By David N. Leff

People don't die of arthritis per se, but the chronic bone and joint disease is a killer of lifestyles and health-care budgets. In 1997, osteoarthritis ranked second only to chronic heart disease among adults receiving Social Security disability payments.

In 1995, according to NIH estimates, 15 percent of all Americans - 40 million - suffered some form of arthritis, and by 2020 those numbers will jump to 18.2 percent - 59.4 million individuals. Billions of dollars spent on over-the-counter pain relievers do just that - nothing more. They allay the hard-to-bear agony of arthritic joints, back, limbs and spine but offer no definitive cure. The only remedy that comes close is surgically replacing hip and knee joints with artificial prostheses. In 1997, hip and knee replacements performed in the U.S. numbered 144,000 and 259,000, respectively.

"Genetic factors," observed developmental geneticist David Kingsley at Stanford University, "are believed to account for half to two-thirds of human arthritis cases, including the three most common types - osteoarthritis, rheumatoid arthritis and ankylosing spondylitis."

It's much the same story in mice, of a strain carrying a certain mutant gene.

The earliest known member of that arthritic rodent tribe came to the attention, 25 years ago, of a caretaker at the Jackson Laboratory in Bar Harbor, Maine - among the world's foremost breeders of animal models for research.

"She noticed animals that were walking with a stiff gait," Kingsley recalled. "And when they examined their feet, they found out that their unusual gait had come about because the joints in the ankles and limbs of the animals had stiffened up and lost mobility. That begins to happen," he went on, "in mouse adolescence - about 4 weeks of age. They start to lose their ability to curl their fingers, and that defect in those digital joints then spreads and eventually affects almost all the joints in the body - the rest of the limbs and the vertebral columns - and eventually a very severe form of arthritis leading to almost complete immobility. By 6 months of age they are dead."

Key Clue: Critter Couldn't Curl Its Fingers

"When the Jackson Lab workers found this unusual rodent," Kingsley continued, "they began examining other mice from the same parents, and found that a new mutation had occurred, which was being inherited as a simple mendelian genetic trait that was responsible for this joint disease."

Kingsley, a Howard Hughes Medical Institute investigator, has now, a quarter-century later, discovered the mutant gene responsible for that mouse trait. This feat involved testing 4,138 animals to identify the chromosome region that contains the gene. Today's issue of Science, dated July 14, 2000, carries his report, titled: "Role of the mouse ank gene in control of tissue calcification and arthritis."

"The trait is an animal model for mineral deposition disease in arthritis," Kingsley told BioWorld Today." And finding the gene has identified a biological mechanism that the body normally uses to control where mineral deposits form. We think that mechanism helps explain the development of arthritis in these animals. It's not a perfect mimic of any particular form of the human disease," he pointed out, "but we thought it an interesting gene 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. There's almost 98 percent homology between humans and mice."

Using their new-found murine ank gene as a genomic guide, the co-authors went on to find the human version of the ANK protein that ank expresses on the short arm of human chromosome 5.

"The long name of the mouse gene," Kingsley noted, "is progressive ankylosis. That's the locus name and its three-letter designation is ank. Ankylosis means the formation of bony bridges across joints - in humans, for example, across vertebrae in the spine. When we identified the mouse gene," he went on, "we were very interested in whether or not it was conserved in other organisms. We found that ank is very highly conserved in vertebrate animals with cartilage and bones.

"We don't find ank in invertebrates," Kingsley observed, "maybe because the gene plays a particularly important role in skeletal biology. As the Science paper suggests," he continued, "the normal function of the ANK protein may be to control the levels of pyrophosphate inside and outside of cells, including chondrocytes. Pyrophosphate has been known for years to act as a potent inhibitor of mineral deposition, and we think that the expression of this ANK protein on cell surfaces allows cartilage to elaborate a natural inhibitor of mineral deposits."

Pyrophosphate Banishes Calcium Encrustation

"If you had a mutation in the ank gene," Kingsley explained, "pyroposphate levels outside the cartilage would fall, and relieve that normal mineralization inhibition. So now ectopic mineral deposits begin to form where they shouldn't. Pyrophosphate," he pointed out," is the active ingredient that works in tartar-control toothpaste by preventing mineralization at the gum line." Such calcium encrustations also gum up the inner walls of boilers, and similar scale builds up inside pots and kettles that allow water to boil away.

"Previous genetic studies in humans," Kingsley observed, "have identified three families with inherited chondrocalcinosis - deposition of calcium in cartilage - and arthritic joint disease. These linkage studies have shown that chondrocalcinosis maps to a region in human chromosome 5, which we now know contains the human ank. However, we have not yet shown that the human version of this gene is responsible for those traits in the three different families previously mapped to this same area. That's an important area for future research, an area that we're actively pursuing. So I don't think that in the short term this is going to lead to a dramatic new cure for arthritis.

"I do think," Kingsley added, "that this gene is an interesting candidate as a drug target. You'd have to increase its activity, not decrease it. And the other long-term potential," he concluded, "would be to try to target the biological process that we think the gene acts in. Particularly to manipulate the levels of mineralization inhibitors - pyrophosphate or its analogues."

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