Waste DNA a Possible Cause of Arthritis

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Waste DNA a Possible Cause of Arthritis

By Rhitu Chatterjee

ScienceNOW Daily News

26 October 2006

DNA may be the basis for all life, but it can also be a toxic waste

product. According to a new study, mice will develop symptoms

characteristic of rheumatoid arthritis if they can't break down and

dispose of unwanted DNA. The findings suggest a new cause for the

disease in humans.

Like most of the molecular cogs that keep the human body running

smoothly, DNA eventually outlives its usefulness and must be

discarded. Red blood cells have no need for DNA and eject it once

they become mature, and dying cells disintegrate, releasing DNA into

the body. Special immune cells called macrophages function like

garbage collectors, picking up this waste DNA and breaking it down.

Biochemist Shigekazu Nagata of Osaka University Medical School in

Japan and his colleagues wondered what would happen if these cellular

garbage collectors went on strike. His team genetically modified a

group of mice so that their macrophages could no longer make an

enzyme called DNase II, which is crucial to degrading DNA. As

expected, waste DNA piled up inside the animals' macrophages. What's

more, the mice developed symptoms typical of rheumatoid arthritis in

humans: Their joints became inflamed and were filled with immune

system chemical messengers, such as TNF-α, which make the immune

system turn on the body.

The team suspects that the excess load of waste DNA somehow

stimulates the macrophages to release TNF-α. When the researchers

used antibodies to block TNF-α activity in the mice (one of the

treatments for rheumatoid arthritis), the symptoms of disease were

significantly reduced, the authors report online today in Nature. " If

we could find human rheumatoid arthritis patients carrying a defect

in degrading DNA in macrophages, a new treatment would be developed, "

says Nagata. Anti-TNF-α drugs are currently available, but they work

in only about a third of the patients and increase the risks of

lymphoma and serious infections.

" This is intriguing and probably very important, " says arthritis

expert Firestein of the University of California, San Diego,

because it provides an alternate model for arthritis development.

Current views focus mainly on how other kinds of immune cells--the

body's T cells--contribute to the disease, he says. Still, Firestein

notes, the results need to be borne out in humans before scientists

start investigating new treatments for the disease.

http://sciencenow.sciencemag.org/cgi/content/full/2006/1026/2