Arthritis: A Gene for Smooth-Running Joints
Michael Hagmann, Science Reporter

A new study suggests that a genetic defect in mice causes the joint's cartilage cells to pump insufficient amounts of pyrophosphate-- a natural water softener -- into the joint cleft, and this in turn leads to the formation of bony spurs that eventually stiffen the joints completely. Because humans have an almost identical gene, and disorders such as osteoarthritis also feature an abnormal outgrowth of bones, some arthritis researchers are hopeful that these new findings may point the way toward a new class of pyrophosphate-based drugs similar to the anti-scaling chemicals in washing powders and toothpaste. But, as many of the researchers point out, the numerous roads that lead to human joint degradation make a single cure-all unlikely.

Andrew M. Ho [1*], Michelle D. Johnson [1*], and David M. Kingsley [1, 2], "Role of the Mouse ank Gene in Control of Tissue Calcification and Arthritis," Science, Vol. 289, No. 5477, pp. 265-270 (July 14, 2000).
1. Department of Developmental Biology and
2. Howard Hughes Medical Institute, Beckman Center B300, Stanford University School of Medicine, Stanford, CA 94305-5327, USA.
* These authors contributed equally to this work.
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Mutation at the mouse progressive ANKylosis (ANK) locus causes a generalized, progressive form of arthritis accompanied by mineral deposition, formation of bony outgrowths, and joint destruction. Here, we show that the ank locus encodes a multipass transmembrane protein (ANK) that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells. A highly conserved gene is present in humans and other vertebrates. These results identify ANK-mediated control of pyrophosphate levels as a possible mechanism regulating tissue calcification and susceptibility to arthritis in higher animals.

Gene Linked to Arthritis Located

4:14 PM EDT; July 13, 2000; Washington, D.C. (AP) -- Researchers experimenting with mice have found a gene that may play a role in preventing arthritis-like disorders in joints. In a study to be published Friday in the journal Science, David Kingsley, a Howard Hughes Medical Institute researcher at Stanford University, reports that a gene called ank appears to help produce a fluid that keeps joints operating smoothly. When the gene is flawed, Kingsley and his co-authors said, there can be a buildup of mineral deposits that causes joints in mice to become inflamed. Eventually, the joints are destroyed.

The gene was located by studying a mouse species that naturally develops a severe progressive arthritis. Kingsley said the researchers found the gene makes a protein ANK that causes the movement into the joints of a fluid, called pyrophosphate, which prevents the buildup of calcium in the joints. Pyrophosphate is a chemical now used in some toothpastes to control tartar and the buildup of hard plaque on tooth surfaces. When the ank gene is mutated, such as in the tested mouse, minerals are deposited in many of the bony joints, causing them to stiffen and eventually to not move at all.

Kingsley said that the type of arthritis found in the mouse is very severe and not a perfect mimic of human arthritis, although some of the same processes are involved. "By studying a severe form of disease in an animal model, we hoped we might be able to identify basic molecular mechanisms that may apply to milder forms of disease as well," Kingsley said in a statement. Kingsley said the ank gene is present in humans and in most other vertebrates, but not in invertebrates, which are animals that lack boney skeletons. "This suggests that the gene may control some process specific to vertebrates, like the function or maintenance of cartilage and bone," he said. Arthritis is a group of diseases that affect about half of people 65 and older, accounting for about $100 billion annually in medical costs in the U.S.
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