The most common form of arthritis, usually attributed to "wear and tear" of aging joints, is caused by a genetic defect in some cases, researchers announced yesterday.
Osteoarthritis, which affects an estimated 16 million Americans, has never before been linked to an inherited defect. The scientists said that the newly recognized mutation may account for only a minority of cases of the disease. But they added that the discovery suggests that other mutations, as yet unrecognized, may underlie other cases. Most cases of osteoarthritis, researchers say, may result from a combination of some genetic vulnerability and environmental factors.
"A single genetic flaw can cause at least one form of osteoarthritis, and perhaps can cause others," said Lawrence E. Shulman, director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, (NIAMS), which paid for the research.
The researchers said that knowing the mutation will make it possible to insert the defective gene into mice, creating an animal model to test new treatments for osteoarthritis. It may also make possible the development of tests to identify people who carry the mutation and who are likely to develop the disorder.
Researchers said it was unlikely that so-called gene therapy could correct genetic mutations in people with osteoarthritis. However, since carriers of the mutation inherit two copies of the collagen gene -- one normal and one faulty -- the researchers said it may be possible to find drugs that would favor production of the protein made by the normal gene, rather than the defective one.
The mutation underlying osteoarthritis creates an error in the genetic information used by cells to manufacture so-called type II collagen, the tough protein that provides most of the strength and resilience in the cartilage, or gristle, that covers bones at joints. At a certain point when manufacturing the chain-like protein, the cell adds the wrong molecular "link" to the chain, inserting an amino acid called cysteine instead of one called arginine.
"We know the gene, we know the protein the gene makes, and we know exactly what is wrong with the gene," said Darwin J. Prockop, chairman of the biochemistry department at Jefferson Medical College and a co-leader of the research team. The finding was reported in the September issue of the journal Proceedings of the National Academy of Sciences, which was mailed to subscribers yesterday.
Osteoarthritis occurs when the cartilage lining and cushioning the joints becomes damaged. Although it can result from joint deformities, injuries or infection, most cases develop for unknown reasons. Obesity and stress on joints, caused by certain occupations or sports, are risk factors. Most people with the disorder do not develop symptoms until they are in their fifties.
To identify the mutation, the research team tested 19 people from three generations of an Ohio family, many of whose members developed severe osteoarthritis beginning in their teens and twenties. Researchers established that nine family members with the disorder carried an identical defect in one copy of the gene for collagen II. They also carried a normal copy of the gene.
Ten other family members who did not have arthritis each carried two normal copies of the gene. The researchers tested 57 other healthy people outside the Ohio family and found no one who carried the mutation.
Prockop said nine other osteoarthritis-prone families are now being tested by his team and by Finnish researchers. Two families appear to carry the mutation, and seven others apparently do not. This means the genetic defect cannot be the sole cause of osteoarthritis but does not rule out the possibility that different mutations are producing similar effects.
Prockop said scientists do not yet know what percentage of osteoarthritis is caused by the known mutation, or by other possible inherited defects. "We don't know . . . if we are going to find different defects in the same gene or in different genes," he said.
Roland W. Moskowitz, a professor of medicine at Case Western Reserve University and a coauthor of the study, said about one-fourth of collagen II in the arthritic joints of the Ohio patients was the abnormal form. He suggested that the abnormal protein may be unusually vulnerable to damage or to chemical breakdown, or that it may interact with other components of the joint cartilage, making it weaker and more easily injured.