shown to be a positive regulator of OPC differentiation. However, the nuclear receptor (NR) binding partner of RXR-γ has not been established. In this study we show that RXR-γ binds to several NRs in OPCs and OLGs, one of which is vitamin D receptor (VDR). Using pharmacological and knockdown approaches we show that RXR–VDR signaling induces OPC differentiation and that VDR agonist vitamin D enhances OPC differentiation. We also show expression of VDR in OLG lineage cells in multiple sclerosis. Our data reveal a role for vitamin D in the regenerative component of demyelinating disease and identify a new target for remyelination medicines.




New work from Prof ffffffffrench-constant and Franklinstein show that vitamin D can now affect oligodendrocyte function. (see picture myelin green, nerves red). Many many genes have gene response elements that respond to vitamin D and the receptor that they hope will be the switch factor for myelin repair is called RXR.

They find that this too has a vitamin D receptor response element, so vitamin D aid recovery and show that this can aid remyelination. This is implied here and I guess the data will be out eventually.

They were using rat cells and these beasties live in the dark and so no quite human however importantly, the system was really pushed to show this effect. In the original experiment when the precursor cells were treated with vitamin D there was no difference in proliferation, differentiation or survival.

What they had to do was first ensure that there was no vitamin D response and then add it. Then they showed it stopped vitamin D proliferation but it enhanced differentiation.

However, ask yourself this! Many of you have done the experiment already. There are loads of you out there who are taking ProfGs advice and scoffing vitamin D tablets, as we have no sun in Northern Europe at the minute.

Did Vitamin D supplementation make a dramatic impact to your symptoms that should have been repairing in droves? If the simple belief was correct? Do you feel it happening when out in the sun maybe the best treatment for MS is a deck chair on the promenade. 
I suspect we know the answer to this experiment? 

I expect that more than just VD will be needed to get repair but with the X (RXR) factor being stimulated too. However after Vitamin D did you feel it happen? Let's have your views?

Irrespective of this make sure you are vitamin replete to ensure good bone health and who knows it can be helping the myelin.

34 comments:

  1. This comment has been removed by the author.

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  2. Me thinks this one will go in the same direction as the Biotin study, but we live in hope.
    Regards as always.

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  3. Prof M, The most sensible thing you have ever said. My mum will have read a report in the Daily Mail and I will get the usual call 'saying 'isn't it great, getting in the sun will repair MS damage'. I don't know Profs FF and F., but I would like to tell them to **** off on the basis that reports like this raise hope and come to nothing. They announce c.5 years ago that they had identified a target - Prof Coles has been tasked with leading on the human trials, but this (according to his website) hasn't started because of funding problems. I would bring in a rule that researchers could only publish material after a Phase 1 trial has taken place. I've lost track of the early research papers which hint at a miracle cure and then are never seen again. on Vitamin D and remyelination
    Publish | Delete | Spam

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    1. My Mum sends me clippings from the Mail on MS related "cures" on a regular basis, why she reads that rag I'll never know.
      "I would bring in a rule that researchers could only publish material after a Phase 1 trial has taken place."
      That would mean hardly anything would ever get published! We do need to publish experimental work to provide the impetus for clinical trials. BTW a phase 1 study is merely to address safety of a compound/treatment a phase II study measures efficacy.

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    2. Dear Anon
      I think it is unfair to blame Profs ff and f for false hope. They are doing their bit to push back the bounderies of science and their work says make sure you are vitamin D replete as it will help in the repair process.But it is the so called journalists that make up the story and over egg the pie.

      My experience with the media is that the story is invariably not right so do not get your hopes up every time you pick up "News of the World" (ps. I know its was shut down).

      We are being asked all the time what is the Impact of the work. So they collect metrics, one metrics will be how many times the work is cited in the media. Therefore the University Press departments do court this and they are part of the problem of hype

      (http://www.cam.ac.uk/research/news/vitamin-d-could-repair-nerve-damage-in-multiple-sclerosis-study-suggests)

      Anyway yes they found a target years ago and you have not seen any action but this is the pace of academics developing trials. They have to fight to get the funding and we have reported many times that the amount of funding for trials is essentially capped. Academic trials seldom get more than about £2,000,000 but pharma spend fifty times that (now some of that is because they are paying for salaries of many people and fees to the Universities/Hospitals).

      Now can they get the drug because this needs to be paid for. If no-one wants to donate it then is this a problem. So say I want to do a trial in 200 people with beta interferon for 2 years. Then that is going to cost 200 x 2 x$50,000 = $10,000,000. But Bexarotene cost less at $1,000-£2,000 a month so $12,000 a year so 24,000 x 200 = 48,000,00-960,000 before you do anything.

      Next problem who is going to pay for the trials and development costs of licencing for a Bexarotene (RXR agonist old drug) no or useless patent protection. Frankly no-one.

      Next how do you use such a drug a quick plus and hope what's there regenerates or is it a long term treatment. If it is what are going to be the side-effects of ling term treatment, virtually every molecule that has been found to be an oligodendrocyte differentiation factor are intracellular factors ubiquitously expressed all the body and so inhibiting them will I predict have issues.

      If researchers only published after phase I then there would be so little to publish.

      As to miracle cures we have them every week, if I did reports on all the animal work published you could get your weekly dollup of hope every week.

      Only Publishing after phase I

      I am however actually trying to do this but it is not good for anybodies careers. The VSN16R molecule I talk about was first tested in animals on 26:11:2001 and still no publication. But when you don't know how it works if makes it difficult you have over 30,000 targets in the genome how do you find it?

      We have but and are trying to publish but when you referees say: spasticity only involves extensor muscles (WRONG) and is only due to motor nerves (WRONG) and spinal reflexs have nothing to do with spasticity (WRONG)....I cringe and despair so there is pain on both sides I am afraid (rubbish referees and issues of funding on one side and false hope [helping you to get funding] on the other

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    3. P.S. One can also ask why were pharma not interested the company making the little blue pills had a load of RXR agonists in their portfolio. Maybe they are not interested in MS, they are certainly not interested in the UK as they have closed virtually all their research here:-(

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    4. There's no problem publishing research papers in the medical press, but please don't let the tabloids and the general media get hold of it. Best thing my neurologist taught me at diagnosis, don't believe the press or TV, you'll get it from the clinic first.

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  4. So no experiences did your symptoms improve after taking high dose Vitamin D?

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    1. Nah, Mouse. I have PPMS and take 10,000 vit D3 each day and work on a tan every summer by laying scantily apparel in our porch at home. (Heat exacerbates my MS symptoms so sunbathing is an undesirable but necessary evil.)

      My GP says I am dangerously vitamin D3 replete, though I've told him I'm not willing to scale back primarily because of the facts on this blog. My PPMS, by it pathological nature, continues to progress, therefore, vitamin D3 is not fixing or curtailing my MS damage. Vit D3 ,in my opinion, is not remyelin'ative (coined a new term there).

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    2. GP's tend to have an odd idea of what level of vitamin d is dangerous, mainly because they were told vitamin d was dangerous at medical school. If your blood calcium levels are normal there is no danger and as consumption increases with supply if you have taken that amount for a month or so it will not rise.

      It is not that vitamin d is good for you, it is that a lack of it is bad. Once you are no longer deficient extra has no effect. However, no one knows what counts as 'no longer deficient'.

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    3. No symptom improvement after taking 5000 IU daily. I was pretty low when I was diagnosed at 17ng/ml.

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  5. Symptoms may not improve but maybe do not deteriorate as otherwise may have done?

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  6. MD, what concentrations of vitamin D were effective in these experiments? Are they close to physiological concentrations in humans? And how steep was the response, and did it level off? Going from zero vit. D to some effective concentration may be very different than going from this effective concentration to 10 times higher vit D concentrations.

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  7. Well if the Docs want to take this story of Vitamin D to the test has a group of "doctors" gere um Brazil (do not know if I can call them doctors, are even more to Docs. Frankensteins) making totally experimental treatments in patients who "proposes" this, in the hope that MS 'short of time. " I know some who had significant improvement, with a reduction of symptoms, some claiming until their symptoms have disappeared. All of these patients have RRMS. While others do not respond, and mostly has progressively. So, I am not a researcher or anything but I do not believe that Vitamin D is the "miracle" solution for MS, but I believe it can assist yes, that somehow participates in the pathophysiological process of the disease. I myself take Vitamin D every day, I checked my levels of it are stable and do not feel worsening of symptoms ... So maybe science still takes to reach a consensus on this issue ... And no theories of "conspiracy "but as to Bexarotene believe the Big Pharma has no real interest in curing or remielizar anything definitively, unfortunately ...

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    1. So are you suggesting that 'real' doctors as you would call them have more success in treating MS patients with conventional drugs than professor Coimbra?

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  8. whenever I read articles on demyelination I think about initial CNS myelination in the developing infant. Mothers in equatorial regions have greater amounts of breast milk vit D than those at increasing latitudes. VIt D supplements has even been recommended, 5000 IU mainly for proper bone growth. http://www.sciencedaily.com/releases/2014/06/140606184845.htm
    Since vit D may be important in differentiation of OPCs and myelination has anyone looked at myelin density in children from differing latitudes?

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  9. Ah MD and the study in question used which form of Vitamin D, D3 (cholecalciferol) or D2 (ergocalciferol) or the two forms together?

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  10. I thought the following is interesting with regards to vitamin D.

    "How well vitamin D works depends on the amount of other vitamins and minerals that are present in your body. The other vitamins and minerals needed to help vitamin D work well are called cofactors.

    To get the most benefit from vitamin D, you must have other cofactors in your body. Vitamin D has a number of cofactors; the ones listed below are the most important.
    •Magnesium
    •Vitamin K
    •Zinc
    •Boron
    •Vitamin A

    source Vitamin D Council
    http://www.vitamindcouncil.org/about-vitamin-d/vitamin-d-and-other-vitamins-and-minerals/

    A healthy diet should contain enough of these other vitamin and minerals, so having a healthy diet is pretty important.

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    1. There is starting to be quite a bit of research out there showing that Vit K2 is essential to help Vit D send calcium to where it should be - in your bones and not in your blood. For example some studies have shown that fracture risk in the elderly is reduced in those who are taking Vit K2 as well as D3 when compared to taking just Vit D3 by itself (don't have time right now to find the links to include here). Vit K2 is generally made in your gut from Vit K1. Given some of the research indicating that an unbalanced gut biome may have impacts auto-immune diseases I find this quite interesting. I suspect that the almost complete lack of knowledge in dietician and GP land about the role of K2 probably has a lot too do with the panic attacks that arise over high Vit D3 intake and/or levels.

      In my entirely non-randomised trial of N=1 (i.e. me) I knew that my gut was not happy - not from bad diet but probably just from all the other crap (such as high stress, drug side effects, MS etc) that my body was having to deal with. Some months ago I started taking probiotics daily, my gut became much better and started to behave a bit more normally. I take K2 now with my Vit D3, as well as extra magnesium. Now feeling better in myself than I have done for a long time. No improvement in MS symptoms, but quite a lot of other niggling uncomfortable things are better than they were.

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    2. Vitamin K is in leafy green vegetables. Had a roast today for lunch with an extra portion of brussels sprouts.

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    3. Hope no-one is standing downwind of you ;-)

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    4. To Anonymous on 12 Dec at 3.04pm
      Vit K1 is found in green leafy vegetable not Vit K2. Vit K2 is synthesised in your gut from K1, and the only dietary source of K2 that I have found is natto, a fermented Japanese foodstuff. Hence my comments about gut biome - if your gut biome is out of balance there is a good chance that synthesising K2 could be up the putt. I love all leafy green veggies (except celery) and eat heaps of them, but things were definitely out of kilter until I started taking the probiotics. Not all stuff to do with gut biome belongs in the hippy dippy camps, and there is a significant amount of conventional and legitimate research around to do with the impacts of unbalanced gut biome.

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    5. I found this about dietary source of K2:

      https://en.wikipedia.org/wiki/Vitamin_K2

      'Natural K2 is also found in bacterial fermented foods, like mature cheeses and curd. The MK-4 form of K2 is often found in relatively small quantities in meat and eggs. The richest source of natural K2 is the traditional Japanese dish natto[14] made of fermented soybeans and Bacillus subtilis, which provides an unusually rich source of K2 as long-chain MK-7: its consumption in Northern Japan has been linked to significant improvement in K vitamin's status and bone health in many studies.'



      Some other webpages suggest eggs, butter, dairy, vegetables fermented (if specific starter cultures are used), goose liver pate and certain cheeses like brie and gouda are high in K2.

      Most yoghurts have low amounts of vitamin K2. Certain types of cheeses are very high in K2, and others are not. It depends on the specific bacteria. Not all fermented food will be high in K2, but some fermented foods are very high in K2, such as natto. Miso and tempeh are not high n K2.

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    6. Some websites are suggesting vitamin K2 specifically MK7 is needed. Though the Vitamin D Council have not been specific about the type of vitamin K required as a cofactor for vitamin D which would be helpful.

      MK7 is the type often (but not always?) found in vitamin K2 supplements.

      The following article discusses different cheeses and their vitamin K2 content including MK7. Full text free to read.

      http://www.journalofdairyscience.org/article/S0022-0302(13)00034-9/fulltext

      Quantitative measurement of vitamin K2 (menaquinones) in various fermented dairy products using a reliable high-performance liquid chromatography method.

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    7. If there are going to be vitamin D trials for MS then wouldn't it be an idea these cofactors need to be considered??

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  11. As the VDR will be to 1,25(OH)D the active form of vitamin d and the levels of 1,25(OH)D are tightly controlled in the body, would you expect to see an effect from increased vitamin d intake. You see the opposite in the blood when 25(OH)D is normal 1,25(OH)D is normal but when 25(OH)D is low 1,25(OH)D is high. The concentration of 1,25(OH)D is less than 1/1000 that of 25(OH)D. This along with blood calcium level control is probably one of the last systems to fail, use by the immune system is likely to close down much earlier.

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  12. Probably it can help remyelination but still you have to stop the damage too to make it possible to heal I think. In my opinion remyelination alone wont be enough especially for progressive patients where the damage occures continiously (RRMS at least gives time to remyelinate between attacks), if there is more damage than healing you wont see any results I think (of course it still should slow the progression but you need years to find it out how much it slows).

    "Did Vitamin D supplementation make a dramatic impact to your symptoms that should have been repairing in droves?"

    Why would it dramatically effect? In lab environment it enhanched remyelination with 80% but it is a lab environment, I dont think so that in a human body the same could be achived with supplement tablets but still if it would increase rem. rate by lets say 10-20% (but we dont even know much we would need to take to achive this ) it would not be an instant effect but something that happens over months/years but I think that still would be a result giving many additional years to MS patients. But still to achive something that really matters you need to stop the damge too not just remyelinate to slow it.

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  13. I doubt very much that, presuming a healthy diet and no deficiencies, any vitamin supplement on its own will do anything dramatic for MS. Starting to take 800IU of vitamin D made no perceptible positive difference to my MS.

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    1. The problem is most people are vitamin d deficient, and the RDA has been shown in two independent studies to be out by a factor of 10. It should be somewhere between 5,000 and 10,000IU units. The problem is not with data or interpretation it was a simple statistical error.

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    2. While better than nothing or a lesser amount, 800 IU of Vit D3 is too low to do any good. Even the good folks at Barts have stated many times on this blog that they follow the recommendations of the Vit D Council and take 5,000 IU a day. If, like me,you have very fair skin and burn within 10 minutes in the sun, Vit D supplementation is the only way to get enough Vit D

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    3. This page from the Vitamin D council suggests doses according to blood level: http://www.vitamindcouncil.org/further-topics/i-tested-my-vitamin-d-level-what-do-my-results-mean/

      Given that I had my first ever noticeable relapse activity after beginning vitamin D supplementation (although I believe this to be coincidental not causative), I can't say this did much for faith in it doing anything much for me. I also have strong bones and very good teeth, so find it hard to believe that being low in vitamin D was a decisive factor in my own development of MS.

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  14. ill bet if you paid all these commenters $10,000 they could do trails better , vt d or sun doesn't help me

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  15. I think the discussion of vitamin D3 is very interesting, but it takes a lot more. I am rare in the sense that I've had all of the necessary vitamins and minerals functionally tested using SpectraCell laboratories. I also have MS, going on 10 years now, I'm 23 years old. I had no significant deficiency as measured by final % concentrations of DNA in cultured cells that were given my blood serum and an agar lacking one of each important vitamin mineral. The resulting cell growth was compared to an ideal fully nutrient dense agar, and the percent results help to show the functional level of each nutrient in my blood. Further, despite not being "deficient" in any of 33 nutrient variables tested; I had only 6 that were "Border Line". Mostly minerals, as I do not seem to derive enough minerals from my diet. Further, despite being male, and having MS for many years, I believe strongly that I have not suffered any significant disability due to my lifestyle of using a myriad of high quality vitamin and dietary supplements along with avoiding obviously unhealthy foods, and not avoiding exercise as well. Only recently have I had the opportunity to check the efficacy of my functional nutrient levels. Now, as this discussion is intended, My vitamin D3 3 (cholecalciferol) level scored in the ideal range in this test, as well as a separate blood level test indicating 56.1 ng/ml which is slightly lower than my original test about a year ago of 58.9 ng/ml. However this clearly demonstrates an ideal or almost ideal level of all nutrients. I have taken 5000iu D3 for many years and just two years ago increased to 10,000iu per day (not as consistent use). At least in my case, this relatively consistent amount of oral vitamin D 3 has maintained my levels only to within the normal range or 30-80ng/ml. Despite significant lesion activity over the years, I have maintained only superficial deficit (like name memory) and only few and extremely mild exacerbations relative to the disabling first. There is very little Sun in my area or northern Wisconsin much of the rear. I believe that my levels of vitamin D vary significantly throughout the year remaining stably over 50 in the winter, but rising to as high as over 60 in the summer due to my ongoing supplementation.

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