July 11, 2000 - By Susan Ipaktchian
STANFORD – A substance commonly added to toothpaste to prevent tartar build-up on our teeth may be the same material our bodies use to prevent calcium and minerals accumulating in our joints and forming the deposits associated with arthritis.
Stanford scientists have found a mouse gene that transports this substance, pyrophosphate, into and out of cells. If the gene is defective, the animals have severe arthritis. The researchers also identified the human version of the gene and confirmed that it lies in a region of DNA previously implicated in human joint disease, suggesting that disruptions in this gene may underlie arthritis in many different animals.
'The ank gene may provide a natural form of tartar control for the joints of vertebrates,' said David Kingsley, PhD, a Stanford developmental biologist and Howard Hughes Medical Institute investigator. Kingsley is senior author of a paper describing the findings in the July 14 issue of Science.
Arthritis is one of the most common human health problems. Its underlying causes are not well understood but genetic factors are believed to account for half to two thirds of human arthritis cases, including the most common types such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, says Kingsley. The incidence of osteoarthritis, the most common joint disease of humans, increases with age and is most frequent in people greater than 60 years old.
Kingsley’s group uses genetics to study the development of bones and joints in vertebrates, or animals with backbones. 'Very little is known about how joints are formed and how they’re maintained after birth. And maintenance of joints, or lack of it, is a very common problem in humans,' said Kingsley.
The ank gene that the team found produces a protein that spans the membrane surrounding cells. This protein is believed to shuttle pyrophosphate – a strong inhibitor of calcification and bone mineralization – into and out of cells. Pyrophosphate’s ability to inhibit mineral deposition is the reason it is the active ingredient in many tartar control toothpaste formulations. Also, derivatives of pyrophosphate are sometimes used in water heaters to prevent scale formation in water pipes.
Cartilage in the joints is one of the few locations in the vertebrate skeleton that normally remains unmineralized. The ank gene is expressed in these regions and is believed to be essential for normal joint maintenance. Kingsley and his colleagues believe that if there is a defect in the ank gene, the shuttle transporter stops working and pyrophosphate accumulates inside cells. The concentration of pyrophosphate in the fluid that bathes the outside of cells drops, allowing mineral deposits to form. The resulting mineralization of cartilage, deposition of bone in and around joints and eventual joint destruction are classic symptoms of arthritis.
Mice carrying the defective ank gene have long been studied as a model of arthritis. These mice have decreased mobility of their ankle and toe joints, which progresses to most joints throughout the limbs and spinal column. Like arthritis in humans, the condition becomes more severe with increasing age. According to Kingsley, the type of arthritis from which the ank mice suffer is not exactly the same as any single form of human arthritis – it is much more severe and widespread than that typically seen in humans. But many of the mouse symptoms are similar to those found in human arthritic diseases, including cartilage erosion and bony outgrowths seen in osteoarthritis and fusion of the vertebrae seen in ankylosing spondylitis.
'It’s not a perfect mimic of any particular form of arthritis but we thought it an interesting mutation to study because what’s happening in the animals has lots of similarities to the pathological process that occurs in many forms of human arthritis,' Kingsley said.
His group is the first to pinpoint the ank gene, identify the protein encoded by it and construct a model explaining how the ank protein may be involved in arthritis. The researchers found the human version of the protein using the mouse ank protein as a guide. They are almost identical in the two species suggesting that the function of the ank gene may be same in all vertebrates.
Kingsley and his team are now trying to determine whether the defect in the ank gene found in these mice is exactly the same as that found in people who suffer from particular forms of inherited arthritis. They are also planning to study the gene in patients with other kinds of arthritis and painful joint disorders.
Co-lead authors of the study are Andrew Ho and Michelle Johnson, MD/PhD graduate student and research associate, respectively, in the department of developmental biology. Funding for the study was provided by the National Institutes of Health, the Medical Scientist Training Program at Stanford, Smithkline Beecham and the Howard Hughes Medical Institute.
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