Potential Cause of Arthritis Discovered
Wed Aug 21, 1:34 PM ET
By Greg Frost

BOSTON (Reuters) - In a finding that could lead to new treatments for arthritis, U.S. researchers said on Wednesday that naturally occurring carbohydrates may be the elusive cause of the debilitating illness.

The carbohydrates, known as glycosaminoglycans, appear to activate cells that are part of the body's immune system, causing the painful inflammation that afflicts hundreds of millions of people around the world, they said.

"This study shows that rheumatoid arthritis may result from the body's mishandling of its own carbohydrates that, under normal circumstances, would not be interpreted as a threat," said Julia Wang, the study's lead researcher.

Wang, who presented her research at the national meeting of the American Chemical Society, said her finding has come under heavy attack because it challenged the conventional thinking that peptides -- little pieces of protein -- are responsible for auto-immune diseases like arthritis.

"The concept that carbohydrates can be responsible for auto-immune diseases is completely new," she told Reuters. "People simply don't want to recognize it. They've been taught peptides are responsible, which is understood."

Although there have been promising advances in treating the symptoms of arthritis, its causes have remained a mystery.

"The problem is that people have been trying to search to understand arthritis by sticking to the old dogma, but that hasn't solved the problem," said Wang, a researcher at Boston's Brigham and Women's Hospital in Boston and a professor at Harvard Medical School ( news - web sites).

The new research marked the first time glycosaminoglycans, a major component of joint cartilage, joint fluid, connective tissue and skin, have been associated with the condition.

Wang said she and her colleague Michael Roehrl studied the effects glycosaminoglycans had on mice, which subsequently experienced arthritic symptoms including swelling, inflammation and joint damage. She also looked at human tissue taken from arthritis patients and found the same type of cells that bind to GAGs.

Wang said subsequent research would most likely focus on developing drugs aimed at stopping the growth, expansion or adhesion of immune cells that react to glycosaminoglycans.

John Mekalanos, professor and chairman of microbiology and molecular genetics at Harvard Medical School, called the research extremely promising.

"We are clearly a step closer to understanding the causes of a disease that has left the medical community with unanswered questions and many patients with discomfort and pain," he said in a statement.

Another blow for carbohydrates and chalk one up for protein! Wow!!!!

Now, I'm curious which carb foods, if not all, have GAGs in them.

;-Deb

GAG's are not found in food, they are highly specialized polysaccharides that are made in our own bodies. They make up the structure of, or have specific functions in certain tissues .. such as cartilage, heart valves, synovial fluid (the "lubricant" in our joints), cell membranes, etc, etc

Chondroitin sulphate, which is a popular supplement used for arthritis and joint problems, is a glycosaminoglycan. So is heparin, which is an anticoagulant and prevents blood clots.

For everything you ever wanted to know about GAG's, check out this Biochemistry text, from Indiana State University. Glycosaminoglycans.

Doreen

So this mean that arthritis is probably not diet related? Oh, well. I was hopeful that there was one more thing to add to the long list of "cures" made by low-carbing .

Needless to say, my specialty is not in any kind of medicine. I'm a computer nerd .

;-Deb

Reuters Health: Carbohydrate Attack May Be Arthritis Culprit

BBC Health News: Arthritis cause 'identified'


By Anne Harding

BOSTON (Reuters Health) - A Harvard researcher has proposed a totally new offender in the abnormal immune system attack that leads to rheumatoid arthritis: naturally-occurring carbohydrates.

These carbs aren't starches or sugars, but more complex molecules known as glycosaminoglycans (GAGs), which compose much of the body's connective tissue and are also found in the fluid within the joints.

Rheumatoid arthritis occurs, according to Dr. Julia Ying Wang's theory, because immune system cells called antibodies target GAGs, binding to them and then accumulating in the joints, leading to pain and inflammation.

Rheumatoid arthritis is a chronic disease in which the body's own immune system attacks the tissue lining the joints. It is more common in women, tends to strike between the ages of 36 and 50, and results in chronic destruction and deformity of the joints.

The Harvard Medical School assistant professor reported her findings here Wednesday at the American Chemical Society's annual meeting. The research, she said, offers the prospect of a treatment for this debilitating disease.

Wang has encountered some resistance to her findings, she noted. Proteins and fragments of protein called peptides are conventionally thought of as immune system triggers, but carbohydrates are rarely considered to play a role in immune reactions.

The Harvard researcher decided to study GAGs' role in rheumatoid arthritis because the carbohydrates are a major component of joint tissue, and because people with the disease are known to have higher levels of certain GAGs in their joints.

To investigate, Wang and her colleagues injected mice with GAGs. The mice, they found, developed chronic rheumatoid arthritis-like symptoms, including inflammation and swelling of the membranes lining the joints, the tissue surrounding the tendons, and the skin. Some animals developed erosion of the bone.

Antibodies were binding to GAGs, she and her colleagues found, and accumulating in the animals' joints.

Wang and her colleagues have since found GAG antibodies in tissue from rheumatoid arthritis patients. This is the first time, she notes, that such antibodies have been seen in animals or humans.

These antibodies may be part of the body's response to bacterial infection, Wang said. Many bacteria, including the bug responsible for flesh-eating disease, carry GAG-like molecules on their surface, and the body's own immune cells also secrete GAG when fighting infection.

This can prime immune cells to mistakenly target the GAGs that make up the body's own tissues.

Wang is now testing molecules with the potential of blocking the binding of GAG antibodies to GAG. Drugs based on such molecules, she said, could offer a treatment for rheumatoid arthritis. And the test she and her colleagues developed to identify the GAG antibodies could also be used as a screening tool, she added, to determine if a patient is at risk of developing the disease.

Also from USA Today

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Carbohydrates may be the culprit behind painful rheumatoid arthritis
Thu Aug 22, 8:12 AM ET

Anita Manning USA TODAY

Researchers in Massachusetts say they have found a long-sought cause of rheumatoid arthritis, a finding that could point to new areas of research and the development of new drugs to halt the debilitating and painful disease, which affects 2.1 million Americans.

Julia Ying Wang and colleagues at Brigham and Women's Hospital, Boston, and Harvard Medical School ( news - web sites) reported Wednesday that an abnormal immune reaction to carbohydrates in joint cartilage appears to cause the inflammation and swelling of joints characteristic of the disease.

Wang, who presented her findings at a meeting of the American Chemical Society in Boston, says the immune system's ''mishandling'' of carbohydrates called glycosaminoglycans, or GAGs, is an underlying cause of the disease, though why the unusual immune response occurs is not clear.

Previous studies have found elevated levels of GAG in patients with rheumatoid arthritis, Yang says, but until now, research has focused on proteins as a possible cause of the disease, not carbohydrates. ''People think sugars (a carbohydrate) don't do anything,'' she says.

GAGs are a natural part of cartilage and other connective tissues, and are not affected by consumption of carbohydrates.

In arthritic mice and in tissue taken from humans with the disease, Yang found immune-system cells that attach to GAGs in joints. The buildup of these cells causes inflammation and swelling.

High levels of GAG, she says, could be caused by bacteria, which produce enzymes that break down connective tissue, releasing the carbohydrates. And many bacteria and other organisms produce GAG on their cell surfaces, she says, so the immune response to an invading microbe, may mistakenly discern GAG in healthy cartilage as another invader. ''That might explain why so many infections can lead to arthritis,'' she says.

The connection between rheumatoid arthritis and a natural component of cartilage is ''potentially of extreme importance,'' and ''represents an entirely new avenue in which we might begin to explore this disease,'' says John Klippel, medical director of the Arthritis Foundation, who was not involved in the research.

''We don't think of carbohydrates as something that can engage the immune system,'' he says. ''The study would suggest there are cells in the joints interacting with this carbohydrate. One would want to know more about where these cells came from, so you could think about blocking the cells from generating or blocking their interaction with the carbohydrate.''

The finding ''will stimulate an enormous amount of interest'' in further research and could lead to new drugs that would treat the cause of the disease, rather than its symptoms.

http://story.news.yahoo.com/news?tm...satoday/4382294

Would be interesting to say if there is any relation to one's diet.

Wa'il

This quote would appear to say that there is no relation to diet. Oh well.

;-Deb

This quote may or may not be true, but in either case that still does not let diet off the hook as being the foundational cause of arthritis.

If the GAGs are not made from the consumption of carbohydrates they could be made during the bodies construction of cartilage or during the recycle of old cartilage molecules. The GAGs could be an intermediate molecular structures that cannot be completed into the final cartilage structure because of deficiencies in the diet. This could be similar to homocysteine that is an intermediate and harmful protein. An amino acid deficiency could leave the GAGs in this uncompleted and harmful state in the same manner as homocysteine.

Arthritis seems to have a connection with a protein deficiency in the diet that is therefore more common in high-carbohydrate diets. Elderly women commonly express a dislike for red meat and appear to eat less meat than men. These women also have a higher incident of arthritis than men. This does not prove a direct link but raises the possibility a few points.

Personally, I had a slight problem in both knees that caused pain during inactivity, such as sitting for long periods of time. This condition was completely healed by the Atkins' low-carbohydrate diet during the last three years. I am convinced that low-protein diets cause weak and troublesome connective and lubrication tissues in joints.

Kent

New York Times, August 22, 2002

Study Suggests Carbohydrates Are Attacked in Arthritis
By KENNETH CHANG


Scientists may have discovered an important, unexpected clue in the long, elusive search for the cause of rheumatoid arthritis.

Rheumatoid arthritis, a disease without cure that afflicts more than two million people in the United States, is thought to be caused by out-of-control immune cells that mistakenly attack cartilage and joints.

But scientists have been unsure exactly what in the cartilage and joints the immune cells are attacking.

In such autoimmune diseases, the body's defense system typically turns against itself by homing in on and destroying one of the body's proteins. Some scientists have proposed that rheumatoid arthritis attacks collagen, a fibrous protein in cartilage, bone and connective tissues, but the evidence has been ambiguous.

The new research suggests that the target of destruction is not a protein, but carbohydrates.

"There has to be some sort of attraction," said Dr. Julia Y. Wang, a professor of medicine at Harvard Medical School and Brigham and Women's Hospital in Boston. "Our study for the first time identifies a direct link between carbohydrates in our tissues, the immune system and rheumatoid arthritis."

Dr. Wang and Dr. Michael H. Roehrl of Harvard believe the target is a type of carbohydrate known as glycosaminoglycans, a major component of cartilage, joint fluids, connective tissue and skin.

If true, the findings could lead to drugs that reduce or disarm the rampaging cells.

Dr. Wang presented the findings yesterday at the national meeting of the American Chemical Society in Boston. Other scientists will have to repeat the experiments before the theory gains acceptance.

"I think this is of considerable interest and potentially very important," said Dr. John H. Klippel, medical director of the Arthritis Foundation. "It opens a new way of thinking about this disease. We don't think of the immune system as responding to complex carbohydrates."

In the experiments, Dr. Wang and Dr. Roehrl injected glycosaminoglycans into mice, inducing arthritis-like swelling and inflammation around the animals' joints. "The bones start to erode," Dr. Wang said.

The mice also developed lesions in their tendons and skin, also symptoms of rheumatoid arthritis.

The researchers developed a test to find immune cells that bind to glycosaminoglycans. The test revealed high concentrations of the cells not only in and around the mice's rheumatoid lesions, but also in bone marrow.

Dr. Wang said she believed that the body produces the carbohydrate-binding cells in bone marrow as a normal matter of course to control the level of glycosaminoglycans in the blood. When the level of the carbohydrate soars for some reason, she said, the immune system appears to respond by churning out more immune cells and some of the excess miss their intended targets in the blood and bind to glycosaminoglycans in the joints instead, to disastrous effect.

Tests on joint tissue from nine human arthritis patients showed the immune cells in people suffering from rheumatoid arthritis, but not other forms of arthritis, which are not autoimmune diseases. Dr. Wang said she did not know why the carbohydrate levels might become elevated.

Rheumatoid arthritis accounts for about 2.1 million of the 42 million cases of arthritis in the United States and strikes fairly young in life, usually middle age, but sometimes as early as the 20's and 30's. About three-quarters of patients are women.

Currently, some drugs alleviate the disease's painful swelling, but there is no cure.

Unfortunately, if this research turns out to be true that the body is fighting its own natural components of joints: glycosaminoglycans, then people are taking the wrong supplements for joints. Supplements taken to improve joints generally include stimulants of glycosaminoglycan production. If too many glycosaminoglycans cause arthritis, then taking these supplements causes rheumatoid arthritis.

Glucosamine Sulfate

Glucosamine has several important functions in the joints. It stimulates the production of two very important components of the joint—proteoglycans and glycosaminoglycans. These special proteins serve to bind water in the cartilage matrix, providing a cushion between the various bones of the joint. Glucosamine also regulates cartilage metabolism, helping to keep cartilage build-up and break-down in balance.

Chondroitin Sulfate

"Chondroitin sulfate as well as shark cartilage, bovine cartilage extracts, and sea cucumber contain a mixture of intact or partially hydrolyzed GAGs (glycosaminoglycans)... Chondroitin sulfate is composed of repeating units of derivatives of glucosamine sulfate with attached sugar molecules."5

The combination of these two supplements has been developed into drug form:

http://www.cdc-cdh.edu/hospital/cardio/art23.html

However, these supplements may help osteoarthritis while exacerbating rheumatoid arthritis.



http://www.willner.com/References/webref02.htm

I took glucosamine sulfate and chondroitin sulfate for several years and thought it was doing some good, but I now believe the improvements in my joints came from the low-carbohydrate diet as expressed above.

I would expect these molecules to be to large to pass through the gut - blood barrier and cannot be absorbed as taken. Perhaps they are broken down into usable components that can pass the barrier, or they are broken down in a manner that makes them completely harmless and unusable. I suspect the latter may be the case.

Please post the link if anyone has a scientific explanation.

Kent

I'm not a medical expert, I only know what works for me. Since about 1 month after starting this WOE, I stopped taking my arthritis medicine. Before, even with the meds, I hurt badly. I don't know if it is the diet or not, but I am not about to go back to the old way of eating just to find out.

This site lists the first treatment for arthritis as low-carbing:

Treatment: decreasing inflammation and counteracting joint deterioration from oxidative stress and free radical damage.

Food

One of the most promising methods of treatment is through balancing the micro-hormones called eicosanoids (for example prostaglandins) by
Using protein instead of carbohydrate as your main energy source; see
Low Carbohydrate diets


http://www.loudzen.com/canary/conditions/arthritis.html

From these studies, apparently oral glucosamine is metabolized and has an effect although the underlying mechanism is unknown. It is thought to suppress the immune system which is advantageous when there is an autoimmune disease present. However, glucosamine is known to increase insulin resistance. It could be a two-edged sword if it helps arthritis by decreasing the immune system response, but since it also increases GAG, then it may aggravate rheumatoid arthritis.



Br J Community Nurs 2002 Mar;7(3):148-52

Glucosamine therapy compared to ibuprofen for joint pain.

Ruane R, Griffiths P.

Primary Care and Community Pharmacy, King's College London.

To determine the effectiveness of oral glucosamine with ibuprofen for the relief of joint pain in osteoarthritis a mini-review (Griffiths, 2002) of double-blind randomized controlled trials comparing the two was undertaken. The population was adult patients diagnosed with osteoarthritis at any site. The outcome was arthritic pain reduction. Searches on Medline, Embase, AMED, the Cochrane Library and the Merck index identified four trials. Of these, two studies were obtainable and were included in the review. Both compared 1.2 g ibuprofen daily with 1.5 g glucosamine sulphate daily, in three divided doses. The combined number of participants in the studies was 218. The results of these studies showed glucosamine to be of similar efficacy to ibuprofen. The conclusion is that glucosamine is effective in relieving joint pain associated with osteoarthritis. Glucosamine's pain-relieving effects may be due to its cartilage-rebuilding properties; these disease-modifying effects are not seen with simple analgesics and are of particular benefit. In practice glucosamine can be used as an alternative to anti-inflammatory drugs and analgesics or as a useful adjunct to standard analgesic therapy.

-------------------------------------------



Immunosuppressive effects of glucosamine
Linlin M et al

Running title: Glucosamine immunosuppression
The American Society for Biochemistry and Molecular Biology, Inc.
JBC Papers in Press. Published on August 9, 2002 as Manuscript M2049242002

Summary:
Glucosamine is a naturally-occuring derivative of glucose, and is an essential component of glycoproteins and proteoglycans, important constituents of many eukaryotic proteins. In cells, glucosamine is produced enzymatically by the amidation of glucose-6-phosphate and can then be further modified by
acetylation to result in N-acetylglucosamine. Commercially, glucosamine is sold over the counter to relieve arthritis. While there is evidence in favor of glucosamine’s beneficial effects, the mechanism is unknown. Our data demonstrate that glucosamine suppresses the activation of T-lymphoblasts and dendritic cells in vitro, as well as allogeneic mixed leukocyte reactivity in a dose dependent manner. There was no inherent cellular toxicity involved in the inhibition and the activity was not reproducible with other amine sugars. More importantly, glucosamine administration prolongs allogeneic cardiac allograft survival in vivo. We conclude that, despite its documented effects on insulin
sensitivity, glucosamine possesses immunosuppressive activity and could be beneficial as an immunosuppressive agent.

Introduction
Glucosamine is a naturally-occuring sugar that is synthesised by virtually all cells. Upon uptake, glucose is immediately phosphorylated and enzymatically converted into a series of substrates that will either be converted into glycogen, lipids, proteins or used to generate ATP and CO2. 2-3% of glucose-6-phosphate, the immediate intracellular glucose derivative following uptake, is diverted into a pathway known as the hexosamine biosynthesis pathway (1,2). The rate-limiting
enzyme, glutamine:fructose-6-phosphate amidotransferase is responsible for the commitment of glucose derivatives into the pathway, ultimately resulting in the formation of glycoprotein precursors (3). Glucosamine is not secreted outside of cells, but exogenously-added glucosamine is taken up by glucose-transporters (GLUT-2 and GLUT-4) and then phosphorylated (4,5).
In 1953, Quastel and Cantero demonstrated that glucosamine possessed tumor-inhibitory activity (6). Since then, a number of reports confirmed the tumoricidal activity of glucosamine (7-16). Glucosamine has been shown to inhibit nucleic acid and protein biosynthesis and irreversible damage to organelles in tumor cells, but not in normal cells (8-15,17-20). In addition, glucosamine also inhibits platelet aggregation and ATP release induced by Staphylococcus aureus, ADP, epinephrine and collagen (21). The mechanisms by which glucosamine acts are not completely clear, however, it has been shown to alter the ultrastructure of plasma and intracellular membranes (9,22), to inhibit membrane transport of nucleosides (14,15) and reportedly to shift its distribution from glycoproteins to glycolipids (22).
O’Neill et al. demonstrated that monosaccharides, especially aminosugars, were able to inhibit cytotoxic T-lymphocyte function in culture preventing target lysis in a CTL clone-specific manner (23). In 1989, Yagita el al. further demonstrated that free hexosamines were able to inhibit NK cell cytotoxicity in culture (24,25) and that hexosamine release by tumors could, in part, explain escape of tumors from immune cell lysis (24). Since then, other than the observation that Amiprilose, a synthetic monosaccharide, was able to attenuate T-cell activation in a dose-specific manner (26), no other work has been published on the utility of sugar derivatives, especially amino sugar derivatives
(glucosamine, mannosamine, lactosamine, fructosamine), as immunoregulatory agents However, a recent report by Gouze et al. demonstrated glucosamine-dependent inhibition of NF-kB activity in rat chondrocytes and IL-1b bioactivity by upregulation of the type II IL-1 decoy receptor (27).
Glucosamine has received considerable attention in the past five years as an agent that may be beneficial for arthritis in a number of studies (28-31). Sold mainly over the counter in various formulations (glucosamine sulfate, glucosamine sulfate with chondroitin sulfate), the manufacturers suggest that the beneficial effects of their compounds are due to the construction of joint cartilage, of which one of the constituents is glucosamine in the form of glycoproteins of structural proteoglycans. A recent study in humans demonstrated beneficial effects of glucosamine in arthritis, although no firm conclusions could be made (28). The actual mechanism by which glucosamine may benefit the patient remains unknown, although very recent investigation suggests that it may interfere with pro-inflammatory cytokine action on human chondrocytes (32).
Glucosamine, however, induces insulin resistance in the absence of high glucose or glutamine (2) as well as insulin resistance in isolated rat muscle (33). Glucosamine has also been shown to modulate the effects of insulin and glucose on pyruvate kinase (34), glycogen synthase (33,34) and transforming growth factor alpha gene expression (35). A short-term exposure of cultured rat
adipocytes to glucosamine decreases GLUT-4 activity and longer, 16 hour incubations, result in decreased GLUT-4 cell surface levels (36). Furthermore, glucosamine infusion can induce insulin resistance in normoglycemic, but not hyperglycemic rats and this is accompanied by impaired GLUT-4 translocation to the cell surface of skeletal muscle in response to insulin (37). Insulin sensitivity in rat cardiac muscle and liver has also been shown to be affected by glucosamine infusion (38). More importantly, acute glucosamine infusion into humans has been demonstrated to mimic some of the metabolic aspects of insulin resistance in human type 2 diabetes mellitus (39).