Glucosamine Pain/Inflammation Relief

Glucosamine supplements work through effects on the gut that contribute to general anti-inflammation. It is thought that glucosamine interacts with tissue transglutaminase and blocks production of signaling molecules for chronic infammation. It should also be effective against inflammatory diseases of the intestines, joints and elsewhere.


Cartilage and other connective tissues are made up of collagen protein fibers embedded in a matrix of polysaccharide, chondroitin sulfate. The tightly packed, twisted proteins of the collagen in the negatively charged, acidic polysaccharide act like a fiber reinforced, dense gel that provides impact resistance for long bone joint surfaces, as well as the stretch-resistance and elasticity for tendon and ligaments. Collagen in cartilage is comparable to cellulose (crystallin neutral polysaccharide fibers) embedded in the acidic polysaccharide (pectin) of plant cell walls.

The connective tissue polysaccharides are glycosamino glycans, GAGs, the most intensely negatively charged molecules in the body. They are more negatively charged than the nucleic acids, and the proteins that bind to the negative charge of the phosphates of nucleic acids will preferentially bind to GAGs if they get a chance. An example of this is the removal of small, highly positively charged peptides, protamines, used to pack the chromosomes of sperm. These small proteins bind strongly and can only be removed from sperm chromosomes in fertilized eggs, by the brief introduction of GAGs. Heparin is the most negatively charged, most highly sulfated of the GAGs and protamine, is used medically to neutralize excess heparin that has been injected to block blood clotting.

GAGs are composed of alternating amino sugars, e.g. glucosamine, and uronic acids, e.g. glucuronic acid. These are among the most primitive of polymers and may have evolutionarily predated the nucleic acids. It was initially suspected that glucosamine supplements contributed directly to the production of the glucosamine-rich GAGs of the cartilage of joints and thereby helped to reduce joint pain. This is unlikely, however, because the level of glucosamine in the blood is normally vanishingly low and glucosamine supplements increase the level only a tiny amount. Further reflection on the negligible pain relief of meat that contains huge quantities of glucosamine in its connective tissue, confirms that supplemental glucosamine could not impact joint pain by its impact on GAG synthesis.

The usefulness of glucosamine in reducing inflammation and joint pain is based on its impact on the small intestine. I came to this conclusion through analysis of recent studies of inflammatory diseases of the intestines, e.g. celiac and inflammatory bowel disease. These diseases are autoimmune diseases in which the body produces antibodies to inappropriate proteins in the diet or of intestinal cells. The first step in the diseases is the shift to an inflammatory physiology of the intestines. The intestines normally respond to cellular antigens and food antigens with specific anti-inflammatory signals that actively suppress antibody production and lymphocyte activation, i.e. immunological tolerance. Infection of the intestines by a pathogen triggers an inflammatory physiology that is intolerant and immunologically aggressive. Antigens in this environment are presented to the immune system and antibodies are produced. Proteins with heparin-binding domains, e.g. nuclear proteins that would otherwise bind to nucleic acids or signaling proteins that bind to heparan sulfate proteoglycans, or allergens that have strong heparin-binding domains for unknown reasons, are strong immunogens in this context. An enzyme that is normally bound to the surface of the intestines, but is also brought into cells for additional signaling purposes, is tissue transglutaminase, tTG. In the gluten allergy disorder, celiac, antibodies are produced against the body’s tTG. This disorder is poorly understood, but I will try to use what is known to explain the use of glucosamine in pain relief.

Our focus in glucosamine pain relief is on the structure of glucosamine and how this molecular structure is integral to inflammation through the action of the enzyme tTG. Glucosamine is just a glucose sugar molecule with a nitrogen, amino group, added to one of the carbons. In a similar way, glutamine is just a glutamic acid with an amino group added to one end. Tissue transglutaminase is an enzyme that transfers the glutamic acid of glutamine from one molecule to another. As tTG transfers these glutamic groups, it forms intermediate structures with its own amino acids forming bonds to the glutamic group. Thus, wheat gluten, or gluten fragments with long stretches of glutamines, binds directly to make a tTG-gluten complex. Because tTG has strong heparin-binding domains, there is a tendency for the tTG-gluten complexes to be brought into intestinal cells and in an inflammatory physiological state, to be presented to the immune system for antibody production. As a result, antibodies to both tTG and gluten are produced as a consequence of certain forms of intestinal inflammation.

Another key observation was that many of the proteins involved in inflammatory signaling of the intestines are glycoproteins with unusual modifications of their attached sugar chains. Antibodies can be made and used to identify these unusual modifications. The modifications turned out to be attachment of glutamic acid through its carboxyl group to the amino group of the glucosamine of the glycoprotein sugar chains. It was this linkage that drew my attention, because it is similar to the way that tTG forms intermediates with the glutamines of proteins. It seemed obvious that tTG was the enzyme that was adding the glutamic acids (carboxylation) to the glucosamines of the intestinal glycoproteins! A search of the scientific literature revealed that glucosamine is in fact an inhibitor of tTG, showing that glucosamine binds to the enzyme, probably forming an intermediate as it does with glutamine.

The central piece of this complex puzzle was the observation that antibodies used to identify the carboxylated glycans (the sugar chains of the glycoproteins that have glutamic acid added) can block inflammation in inflammatory bowel disease. This suggests that some form of the glutamic acid/glucosamine conjugate to which the antibody binds is involved in inflammatory signaling. AGE receptors were implicated, because these receptors trigger inflammation and they are glycoproteins on the surface of the intestinal cells that are observed to by carboxylated with glutamic acids. AGE is an acronym for advanced glycation endproducts, the molecules formed at high blood sugar levels in diabetics, as glucose chemically interacts with the amino groups (frequently the lysines of heparin-binding domains) of proteins on the surface of the vascular system.

I think that glucosamine in supplements lowers inflammation and decreases pain by forming conjugates with glutamine through the enzymatic action of tTG. This action and the inactivation of tTG by the formation of tTG/glucosamine conjugates lowers inflammatory signaling and could perhaps block the formation of the toxic gluten/tTG/antibody amyloids characteristic of celiac. Glucosamine/glutamic acid conjugates may also be substrates for direct interactions with the AGE receptor.