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DURHAM, N.C. – Scientists at Duke University Medical Center
may have solved the mystery surrounding the healing properties
of gold – a discovery they say may renew interest in gold salts
as a treatment for rheumatoid arthritis and other inflammatory
diseases.

Physicians first used injections of gold salts in the early
1900s to ease the pain and swelling associated with arthritis.
But treatment came at a high cost: The shots took months to
take effect and side effects included rashes, mouth sores,
kidney damage and occasionally, problems with the bone marrow's
ability to make new blood cells. Recently, new treatments like
methotrexate and biologically engineered drugs have replaced
gold as a preferred treatment, and gold salts, while remaining
effective, are usually administered as a last resort.

But Dr. David Pisetsky, chief of the division of
rheumatology and immunology in the department of medicine at
Duke, says "we shouldn't dismiss gold salts so quickly. We
scientists have really never understood why gold works. Now
that we have a better handle on its action, we may be able to
use that mechanism to create new and better gold-like drugs to
treat arthritis."

Pisetsky had long been interested in a particular molecule,
HMBG1, which provokes inflammation, the key process underlying
the development of rheumatoid arthritis. HMBG1 is a
dual-function molecule, which means that it behaves one way
when it's inside the nucleus of a cell, and quite another way
when it's released from the cell.

Pisetsky says that inside the nucleus, HMGB1 is a key player
in transcription, the process that converts genetic information
in DNA to its RNA equivalent. But when HMGB1 is released from
the cell – either through normal processes or cell death – it
becomes a stimulus to the immune system and enhances
inflammation.

"Interestingly, HMGB1 is not produced evenly throughout the
body," says Pisetsky.
"There is an unusually high amount of it in the synovial tissue
and fluid around the joints – where arthritis occurs."

Pisetsky, working with colleagues at the University of
Pittsburgh and the Karolinska Institute in Sweden, stimulated
mouse and human immune system cells to secrete HMGB1, then
treated them with gold salts. They found that the gold blocked
the release of HMGB1 from the nucleus. That, in turn, should
lessen the amount available to provoke the body's immune
system, weakening the inflammatory response.

"Basically, keeping HMGB1 corralled inside the nucleus is a
good thing, when it comes to arthritis," says Pisetsky.

Pisetsky says gold inhibits the release of HMGB1 by
interfering with the activity of two helper molecules that ease
HMGB1's release from the cell, interferon beta and nitric
oxide.

The study will appear in the January, 2008 issue of the
Journal of Leukocyte Biology, but a preprint is already online
at the journal's website at: http://tinyurl.com/3cd957.

"Now that we have identified at least one of the ways gold
can help arthritis sufferers, perhaps we can use that knowledge
to build new and safer-acting, gold-based treatments," says
Pisetsky, a senior author of the study.

Pisetsky is encouraged by the results but says additional
studies need to be done to find out if the same mechanism is
active in animals and people and not just in laboratory
studies.

Co-authors of the study include lead investigators Weiwen
Jiang, from Duke University, and Cecilia Zetterstrom, from the
Karolinska Institute; Heidi Wahamaa, Therese Ostberg,
Ann-Charlotte Aveberger, Hanna Schierback and Ufl Anderson from
the Karolinska Institute; Helena Erlandersson Harris, senior
co-author, from the Medicine and Rheumatology Unit of the
Karolinksa University Hospital and Michael Lotze, from the
University of Pittsburgh.

Support for the study comes from the Karolinska Institute
King Gustav V 80-year Foundation, the Freemason Lodge Barnhuset
in Stockholm, the Foundation for Technical Support to Disabled,
the Swedish Research Council, the Swedish Rheumatism
Association, the Lupus Research Institute, the VA Medical
Research Service and the National Institutes of Health.