Thyroxine increases collagen type II expression and accumulation in scaffold-free tissue engineered articular cartilage

Yet again, a non-endocrinological application of thyroid hormone - in this case levothyroxine (T4).

Interesting to know if there is anything specific about T4 - would T3 (in appropriate doses) have had the same effect?

Given the number of people who suffer joint and other collagen-related issues, simply identifying that there is a direct effect of thyroid hormone on collagen might be a major step in itself. I keep hoping that a comprehensive understanding of the actual effects of thyroid hormone at the fundamental biochemical level would help to support the numerous signs and symptoms reported by patients.

Tissue Eng Part A. 2017 May 26. doi: 10.1089/ten.TEA.2016.0533. [Epub ahead of print]

Thyroxine increases collagen type II expression and accumulation in scaffold-free tissue engineered articular cartilage.

Whitney GA1,2, Kean TJ3, Fernandes RJ4, Waldman SD5, Tse MY6, Pang SC7, Mansour JM8,9, Dennis JE10.

Author information

1 Benaroya Research Institute, Hope Heart Matrix Program, Seattle, Washington, United States.

2 Case Western Reserve University, Biomedical Engineering, Cleveland, Ohio, United States ; g.adam.whitney@gmail.com.

3 Baylor College of Medicine, Orthopedic Surgery, Houston, Texas, United States ; thomas.kean@bcm.edu.

4 University of Washington, Orthopedics, Seattle, Washington, United States ; rjf@uw.edu.

5 Ryerson University, Chemical Engineering, Toronto, Ontario, Canada ; swaldman@ryerson.ca.

6 Queen's University, 4257, Biomedical and Molecular Sciences, Kingston, Ontario, Canada ; yat.tse@queensu.ca.

7 Queen's University, 4257, Biomedical and Molecular Sciences, Kingston, Ontario, Canada ; pangsc@queensu.ca.

8 Case Western Reserve University, Department of Mechanical and Aerospace Engineering, Cleveland, Ohio, United States.

9 Case Western Reserve University, Department of Orthopaedics, Cleveland, Ohio, United States ; jmm12@case.edu.

10 Baylor College of Medicine, Orthopedic Surgery, Houston, Texas, United States ; james.dennis@bcm.edu.

Abstract

Low collagen accumulation in the extra-cellular matrix is a pressing problem in cartilage tissue engineering, leading to a low collagen-to-glycosaminoglycan (GAG) ratio and poor mechanical properties in neo-cartilage. Soluble factors have been shown to increase collagen content, but may result in a more pronounced increase in GAG content. Thyroid hormones have been reported to stimulate collagen and GAG production, but reported outcomes, including which specific collagen types are affected, are variable throughout the literature. Here we investigated the ability of thyroxine (T4) to preferentially stimulate collagen production, as compared to GAG, in articular chondrocyte-derived scaffold-free engineered cartilage. Dose response curves for T4 in pellet cultures showed that 25 ng/mL T4 increased the total collagen content without increasing the GAG content, resulting in a statistically significant increase in the collagen-to-GAG ratio, a fold change of 2.3±1.2, p<0.05. In contrast, another growth factor, TGFβ1, increased the GAG content in excess of three-fold more than the increase in collagen. In large scaffold-free neo-cartilage, T4 also increased the total collagen/DNA at one month and at two months (fold increases of 2.1±0.8, p<0.01 and 2.1±0.4, p<0.001, respectively). Increases in GAG content were not statistically significant. The effect on collagen was largely specific to collagen type II, which showed a 2.8±1.6 fold increase of COL2A1 mRNA expression (p<0.01). Western blots confirmed a statistically significant increase in type II collagen protein at one month (fold increase of 2.2±1.8); at two months, the fold increase of 3.7±3.3 approached significance (p=0.059). Collagen type X protein was below the 0.1 µg limit of detection. T4 did not affect COL10A1 and COL1A2 gene expression in a statistically significant manner. Biglycan mRNA expression increased 2.6±1.6 fold, p<0.05. Results of this study show that an optimized dosage of T4 is able to increase collagen type II content, and do so preferential to GAG. Moreover, the upregulation of COL2A1 gene expression and type II collagen protein accumulation, without a concomitant increase in collagens type I or type X, signifies a direct enhancement of chondrogenesis of hyaline articular cartilage without the induction of terminal differentiation.

PMID: 28548569

DOI: 10.1089/ten.TEA.2016.0533

ncbi.nlm.nih.gov/pubmed/285...

[ Edited 28/05/2017 08:35 ]

If the above paper was of interest, you might find one of its references worth reading - most especially as it it twenty years old and investigated both T4 and T3.

In serum-free culture thyroid hormones can induce full expression of chondrocyte hypertrophy leading to matrix calcification.

ncbi.nlm.nih.gov/pubmed/877...

Chondrocytes (from Greek χόνδρος, chondros = cartilage + κύτος, kytos = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans.

Thanks Wiki.

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  • Very interesting Helvella and so once again the importance of thyroid hormones to our various body systems is demonstrated.. I am currently "over medicated" according to my GP TSH barely measurable, but T4 and T3 still low in range. With the warmer weather various symptoms have improved including problems with my ankle and back.

    When are medic students going to be taught how vital T4/T3 is to EVERY cell in the body and that TSH measurements do nothing to tell you about how much is circulating in our bodies. Not expecting an answer to that question, just my usual rant LOL. Keep up the good work

  • Very interesting. Thanks for posting hellvella.

    I was diagnosed with arthritis at 23 years old. Then it was tendinitis with low grade symptoms of hypothyrodism (casually dismissed of course by the medical profession) presenting in my 30's, but a further 2 decades elapsed before being diagnosed with hypothyrodism which by then was very overt even getting tested for it by that late stage proved to require a fight I knew it was really serious by then and was able to find the energy to stick to my guns and refuse to take no and a prescription for antidepressants for an answer. Good job I did or I'd be up on the mantle with the deceased whippets (RIP) in a casket!

    I have read arthritis can be an early sign of hypothyrodism. I assumed it was a related immune disorder and my thyroid got clobbered later on. This research would imply it can be a direct result of hypothyrodism. Is tendinitis a collagen related disorder I wonder? I feel the three things are related and my newer bakers cyst but have got those knowing smiles when I have expressed this to consultants, who immediately dismiss the suggestion as nonsense and as not being the case in their experience - talk about a self fulfilling prophecy if they simply ignore what their patients actually tell them. I still suspect they are a related cluster of joint/tendon/bone disorders and that hypo is at the bottom of it all no matter what those condescending consultants think.

    Maybe I am right after all and it is those supercilious consultants who are the ones who have got it all wrong.

  • Even if hypothyroidism is not at the base of it all, there seems to be every reason to ask the question.

    In other illnesses, it it very common for all signs and symptoms to be assumed to originate from the same disease. For example, if you have influenza (the real thing - not just a bad cold), the headache, temperature, loss of appetite aches and pains, excess sensitivities, etc., will all be put down to influenza. And anything else will similarly be likely to be attributed to that - even if it isn't actually connected.

  • helvella you are right it may not be all hypothyroid related. Lots of other things can cause illness after all. I suspect there is a genetic component lurking with these things as my dad did not have any thyroid disorder but he did have arthritis. It is all so complex who on this earth could unravel it all and say with any certainty in each case this led to this and this and this. It is just a feeling I have and they say you should listen to your body - mine tells me they are related and it ought to know better than anyone 😂🤣😂

  • I also have same symptoms..Bakers cyst comes and goes but hurts like hell when it's active.

    Are they saying Thyroxine causes these symptoms then ? The blog is all a bit above my head...too technical.

  • No.

    They are saying that when trying to culture cells (e.g. to make "components" to be surgically implanted), the addition of levothyroxine (T4) to the soup they grow the cells in has a profound effect on how the cells grow and mature.

    That is, adding the appropriate amount of T4 is an important improvement in the process. The impact is that this demonstrates the importance of thyroid hormone to collagen structures.

  • That's interesting.

  • Maribee

    The article does not discuss bakers cyst. I have seen one reference saying it is related to hypothyroidism but little else. However, muscoskeletal disorders are more common in people with hypothyrodism so I suspect mine could be related. there is usually an underlying problem with the joint (like arthritis - common with hypothyroidism) that seems to trigger the over production of synovial fluid which needs to go somewhere being strongly encapsulated within the joint so it bulges out the back of the knee , like a lollipop.

    It is not unreasonable in my opinion to wonder if there is a link back to problems being caused by hypothyroidism ... if you get my drift.

    When mine was small it was so painful I could not squat or bend my knees to go down or kneel without being in agony and have to move within seconds. I had a scan (scared the wits out of me those MRI scanners are freaky things when they get going) consultant said it was so small the op might be overkill but it was up to me, so I left it. It has got bigger and bigger but curiously less painful allowing me to kneel as squat for quite a while tho not as long as before it appeared, I am getting foot problems with cramp and it felt like stuff was running inside down the back of my calf two weeks back but it did not hurt so not sure if I had a partial rupture or not or if such a thing is possible. Since I have had very bad cramp, and my foot has had all sort of weird blisters. I saw the doc to get it checked but he says it is ok (it can be serious if it burts with symptoms like a DVT😳 - just in case I you are unaware of this) thankfully he is an expert on the knee so knows all about them. He says it might settle but if not it will be another of those horrible scans if they can get me in the thing without totally freaking out, then reassessment for an op. They won't do keyhole to be sure of not cutting any important structures that might render the foot unusable forever more. You end up with a big scar on the back of the knee. It is not a great op. Sometimes the wretched bakers cyst just reappears too. Weird that they ca come and go so far mi w has just come&coe& come 😂🙄☹️. I

    have never spoken to anyone with a bakers cyst before this - thanks for sharing! I feel less alone with it now which is good.

  • Thanks for all the info.....I am waiting for two knee replacements due to Osteo arthritis which has been caused by my Iron Overload which collects in the joints and destroys the cartilage.

    I can empathise with the MRI ....Ibe been having them in my brain and spine fir many geRs now on a regular basis due to ?Nuerofibromatosis tumours.....just let your mind go blank....at least you know it's gonna be over eventually......good luck...Mari

  • Maribee god you poor thing. You will feel a lot better once the knees are done. I know the MRI panic is silly but nothing I do will calm me down I get more and more anxious and my heartbeats like a power hammer ten to the dozen! All logic goes out the window. It reminded me a little of flying which I dislike so much I no longer take planes anywhere. I think it is more to do with claustrophobia and being trapped when your legs are all restrained too and with the hypo I find it very hard to stay still for long periods so my right knee started twitching what a mare! Jon on earth you go right inside and chill out I just don't know! A the monument I came out of the scanner I felt absolutely fine again no residual anything I found that very strange. I guess it is very unnatural to have all your tissues magnetised and then let them revert to their favoured polarity. It felt like a hurricane was blowing through my knee most disconcerting. I know the images for soft tissue are superb so there is no escaping them if an op is on the cards. As for the noises simply awful!!

  • Can't say I like MRIs! Have had two - the first one was full head and seemed to take ages.

    The second was around ear area, and was much shorter. What was interesting about it was that I "saw" phosphenes. Once I realised something odd was happening, I found the rest of the MRI faded into unimportance, concentrating on the weird lights instead!

    en.wikipedia.org/wiki/Magne...

    Maybe trying to "look" for odd lights would provide something to occupy your mind in the scanner?

  • helvella I tried everything I could thinking of the millions of people who have MRI scans who cope happily with the experience, how important it was for my health, a drop in the ocean compared to a lifetime lived, imagining being on a beach next to the Indian Ocean, etc. But nothing would stop the increasing sense of pure panic and get me outa here fast. I thought I was going to have a heart attack so said I was not feeling too good but thankfully it had finished. I want to be out cold if I have the misfortune to need another. I felt so bad about it I decided I'd rather die than go in one again. I hear they can sedate you. I also wonder if like X-rays they may discover MRI scans are not as benign as first believed. Images of Röntgen's cancerous hand spring to mind!

  • Hi again...I've been in the MRI fir years now routinely as I have inherited Nuerofibromatosis , where you get tumours in the nerve sheaths, brain, spine and soft tissue, you do get used to it but I would ask if you can go in feet first, that's possible as I've had my knees done that way, am waiting for new knee replacements as I have also got inherited Heamachromatosis (iron overload) the body can't get rid of excess iron so it collects in your vital organs and destroys them ,I have early cirrhosis because of undiagnosed condition early enough even though the signs were all there...it's much better to go in feet first, I hate the brain one as your head has to be put into this helmett thing...?UGH!

  • Well I never....tendons have tons of collagen type 2

    en.m.wikipedia.org/wiki/Tendon

  • Very interesting! As you say would be interesting to see results looking at T3.

  • Yes, very interesting.

    Here follows a long and boring bit about my personal experience, but it does relate to whether Thyroxine improves things and how for me T3 pretty much 'cured' me.

    I have a lot of left hip pain and before treating myself, first with T4 and then with T3 was unable to walk very far and had a lot of pain that woke me at night etc.

    I had an xray about 7 years ago, which showed that my hip joints were worn, but not too bad for my age of 45yrs at the time (the radiographer said not quite bone on bone, however the consultant radiologist disputed this and said that he could not see anything above normal wear and tear).

    I have run out completely of T3 now, which for the last 2-3 years, I have taken on its own. I have been taking T4 on its own for the last 3 months. Initially taking 150mg the symptoms all came back with a vengeance, particularly the brain fog and hair loss, weight gain and pain (my husband commented that he had forgotten just how ill I was before I started self medicating). I have now upped the T4 to 300mg and the brain fog has gone and some of the pain has gone, but I still can hardly walk (the pain goes if I sit and rest now though). I have always had a daily yoga practise but for the last few weeks have had to stop.

    I am waiting for my T3 to be released by customs (I presume they are holding it up, as it shows on the Royam Mail site as being at LHR since 27th April but not yet in the Royal Mail system).

    I can't wait to get the T3 again - and hope that I can walk again (and get the less dry itchy skin, no hairloss and waist back!) Not sure whether to get another xray and see whether the hips are now bone on bone (as they feel) or see whether it all gets better again with T3.

  • PiggySue,

    If you ordered UniPharma T3 you should contact the site which sold it to you for a replacement or refund. There is a shortage of UniPharma in Greece and I think the online sites selling it are now running short. The T3 comes from Greece and as it is an EU country it won't have been held up in HMRC customs.

  • Hi helvella

    Hmm, just as a thought re whether T3 would have same effect, I've been on T3 only for nearly 15 yrs and I obviously complained recently about the various "new" symptoms I've had since I appear to have stopped my own production of T4 completely a couple of years back and hadn't considered this aspect.

    I didn't age from when I was 15/16 to 28 at all (lucky I looked 18/19 at that age already) and then looked like early twenties at age 30 and only minutely more until about 34 - where most people still thought I was 25. However, in this last couple of years, I've aged dramatically - wrinkles on forehead and eyes and everywhere and all sorts with extremely dry skin - just assumed I caught up with myself lol! Anyway, I added T4 back in due to very unpleasant other issues which are now clearing up but have noticed in the last week that my skin has plumped back up dramatically and some very deep wrinkles have completely disappeared and hugely better - things which collagen would effect. People have actually been commenting on how well my skin looks again.

    In these last T4 missing two years, my super duper quick healing also took a hit and I could no longer put my legs behind my neck (always had hypermobility lol) - also things that low collagen would impact so I'd be really curious as to whether these will improve also lol :-)

  • Saggyuk how interesting that my aging process was somewhat similar to yours not appearing to age from 12 to 35! I have made up for it now with a horrible scraggy neck like my mother and wrinkles galore on my face I could grow rows of cabages in the furrows in my forehead 😳🤣😊 mind you I could never get my legs around my neck - impressive 🎩🆙

  • Haha, when I was younger it used to really bug me as people wouldn't take me seriously if they didn't know me - like in job interviews, they just thought I looked like a kid lol. I did appreciate it later when I looked a couple of years older but maybe not so much now lol.

    This was mostly during the time I was still very ill and only started aging at the point where I fixed most stuff so have always wondered if my body was put in some form of stasis and repaired rather than replaced or something during this time lol??

  • Saggyuk I looked 20 when I was 12 - imagine the scrapes I got into! I could go into a pub and order drinks without the bat of an eyelid. I liked Simon and Garfunkle and went to see the graduate the other film was women in love I was a tad non plused by all that naked writhing by Oliver Reed - the graduate was an eye opener 😳 music was great! I stayed looking 20 for a very long time - like the portrait of Dorian Grey I guess I sold my soul to autoimmune thyroiditis 😂😂😂

  • Lol, I like the way you put that :-D

    It kind of fitted with the timing too, it's almost as if my body quickly forced me into early adulthood before my thyroid quit completely at age 14, and then kept me that way lol!

    Yes, I could also get in anywhere when I was 14 - it was great in that respect lol. There was one time I was a little bit naughty when I was 13 (stupid naughty not foul) and no one bothered asking my age until I had been at the police station nearly a whole day as too busy with real bad stuff to process me and when they finally asked for their paperwork after interviews and all sorts, you could see there faces drop and turn white as they had not dealt with me as a minor and they all ran out the room - one even spat out his tea explosively. I was then quickly shuffled out without any charges with cash to get taxi home lol. No one would believe how young I was and then no one would believe how old I was - can't win everything I suppose lol ;-)

  • I am sure I have read very recently it is not coincidence to reach maturity early and have autoimmune thyroiditis but where I read it I can't recall

  • Yes, I actually read about it the other day and precocious puberty can be caused by hypothyroidism as am a little concerned with the same issue with my little one at the mo but not so easy to get kids tested it seems! :-/

  • I certainly had stunted growth lol! Everyone said I would be a basketball player as had massive hands and size 8 feet when I was eight yrs old - I stopped at a measly 5 ft 2 at age 13!!!!

  • Saggyuk I was gutted not to get to 6' I was so used to towering over my peers/teachers etc. I did make 5'8"

    Bad scene re getting your little one tested