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_suggests_cause_of_one_arthritis_type+.shtml

Harvard research suggests cause of one arthritis type

By , Globe Staff, 8/22/2002

Shining a light onto the elusive roots of a painful disease,

Harvard researchers announced yesterday that they may have

pinpointed a chief cause of rheumatoid arthritis.

The research, reported at the American Chemical Society's

national meeting in Boston, begins to lift the shroud of mystery

that has long cloaked rheumatoid arthritis, a condition in which

the body fights a molecular war against itself.

Although advances of recent years have yielded some effective

drug approaches, there remains no definitive treatment for the

disease, and the 2.1 million Americans with the disease often

rely on traditional painkillers to relieve their aches.

Biological chemist Ying Wang and Dr. H. Roehrl, a

Harvard colleague, found that carbohydrates common in human

tissue may act like magnets for certain immune cells,

concentrating them in the joints and causing the painful

inflammation and stiffness that characterizes the disease.

''This is potentially of enormous importance,'' said Dr. H.

Klippel, medical director of the National Arthritis Foundation. ''If

we ever hope to work toward a cure, we're going to have to find

out what causes this disease, and this opens up a whole new

way of thinking about it.''

That thinking is already being used by scientists at Harvard and

at Brigham and Women's Hospital to search for treatments that

could reverse the course of rheumatoid arthritis rather than just

relieve its symptoms. If that work continues to prove fruitful, it

could lead to a medication to stop the disease at an early stage,

before it can begin taking its lifelong toll on joints, an advance

especially important today in a nation of aging baby boomers.

There are two major forms of arthritis. Rheumatoid arthritis is an

immune disorder that can strike at any age, even during

childhood, and more commonly affects women.

The other kind, osteoarthritis, is 10 times more common but

often less debilitating, developing in older people as the padding

of their joints wears out.

Wang, who is affiliated with Harvard and the Brigham, said

yesterday that her interest in rheumatoid arthritis was piqued in

part by the experience of her hairstylist, a woman who has

endured the aches and pains of the disease for 35 years, with

swollen hands and ankles and fingers riddled with telltale

nodules.

Wang honed in on a class of carbohydrates called

glycosaminoglycans, identified in laboratory lingo by the

unappetizing acronym GAGs.

Those carbohydrates are ubiquitous in mammals, tending to

clump in soft tissue; essentially, they act like the glue that holds

together constituent parts of skin, cartilage, and the sheathing of

tendons.

Wang theorized that there was something about GAGs that

made them attractive to the inflammatory cells dispatched as

part of the body's immune response. Such cells, typically, are a

good thing: They help attack foreign molecular invaders. They

help heal wounds and vanquish bacterial infections. And, in

healthy people, once their work is done, inflammatory cells

recede.

But in patients with rheumatoid arthritis, those cells do not

recede.

Instead they begin migrating through the body, attracted to GAGs

like metal to a magnet. The inflammatory cells have tiny

molecular doors propped open that allow the cells to become

attached to GAGs.

The consequence is a molecular cascade resulting in joint

inflammation, stiffness, and pain.

To test her theory, Wang performed studies in mice that showed

if they were injected with additional GAGs, throwing the body's

immune system out of whack and spawning inflammatory cells,

they developed chronic rheumatoid arthritis in their paws.

And a review of tissue samples from human patients with the

condition showed that they had clusters of GAGs pocked with

inflammatory cells at pivotal joints.

For scientists intrigued by the complexity of rheumatoid arthritis,

Wang's research provides new, promising evidence of a

long-suspected link between bacterial infections and the joint

condition.

Because the team's research has been conducted primarily on

mice, scientists caution that more research is needed in

humans to definitively establish the link between GAGs and

rheumatoid arthritis.

For other scientists, there is skepticism. Rheumatoid arthritis

researchers have focused on proteins and other causes, rather

than carbohydrates.

''We are encountering a lot of resistance,'' Wang acknowledged.

Dr. Roy Altman, chief of rheumatology and immunology at the

University of Miami, said yesterday that he was puzzled by the

findings, given that some carbohydrates, in the form of sugars,

are actually being used to treat rheumatoid arthritis.

But, Altman said, there are sugars of vastly different molecular

constitution, so it's possible that while one carbohydrate could

help a rheumatoid arthritis patient, another could prove

deleterious.

Mekalanos, chairman of microbiology and molecular

genetics at Harvard Medical School, is writing a commentary

assessing Wang's research to accompany planned publication

of her study in the Proceedings of the National Academy of

Sciences. If Wang's discovery results in a treatment, Mekalanos

said, it would mark yesterday's report as a seminal moment in

arthritis research. He suggested a scenario, for instance, in

which toxic GAGs could be created to kill rogue inflammatory

cells.

''If you could do that, it would be a magic bullet,'' Mekalanos said.

''This could be a very important crossroads in the field if we get

this all the way over the finish line some day and come up with a

cure.''

can be reached at stsmith@....

This story ran on page A1 of the Boston Globe on 8/22/2002.

© Copyright 2002 Globe Newspaper Company.