Glycosaminoglycans (GAGs) May Cause Rheumatoid Arthritis

doctor and patient talking

Rheumatoid arthritis, an autoimmune disease which affects 1.3 to 1.5 million Americans, is the result of the body's own immune cells attacking cartilage and joints. What actually goes haywire in the immune system of a person with rheumatoid arthritis to cause the pain and destruction associated with the disease?

Studies conducted by Dr. Julia Ying Wang of Brigham & Women's Hospital in Boston and Harvard Medical School, along with her colleague Dr. Michael H.

Roehrl of Harvard, were presented at the annual meeting of the American Chemical Society in August 2002 and published in PNAS, tackling this very question.

Prior to the work of Wang and Roehrl, rheumatoid arthritis research largely focused on peptides, or fragments of protein. Wang and Roehrl suggested that glycosaminoglycans, or GAGs, are what causes rheumatoid arthritis rather than proteins.

The GAGs Theory

Glycosaminoglycans are naturally-occurring carbohydrates found in cartilage, connective tissue, joint fluid, and skin. Glycosaminoglycans are complex carbohydrates. They are not affected by the carbohydrates, starches, and sugars we consume in our diet.

Simply stated, Wang's theory proposed that immune system cells, or antibodies, target glycosaminoglycans. The antibodies bind to GAGs, accumulate in the joints, and trigger pain and inflammation associated with rheumatoid arthritis.

The Research

In Wang and Roehrl's study, mice were injected with GAGs.

The mice developed chronic rheumatoid arthritis-like symptoms, including inflammation, swelling, and bone erosions.

Glycosaminoglycan antibodies have since been discovered in the tissue of rheumatoid arthritis patients. It should be emphasized that this was the first time glycosaminoglycan antibodies had been observed in either animals or humans.

Researchers theorized that:

  • GAG antibodies may develop as a result of bacterial infection.
  • High levels of GAG may result when bacteria produce enzymes that break down connective tissue and release carbohydrates.
  • Many bacteria have GAG on their cell surface. In rheumatoid arthritis, immune cells may mistakenly target naturally-occurring GAGs in the body's tissues in the same way they would target GAG on the surface of bacterial invaders.

Researchers hoped that more studies would reveal a way to bind the GAG antibodies, leading to new treatments or medications for rheumatoid arthritis. A study published in 2008, in Arthritis Research & Therapy, revealed more about GAGS:

  • GAG-specific antibodies are not present in neonates (newborns).
  • GAGs are present in high amounts in the serum of adults.
  • GAGs have been categorized as TI2 antigens. B1 B cells are known to be reactive with TI2 antigens.

It was also revealed that anti-GAG antibodies are natural autoantibodies found in healthy individuals. IgM anti-GAG antibodies and some IgG-type anti-GAG antibodies tested were found to be significantly elevated in the sera of patients with rheumatoid arthritis. While the anti-GAG antibodies were present in the systemic circulation, synovial fluid and they were also capable of binding to the extracellular matrix of hyaline cartilage.

Researchers hypothesized that anti-GAG antibody production is "up-regulated" in rheumatoid arthritis perhaps related to the release of cartilage molecules. Interestingly, higher anti-GAG levels are associated with less severe disease activity in rheumatoid arthritis. Researchers concluded that GAGs may serve as an early disease activity biomarker for rheumatoid arthritis.


Glycosaminoglycans Are a Potential Cause of Rheumatoid Arthritis. Proceedings of the National Academy of Sciences of the United States of America. Wang JY and Roehrl MH. October 21, 2002.

Natural Autoantibodies Reactive With Glycosaminoglycans in Rheumatoid Arthritis. Bence Gyorgy et al. Arthritis Research & Therapy. 2008.