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DURHAM, N.C. - Duke University Medical Center and Durham VA Medical
Center researchers have shown that while the mechanical stresses of
normal exercise are important for the health of the meniscus – a layer
of buffering tissue in the knee joint – these stresses coupled with a
potent immune system response can lead to the ultimate degeneration of
the knee joint as seen in osteoarthritis.

Furthermore, the
researchers report, the chemical nitric oxide is a critical "signal" in
controlling how the immune system responds to the stress. This insight
could lead to new therapies for osteoarthritis that would target this
interaction between nitric oxide and the inflammatory response, the
researchers added.

The primary function of the meniscus -- which
is located within the knee joint between the thigh bone (femur) and the
lower leg bone (tibia) -- is to act as a shock absorber and a
distributor of weight within the joint. It is a type of cartilage made
up of a matrix of fibers, primarily collagen, which provide toughness
and durability.

"Contrary to common perception, the meniscus is a
living tissue that is slowly and continually breaking down old collagen
and building new collagen," said Farshid Guilak, Ph.D., director of
orthopedic research at Duke. The findings of the Duke and VA team were
published today (July 1, 2003) in the Journal of Applied Physiology.

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

In their experiments, researchers took samples of
meniscus tissue from pigs, and in a controlled fashion subjected the
samples to various pressures under different conditions. In the first
experiment, they compared the samples that reacted to mechanical stress
with those that did not.

The samples that underwent compression
showed a significant increase in the production of key building blocks
of the meniscus. Specifically, protein synthesis increased 68 percent,
while proteoglycan, the substance that gives the meniscus its ability
to absorb shocks, increased by 58 percent.

It has been postulated
that interleukin-1 (IL-1), one of a family of pro-inflammatory proteins
secreted by potent immune system cells, plays a role in the destruction
of cartilage as seen in osteoarthritis. So the Duke researchers then
performed the compression experiments in the presence of IL-1.

"We
found that the stimulatory effect of the mechanical stress was
prevented by the presence of IL-1," Guilak said. "This finding suggests
that an inflammatory environment may alter the physiological response
of the meniscus to mechanical stress."

Interestingly, however,
the researchers also found that if they inhibited the synthesis of
nitric oxide, the beneficial effects of mechanical stress returned,
even in the presence of IL-1. Nitric oxide is a free-radical which in
elevated amounts can be toxic to tissues. In normal concentrations, it
helps in resistance to infections and in blood vessel dilation.

Furthermore,
when the researchers inhibited nitric oxide, they found a significant
reduction in the breakdown of the meniscus caused by inflammation.

"Although
the mechanisms of the interaction between IL-1 and nitric oxide are not
well understood, it would appear that the negative impact on of IL-1 on
the rebuilding of the meniscus is mediated by nitric oxide," Guilak
said. "It appears clear that both inflammation and mechanical stress
are important factors in matrix turnover in the meniscus.

"No one
has really looked this closely at the meniscus because it was thought
that it was not important to the joint," Guilak continued. "Not long
ago, if the meniscus was damaged, surgeons just removed it. However,
within five to 10 years, patients would develop osteoarthritis. Now,
surgeons are doing whatever they can to preserve the meniscus."

The
Duke researchers are starting a new research effort aimed at better
understanding the role of obesity and exercise in osteoarthritis. While
the benefits of exercise seem apparent, researchers are beginning to
see obesity as a low-grade systemic inflammatory disease, since the
obese tend to have elevated levels of numerous markers of inflammation.
This, Guilak said, offers the potential for developing ways to prevent
or forestall the joint destruction seen in osteoarthritis, which
afflicts an estimated 20 million Americans.

The research was
supported by the Department of Veterans Affairs; the National
Institutes of Health; the North Carolina Biotechnology Center, Research
Triangle Park, N.C.; and Flexcell International.

Other members of
the Duke and VA research team were Sang-jin Shin, Ph.D., Beverley
Fermor, Ph.D., J. Brice Weinberg, M.D., and David Pisetsky, M.D., Ph.D.