Provoking RAGE: Protein fans the flames of cranky joints (Arthritis)
Authors: Chen Ingfei 
Published: August 2003

For people with rheumatoid arthritis, a smoldering fire of inflammation leaves fingers and knees achy and swollen. The disease gnarls and destroys the joints sooner in some people than in others, and scientists now have fresh insights as to why. The new work suggests that blocking a protein called RAGE might help quench the flames.

The cell surface protein's name stands for receptor for AGEs (advanced glycation end products). AGEs are cellular gunk produced when glucose reacts with proteins and lipids, and some experts think that they promote aging (see
"Aging Research Grows Up"
). Ever since cell biologist Ann Marie Schmidt and colleagues discovered RAGE in 1992, they've been stalking other types of molecules that plug into it--and have linked the receptor to diabetes, atherosclerosis, and Alzheimer's disease. Recently, the scientists tracked RAGE to arthritis. The pain and swelling of the illness arise when the body's white blood cells attack joint linings. Schmidt's group found that RAGE binds to molecules unrelated to AGEs called S100/calgranulins, which build up in the joint fluid of rheumatoid arthritis patients. The researchers wondered whether obstructing RAGE would alleviate symptoms.

To find out, Hofmann, Schmidt, and colleagues injected arthritic mice with a decoy receptor--a shorter, soluble version of RAGE--that gloms onto the S100/calgranulins, thwarting them from attaching to real receptors. The mice showed less swelling, redness, and joint damage than their untreated counterparts did. Blood and joint tissue from the controls teemed with three to five times more molecules that provoke inflammation and enzymes that destroy joint tissue than did samples taken from the treated mice. The findings suggest that RAGE cranks up the immune system, Schmidt says.
Analyses of two different full-length forms of RAGE--the normal version and a mutated one that proved to have an extra-sticky binding site--support that idea. Hamster and human cells that produce either protein churned out inflammation instigators in response to S100s, but cells carrying the gummier receptor showed the brawnier response.

Results from human patients also lend credence to the researchers' theory that RAGE fuels arthritis, the team found. The mutant
RAGE
gene was 2.6 times more common in patients than in healthy people. The altered receptor alone doesn't cause the disease, which arises from complex genetic underpinnings, but people who carry the mutation might suffer from a particularly severe form, Schmidt speculates. If so, the research would hold clinical promise. Industry partners are working with the scientists to develop a medicine that stops molecules from turning on RAGE, says Schmidt. In the meantime, she adds, doctors could use currently available drugs more aggressively if they identified patients who carry mutated
RAGE
.

The current work is the first to clearly link RAGE to arthritis, says biochemist Vincent Monnier of Case Western Reserve University in Cleveland. A vigorous RAGE response could be a culprit in additional chronic inflammatory and autoimmune disorders that involve excess S100s, says Schmidt, who points out that the receptor increasingly lives up to its name: "It's turned out there is more rage in it than we ever thought."
--Ingfei Chen

M. A. Hofmann, S. Drury, B. I. Hudson, M. R. Gleason, W. Qu, Y. Lu, E. Lalla, S. Chitnis, J. Monteiro, M. H. Stickland, L. G. Bucciarelli, B. Moser, G. Moxley, S. Itescu, P. J. Grant, P. K. Gregersen, D. M. Stern, A. M. Schmidt, RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response.
Genes Immun.
3
, 123-135 (2002).
[Abstract/Full text]