Articular cartilage consists of cells called chondrocytes in an extracellular matrix made up of a fibrous network of collagen proteins and proteoglycans—proteins with chains of sugar molecules attached. "Collagens give cartilage strength, and the proteoglycans are able to hold water and give resistance to compressive forces," explains biologist Mary B. Goldring of Harvard Medical School.

"Somehow, biomechanical damage [caused by factors such as joint injury or overuse] stimulates the chondrocytes to start making enzymes that break down cartilage," Goldring says. As the cartilage surface gradually erodes under this attack, the underlying bones begin to grate against each other, causing chronic joint pain and swelling. Bony outgrowths often form at the edges of the joint and protrude into the joint space, exacerbating the disease.

Goldring is familiar with these and related phenomena from her own research. She uses a chondrocyte cell-culture system she developed to study how proteins produced in response to inflammation in osteoarthritic joints not only stimulate production of enzymes that break down cartilage but also impair the ability of chondrocytes to repair the damage.

The prevailing view is that the initial stages of osteoarthritis involve an imbalance between production and breakdown of collagen and proteoglycans, which normally turn over at a low level, says Roland W. Moskowitz, a rheumatologist at Case Western Reserve University and president of the Osteoarthritis Research Society International. "We're not sure what kicks off this imbalance," he says, but multiple risks—including aging as well as metabolic factors and various mechanical stresses—could all contribute to the acceleration of cartilage breakdown. Some people also have a genetic predisposition to osteoarthritis. "You may need one or several genes" that predispose to disease, Moskowitz says, "and then something else makes you more susceptible"—for instance, a job involving lots of kneeling, squatting or heavy lifting.

The effects of osteoarthritis range from mild to disabling. People with the disease may awaken with stiff, achy joints or have trouble walking, climbing stairs, getting up from a chair or even holding a pen. Although the best available therapies, which include medication and proper exercise, relieve some of the pain and improve function, they can't stop disease progression. If impairment becomes severe, joint replacement or other surgery is usually the only remaining option. Clearly, as the aging baby boomers now begin to swell the ranks of the roughly 21 million Americans affected by osteoarthritis, the need for new treatments is becoming more urgent.

—Elia T. Ben-Ari

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Reprinted from the HHMI Bulletin,
June 2003, pages 8-13.
©2003 Howard Hughes Medical Institute