A Gene for Smooth-Running Joints

Foot fault. Mineral deposits and bone formation around toe joints of mouse with mutation in the ank gene (mutant foot shown on right, normal skeleton on left).

At first glance, water softeners have little in common with the crippling joint erosion of arthritis sufferers. But researchers have found a mutation in a mouse gene that leads to an arthritis-like condition because it causes the joint's cartilage cells to pump insufficient amounts of pyrophosphate--a natural water softener--into the joint cleft. Some researchers are hopeful that the finding may point the way to a new class of pyrophosphate-based drugs, but others are skeptical.

A team led by Stanford developmental geneticist David Kingsley has been trying to unravel how a strain of mice called ank develop progressive ankylosis, or fusion of the bones, which completely immobilizes, and eventually kills, the animals by about 6 months of age. Other researchers had linked the ank mutation to mouse chromosome 15; in this week's Science, Kingsley's team reports that it's a single typo in a previously unknown gene, which they called ank, that led to a protein about 10% shorter than the normal version. The gene is highly conserved among vertebrates--the human counterpart is about 98% identical--but strikingly absent in invertebrates, which lack skeletons and, hence, bones, joints, and arthritis. Further strengthening the case, in mouse embryos the ank gene is most active in developing cartilage.

Kingsley's team had no idea what the normal gene does, but a team at the University of Tokyo had recently identified the genetic defect behind a similar mouse disease--and determined that its protein product normally generates pyrophosphate on the outside of joint cells to keep the joints scale-free. When the Stanford team measured pyrophosphate levels in cultured cells derived from ank and normal mice, they found that the chemical accumulated in cells from the ank mice but decreased in the culture medium. Kingsley speculates that in its normal form, the ank protein is a pyrophosphate channel that allows pyrophosphate levels to remain high in cartilage throughout life to prevent calcium phosphate crystal formation in the joint cleft.

Matthew Brown, a skeletal geneticist at the University of Oxford says the gene is "a really hot candidate for [human] chondrocalcinosis," a rare genetic form of joint stiffening that leads to crystal deposition and shows a similarly imbalanced pyrophosphate distribution in the joints. But the role of pyrophosphate in osteoarthritis, a much more common ailment, is unclear, says rheumatologist Michael Doherty of the City Hospital in Nottingham, United Kingdom. He points out that some osteoarthritis sufferers have too much instead of too little pyrophosphate in their knee fluid, suggesting a different disease mechanism. "I'd say the likelihood that this leads to some intervention [for osteoarthritis] in the near future is pretty low," he says.

Related sites
The Arthritis Foundation
Arthritis Research Campaign (ARC)

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