By Duke Medicine News and Communications

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.