Engineered rats reveal arthritic surprise.

Engineered rats reveal arthritic surprise

Texas researchers report developing the first animal model for a group of debilitating arthritic diseases that afflict an estimated 200,000 people in the United States. Their work with the genetically engineered rats adds to the growing evidence that a specific human gene may trigger an autoimmune response that causes these painful and poorly understood disorders, collectively known as the spondyloarthropathies.

"This is a remarkable scientific advance," says Lawrence E. Shulman, director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Md.

Biologist Peter Parham at Stanford University calls the report a "landmark" that may help scientists uncover the mechanism causing these inflammatory diseases -- which include, among others, ankylosing spondylitis (fusion of spinal bones), an arthritis associated with the skin disorder psoriasis, and an arthritis accompanied by bowel inflammation. An understanding of how such conditions develop in humans might someday lead to more effective therapies, and perhaps even to preventive treatment.

In 1973, U.S. and British scientists separately reported that 90 percent of people with ankylosing spondylitis carry a gene called HLA-B27, which affects immune system regulation. Soon after, other researchers found that people with other spondyloarthropathies are more likely than the general population to carry HLA-B27. However, many scientists viewed the gene as a red flag marking people at risk, rather than an active player in the development of disease.

Now, Robert E. Hammer and Joel D. Taurog at the University of Texas Southwestern Medical Center in Dallas say their findings suggest that HLA-B27 contributes directly to these disorders.

Hammer and Taurog created several lines of "transgenic" rats by injecting a batch of fertilized rat eggs with HLA-B27 and a second gene that joins forces with B27 to code for a specific protein product. After two to six months, they noted that some of the rats developed the same symptoms seen in the human spondyloarthropathies, including persistent diarrhea, joint inflammation and changes in the skin and nails. Control rats without the human genes remained healthy, the team reports in the Nov. 30 CELL.

The results surprised the investigators, who had spent years trying to develop such an animal model.

"It's as if the things that one sees in a spectrum of patients are compressed and are more dramatic in the rats," Taurog told SCIENCE NEWS. Shulman calls the thickening and scaling of rat skin and nails a particularly striking symptom that closely resembles problems afflicting people with psoriatic arthritis.

The spontaneous development of the disorder as the rats matured hinted that the HLA-B27 gene or its protein product contributes directly to the disease process, perhaps by triggering an abnormal immune response, Parham says. He and others believe the spondyloarthropathies arise when infection-fighting white cells mistakenly attack joints and other tissues.

Taurog speculates that people who inherit HLA-B27 may run an increased risk of developing these diseases after exposure to an environmental trigger, such as a common bacterium. For example, normal intestinal bacteria may have sparked the symptoms seen in the HLA-B27 rats, he says.

He adds, however, that the team has yet to prove HLA-B27's guilt. Jack Strominger of Harvard University agrees. "There's no evidence in the paper that HLA-B27 specifically caused the rat symptoms, which could erupt with the insertion of another HLA gene," he says.

Taurog says further research must erase such doubts before scientists can proceed with the urgent work of preventing these potentially crippling disorders.