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DURHAM, N.C. -- Using a three-pronged approach, basic scientists and
clinicians at Duke University Medical Center hope not only to better
understand the underlying mechanisms of osteoarthritis, but to develop
strategies to help sufferers cope with this debilitating disorder.

The
need is great, the researchers argue, since there are more than 40
million Americans with the disorder, which is known as the
"wear-and-tear" form of arthritis. The other major form, rheumatoid
arthritis, occurs when the body's immune system attacks the linings of
joints.

It is estimated that more than 70 percent of Americans
over the age of 65 show some signs of osteoarthritis, which is
characterized by the slow degeneration of the buffering layer of
cartilage within joints. It occurs most commonly in knees, hips, hands,
neck and lower back.

While one team of investigators will probe
how cartilage cells within joints change in response to mechanical
stresses and immunological factors, another group will use animal
models of the disease to better understand these factors in a living
system. Finally, a group of clinicians will enroll patients in a
clinical trial to investigate the role of obesity in the development of
osteoarthritis and the effectiveness of weight loss in treating it.

"Despite
the extensive impact and consequences of osteoarthritis, very little is
known about its root causes," said Farshid Guilak, Ph.D., director of
orthopedic research at Duke. "We believe that osteoarthritis is not so
much a single entity, but rather a family of disorders involving
genetic and environmental factors. With the average American living
longer and weighing more, osteoarthritis will only become a more
important medical issue."

Guilak leads of group of colleagues
from Duke and the Durham VA Medical Center who recently received a
five-year, $7 million grant from the National Institute of Arthritis
and Musculoskeletal and Skin Disease (NIAMS) to carry out a broad range
of laboratory experiments, as well as a clinical study.

"The
focus of our efforts will be to reveal the novel mechanisms that govern
the interplay between cartilage and joint function, inflammation and
cartilage destruction" Guilak continued. "If we can identify the
mechanisms involved in the onset and progression of osteoarthritis, we
can hopefully develop effective therapies."

Guilak will employ a
unique laboratory system that can test the effects of isolated pieces
of cartilage when placed under pressure in the presence of different
biochemical and immune factors.

The researchers' hypothesis is
that the mechanical stresses of everyday life or normal exercise are
important for the health of cartilage, which is living tissue that is
continually breaking down old molecules in the matrix and rebuilding
new ones. However, when cartilage becomes damaged -- whether due to
immune system responses or obesity -- cartilage cannot repair itself,
leading to the slow process of degeneration.

"We have shown that
mechanical stresses on matrix of cartilage cells in the knee -- such as
what would be expected in normal exercise -- can be beneficial to the
rebuilding process," Guilak said. "However, even slight imbalances can
negatively affect this process. Our studies have shown that
inflammation can cause cartilage in the knee to lose its ability to
build new matrix."

The clinical portion of the study will enroll
280 overweight osteoarthritis patients to determine whether a newly
developed lifestyle behavioral weight management approach, coupled with
pain coping skills, can reduce the pain, physical disability and
psychological distress experienced by these patients. The team will
focus on what occurs in the knee joint.

The researchers are
operating under a relatively new view that obesity is a low-grade
systemic inflammatory disease, since the obese tend to have elevated
levels of numerous markers of inflammation.

"Ten years ago, we
didn't think the immune system was involved in osteoarthritis," said
pain specialist Francis Keefe, Ph.D., co-principal investigator on the
grant. "However, if you look at obesity as if it was a chronic
low-grade fever, that may explain why it is such a major risk factor
for osteoarthritis. By altering the weight of these patients, we may be
able to influence the immune system."

The researchers plan to
study biomarkers of cartilage turnover, pain and inflammation in
samples taken from the blood and the fluid that bathes the joint. They
will also perform gait analyses to see if weight reduction can improve
the mechanics of walking. When cartilage begins to break down, it can
alter one's gait, which then places new and abnormal stresses on other
parts of the joint, which creates a vicious cycle of joint
degeneration, Keefe explained.

"Studies have shown that radical
diets do not work well in keeping the weight off over the long term,"
Keefe said. "Our approach is to address the whole patient and their
lifestyle -- instead of dramatic weight loss, we're looking for a more
modest yet sustained loss."

The team will also be investigating
the role of genetics in osteoarthritis. Lori Setton, Ph.D., Duke
biomedical engineer and grant co-principal investigator, will work with
a mouse model that expresses a mutation in type XI collagen, an
important component of cartilage.

"Our working hypothesis is that
compromised joint cartilage that is low in collagen type XI, is
mechanically weaker, making it more susceptible to the normal wear and
tear of everyday life," Setton said. "So a mutation in the gene that
produces this collagen type could predispose people to the development
of osteoarthritis during functional activity. Mutations of this gene
have also been associated with significant joint inflammation and the
production of proteases that degrade the cartilage matrix."

Setton's
group will use a mouse model developed at Harvard Medical School by
Bjorn Olsen, M.D., and Yefu Li, M.D.. The mice, while otherwise normal,
develop severe cartilage erosion and joint inflammation.

The
researchers will measure the changes that occur within the cartilage
matrix from onset through progression of the disease, with the goal of
understanding the natural course of the disorder. A key component of
the research will be to measure specific "biomarkers," or biochemical
changes in the joint and body fluids that are indicative of
inflammation and joint disease.

These biomarkers will be measured
in blood samples from all three projects in core facility directed by
Duke rheumatologist Virginia Kraus, M.D., who specializes in biomarkers
of joint disease. Simultaneous measures of these biochemical changes
from the bench to the bedside will help identify common warning signals
that are predictive of joint disease, the researchers said.

"After
five years, we hope to have a better understanding of the mechanism of
osteoarthritis, with the ultimate goal of identifying a preventative
treatment that could protect the cartilage matrix during normal
everyday life," Setton said.