Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:
Anti-Inflammatory Diet and Lifestyle.
There are over 190 articles on diet, inflammation and disease on this blog
(find topics using search [upper left] or index [lower right]), and
more articles by Prof. Ayers on Suite101 .

Friday, June 13, 2014

Health and Heparan Sulfate Circulation — Connective Tissue is Alive

Arthritis, Alzheimer’s, diabetes, cardiovascular disease, osteoporosis, cancer, etc. are all diseases of cellular metabolism and secretion.  What goes on inside cells and on their surfaces explains a lot about health and why we get sick.  Cells feed off of what’s around them, use some of those materials to replicate and package up cell-made materials for export.  Eat, replicate and secrete.  Symptoms of disease result if those processes are compromised.

Cell that make Cartilage, Eat Cartilage
The connective tissue that makes up the cartilage of tendons and the non-mineral parts of bones, as well as a layers of skin, is made up of proteins (collagen) and polysaccharides (glycosaminoglycans, GAGs), e.g. heparan sulfate, hyaluronan and chondroitin sulfate, produced by  chondrocytes or fibroblasts.  These proteins and polysaccharides are synthesized and then secreted by cells.  This process goes on continuously, since the connective tissue is alive and literally crawling with cells that make the cartilage.  To keep the connective tissue healthy, the old tissue has to be digested, so that new material can replace it.  Thus, the cells that live in cartilage also eat cartilage.  These cells get all of their nutrients, e.g. protein and carbs, from eating cartilage.  They don’t get glucose and amino acids, or even oxygen (they ferment), from the blood, because there are no blood vessels in cartilage.  The photomicrograph at left shows the red chondrocytes surrounded by a light capsule of heparan sulfate as they burrow through the purple cartilage.  The next micrograph shows the cytoskeleton of actin filaments (stained with a red fluorescent dye, that lies under the cytoplasm of a chondrocyte.  Motor proteins move other proteins, such as syndecans, the proteins to which the heparan sulfate chains are attached, through the  cell membrane (see the animations below.)  The last micrograph shows the green stained microtubule network on which vesicles move to carry heparan sulfate products from one end of the cell to the other (under the actin and past the orange-dyed nucleus) during synthesis and digestion.
Chondrocytes Burrow Through Cartilage
Chondrocytes are the cells that eat and make cartilage, but all of this eating and making goes on at the same time that the cartilage is also holding everything together, i.e. it is still strong.  If cartilage is cut and the cut ends are held tightly together, the chondrocytes will knit the cartilage together and it will become as strong as it was. 

Heparan Sulfate Circulates over the Surface of Cells
Chondrocytes are not actually rigidly embedded in the cartilage, but rather maintain a capsule of heparan sulfate around themselves.  Thus, they continue to secrete a mixture of heparan sulfate, chondroitin sulfate and collagen, but the heparan sulfate is recycled through the capsule and the other molecules merge into the existing cartilage.  Thus, the heparan sulfate is a kind of carrier that keeps the cartilage from “setting up” while it is being made and transported.  Other cells of the body, such as neurons, don’t make cartilage, but they still have heparan sulfate (HS) circulation that is intimately involved in many other processes, such as the action of hormones.  Disruption of HS circulation causes the symptoms of Alzheimer’s or type 1 diabetes, for example, since amyloids assemble as filaments on threads of HS, and the amyloid filaments jam essential HS circulation.  Plaque in atherosclerotic vessels is high in HS content.  HS is also a major component surrounding vessels to form the blood brain barrier and the barrier to protein loss from kidneys into urine or loss into the gut lumin.  Heparin (fragments of HS) is continually released from mast cells in the lining of the gut to prevent pathogens from binding to cell HSPGs. 

video
HS Sweep the Cell Surface
There is a constant flow of heparan sulfate proteoglycans (HSPGs) through the cell membrane from the rear of the chondrocyte to the front where the HS is digested again and the protein that was embedded in the membrane, syndecan, is recycled to the Golgi for another trip.  HSPGs (animation to left with blue protein and yellow HS) are attached to motor proteins that propel them through the membrane along microfilaments of actin that form the cyctoskeleton just under the membrane in the cortical region of the cell.  Thus, the heparan sulfate of the HSPGs stick out like hair from the cell surface and sweep continuously from the back to the front of the cell.  At the front of the cell, the HS sweeps through the intact cartilage and reverses the process of cartilage assembly.  The chondroitin sulfate, collagen and HSPGs are dragged into the cell and digested.  The protein parts of the HSPGs are transported to the Golgi  and the HS is synthesized along with other cartilage components and moved in vesicles along microtubules before it is secreted.

video
HS is Secreted at One End and Eaten at the Other
The animation left shows 1) the initial digestion of the cartilage proteins and polysaccharides on the left.  These cartilage components of amino acids and sugars, are used by the chondrocytes as their sole nutrients 2), and to produce new proteoglycans 3) HS and chondroitin sulfate proteoglycans, in the Golgi, are 4) packaged into secretory vesicles and are 5) secreted on the right.  The HS chains, attached to proteins, are 6) swept through the membrane (see the first animation above) toward the front of the cell, leaving the collagen and chondroitin sulfate for form cartilage behind.  In the process, the heparan sulfate proteoglycans 7) disrupt and solublilize old cartilage ahead as the chondrocytes 8) move through the connective tissue like moles digging through soil.


Other Cell Processes Involving Heparan Sulfate:
  • Amyloids of Alzheimer’s and type I diabetes assemble bound to HS.
  • Hormones bind to receptors wrapped around HS.
  • Blood clotting is controlled by HS.
  • Complement is controlled by HS.
  • Blood brain barrier is composed of HS.
  • Kidney protein barrier is composed of HS.
  • Inflammation blocks HS synthesis and promotes heparanase synthesis.
  • GAGs are animal soluble fiber when eaten and feed gut flora.
  • Pathogens bind to HS.
  • HIV-TAT is transported between cells by HS circulation.
  • Heparin is made by heparanase fragmentation of HSPG in mast cells and is secreted along with histamine. 
  • NFkB activation inhibits HSPG production and stimulates heparanase production.
  • Heparan sulfate proteoglycans organize nerve synapses and acetylcholine esterase binds to HS. 
  • Gastric proteases cleave around heparin binding domains of proteins, e.g. milk, consist of clusters of basic amino acids.  Peptides with heparin binding domain are antimicrobial; all of the heparin binding peptides are subsequently degraded by pancreatic proteases.
  • Heparanase is initially secreted inactive and bound to HSPGs, but it remains bound and is internalized again along with the recycling HSPGs, and is activated before being secreted again.
  • Allergens and autoantigens are unusual proteins with sequences of three adjacent basic amino acids (arginine or lysine) that require HSPG circulation for presentation of the immune system.  Nuclear proteins that interact with nucleic acids have sequences of four basic amino acids, the nuclear translocation signal, and are therefore common antinuclear auto antigens.

27 comments:

Anonymous said...

Art,

Love your blog and refer people to the AI diet all the time, as it has improved my health vastly.

What is the take-away from this post please?

Thanks you.

Charles Grashow said...

So - if "Plaque in atherosclerotic vessels is high in HS (Heparan Sulfate) content" is there a way to decrease the amount of HS in the plaque?

raphi said...

Seeing as how HS & HSPGs are fundamental elements in the broad logistics of presenting, recycling, competitive binding & so on...what kind of question about their roles would you want answered & through what kind of experiment? [10 year time-frame, say, & an NIH-level grant]

Newbie said...

Thank you for this instructive post, it sheds great light on the physiology of cartilage, more in keeping with how we perceive bone as continually changing.I think that this post is meant to show you that cartilage tissue is continually undergoing growth and repair, it is a live tissue. Classic medical teaching doesn't present cartilage in this way - cartilage is just there, and if damaged, its reparative ability is very limited because of the lack of blood supply.
I find this view of cartilage much more in line with how I view the human body.
I'm not sure that you would want to decrease the HS in arterial plaque–we know that organized plaque does cause the majority of heart attacks, it is the friable unorganized plaque that causes most MIs. It sounds from this post that HS is organizing the plaque to limit the potential damage.

Newbie said...

Sorry for the typo - it should read - "organized plaque does NOT cause...."

Lori2 said...

Is there anything that we can actively do to facilitate this process--diet, supplements, daily activity--or is it a body system on autopilot?

Anonymous said...

Dr. existe algĂșn suplemento y dieta especial para reparar y regenerar el cartĂ­lago?
Por favor necesito una respuesta.
Muchas gracias

Anne said...

Hello Dr. Art

I've read from your earlier posts that you recommend l-glutamine to help heal a leaky gut.
However when I supplement with just 5 g/day I develop a very runny nose. I've positively associated this with glutamine supplementation.

I've tried multiple supplement brands with no success.

Do you know what might be causing this reaction?
I thought glutamine would help my immune system function.

Laura Ruane said...

Dr. Ayers,
Thank you for this post.
Five weeks ago I fell off a ladder and severely broke my tibial plateau. Now I have a plate and several screws holding me together, and I'm still not allowed to put any weight on my leg. My doctor has informed me that I WILL definitely develop arthritis in my knee. So I am up for the challenge of preventing this arthritis if I can, and making a full recovery. (I'm 52, and love hiking and backpacking). What do I do? Is there any more advice that you can give me? Thank you in advance since I'm sure you're busy.

Kira said...

Thanks for your posts! I don't have a background in biology, so my questions might seem a bit simplistic.

If cells "eat" old collagen to make new collagen and there aren't blood vessels supplying new building blocks, how can the body add to the connective tissue if it has been damaged or reduced somehow?

Can including bone broth or gelatin in the diet affect the health of the connective tissue? Or is it helpful only in areas where there is a blood supply?

Honora said...

@Laura Ruane: my partner sustained a double spiral fracture to his tibia a few years ago. He has made a full recovery. We do multi-day hiking and climbing trips too. He was in his late 50's at the time. He had an intramedulliary nail, plate and screws inserted at the time via his tibial plateau (I surmise) after they lifted up his knee cap.

Post op, he had a tin of sardines/kiwi/milk biscuit (New Zealand thing...) to aid healing for about a year. He takes glucosamine - may be a waste of time and money - and I make bone broth plus all the bits of the chicken weekly.

He was allowed to go back to full hiking 6 months after the fracture. He learned a lot from following mybrokenleg.com. Hope this gives you some reassurance.

Raj said...

Beautiful video Dr.Art. I always wonder what it would be like when you mean "sweep continuously from the back to the front of the cell" in other posts about HSPG, now I can visualize, thanks.

Dr. Art Ayers said...

Charles,
I wouldn't want to fiddle with the natural control of HS, since it is intimately involved in all body processes and plaque buildup happens as a result of the actual problem, inflammation. The same thing is true of the whole LDL/HDL measurement and statin treatment, which do nothing to cure atherosclerosis and only minimally impact treatment via the effect on gut flora and inflammation reduction. Treatment and prevention should focus on inflammation, and that means that diet, exercise and gut flora should be the focus. My reading of the research literature says that drugs are much less effective and much more expensive.

Thanks for the question.

Dr. Art Ayers said...

Raphi,
HS levels reflect bodywide inflammation, so if the medical industry is serious about treating and curing most major disease, it should have a method for measuring blood protein saturation with HS. This idea is corrupted by the uninformed view that heparin only impacts clotting, which is seen as an empirical rather than a diagnostic process, with a goal to avoid excess/deficient levels rather than learning a measure of initial HS saturation that would reflect inflammation level.

There is also a general ignorance of the role of HS recycling and the impact of blocking that system by amyloids. I think that this is a major source of disease symptoms and traditional drugs such as berberine may be very important in treating many diseases.

The hydrophobic binding of basic amino acids in heparin binding domains and similar binding in nuclear translocation signals, carbohydrate binding domains, alkaloids and plant polyphenols, is poorly understood and ignored in cell processes and drug design. I think that the use of PEG in protein crystallization systematically perturbs structures to ignore surface hydrophobic bonding involving heparin, carbohydrates and alkaloids/polyphenols.

Allergy, autoimmunity and vaccine design could be rapidly promoted by examining the common sequence motifs, e.g. basic triplets, of auto antigens and allergens. This would lead directly to the translocation system that will be a parallel to the nuclear translocation system and the dilysine secretion system in bacteria, and perhaps the DNA import system.

The impact of pharmaceuticals on gut flora as a consequence of their inherent antibiotic activity is a major deficiency in drug evaluation. I think that most therapeutic impact of drugs occurs through the gut flora. I assume that pharma knows this, but does not communicate this to the public, because it would be readily determined that picking the right phytochemicals in spices could eliminate the need for pricey drugs.

I think that the 10 year time frame would permit a small group of bright people to understand the 10 major diseases just by examination of the current scientific literature. The experiments have already been done, but are grossly misinterpreted, because the investigators are too provincial and don't understand basic biochemistry and cell bio. I think that too many experiments and too little thought is confusing modern research. There should be more theoretical biologists.

Thanks for the thought provoking question.

Dr. Art Ayers said...

Anonymous,
To enhance cartilage and connective tissue integrity it is important to eliminate chronic inflammation, since inflammation turns off HS production and stimulates heparanase. That means that my Anti-Inflammation Diet and recommendations are a guide to HS health.

Dr. Art Ayers said...

Anne,
I recommend glutamine for gut integrity, but I only recommend any supplement for temporary and not routine use.

I take omega-3 and vitamin D, but those are just because I don't rigorously follow my own eating advice. It would make more sense to take neither and test my vitD to detect any inflammation by a drop in serum D.

Thanks for the question.

Dr. Art Ayers said...

Laura,
Development of arthritis after an injury and with hunks of metal in your body happens, from my perspective, for two reasons. The first is that the injury tissue damage and metal cause local and chronic inflammation. Second, the antibiotics used to prevent infection wiped out your gut flora and production of Tregs. Inflammation plus crippled Tregs is the formula for autoimmunity and arthritis.

Not to worry. That also means that repair of your gut flora and controlling inflammation should avoid arthritis. Note that the medical industry makes all of its money by treating the symptoms of inflammation and damaged gut flora.

Keep monitoring your serum vitamin D. If you can maintain it in the high range of normal, then your control of inflammation is succeeding.

Maintain a high 0mega 3/6 ratio.

Repair your gut flora. See my numerous articles on the subject and check out my articles on resistant starch for more references.

Follow my Anti-Inflammatory Diet and get as much exercise as you can.

Depression is a symptom of chronic inflammation and should be a natural outcome of surgical implants. That is just poor management of inflammation and you are correct that you can do much better.

You should not expect arthritis and your body can adapt to an amazing degree.

Let me know how you progress.

Dr. Art Ayers said...

Kira,
Collagen is just like soil with earthworms constantly mixing in the leaf litter from the surface. New nutrients leach in from the surface and the whole physical structure is constantly rejuvenated. That is how bones can be gradually bent.

The need for continual rejuvenation is also why drugs to harden bone by killing cells that digest bone, don't make sense. It also means that chronic inflammation, which decreases HS production, leads to connective tissue damage.

Thanks for the question. Don't be bashful about asking what appear to be simple questions. I don't claim that I have answered or can answer the most basic.

I don't worry about trying to supplement with the amino acids and sugars that make up connective tissue, because every cell makes its own from dietary protein. Meat, after all, contains a lot of connective tissue, including soluble fiber in the form of chrondroitin sulfate and heparan sulfate.

Dr. Art Ayers said...

Hi Raj,
Thanks for all your comments. I have a hard time knowing what gets across. A lot of basic ideas are poorly communicated in text books and there are many large errors.

Thanks for reading and asking for clarification.

steve said...

Follow my Anti-Inflammatory Diet and get as much exercise as you can.

How much exercise do you recommend?
I don't believe i see a rec. anywhere on your website.
Thanks

Dr. Art Ayers said...

Steve,
You are right. I am no expert on exercise, but see the benefits. Mark's Daily Apple can give you better advice on exercise. I focus on the impact of the other two of the big three: diet and gut flora.

Health = diet + adapted gut flora + exercise

Thanks for the comments.

Laura Ruane said...

Honora, Thank you for your encouraging comment. It gives me hope. It's funny that you mention sardines as I've been eating smoked herring. I've also been taking glucosamine, but who knows about that. Thanks again,
Laura

Laura Ruane said...

Dr. Ayers,
Thank you for your response. I went to see the Dr. again last Thursday and he did more x-rays. He says that I'm healing well but he already sees arthritis. He says that arthritis is a lack of cartilage, and that our bodies don't make new cartilage. My cartilage was damaged, and then the inflammation is from that. I believe you about the metal not being a good thing since it is a foreign substance in the body. I've been taking Vit D3 and K2 since I've gotten home from the hospital, but haven't gotten my levels checked. I'm also working on getting my good flora back.
The Dr. said I can begin bearing weight on my leg and can start PT, so I've been walking with my walker around the house. My leg feels OK but my foot is severely swollen, so walking feels terrible.
Thank you for the advice.

raphi said...

Thanks for the thoughtful reply Dr.Ayers, there's so much there. I will discuss your answer with my tutors & professors from Staffordshire University, reporting back if there's anything worth mentioning.

raphi said...

Thanks for the thoughtful reply Dr.Ayers, there's so much there. I will discuss your answer with my tutors & professors from Staffordshire University, reporting back if there's anything worth mentioning.

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