New Study to Improve Understanding of Osteoarthritis

DURHAM, N.C. -- Using a three-pronged approach, basic scientists and clinicians at Duke University 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," said Setton,associate professor of biomedical engineering. "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 at the Pratt School of Engineering 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.