BioWorld International Correspondent

LONDON - The discovery of a variant gene that is more common in women with osteoarthritis of the hip is forcing researchers to reconsider their ideas about how the disease is caused. The latest insight could lead to novel ways of preventing or delaying the onset of osteoarthritis, including new drugs.

Researchers in Oxford, UK, and La Jolla, Calif., found that women with osteoarthritis of the hip are more likely to have a polymorphism in a gene called FRZB, which plays a role in cell signaling.

John Loughlin, musculoskeletal sciences professor at the Botnar Research Centre at the University of Oxford, told BioWorld International: "For people working on osteoarthritis, this finding represents almost a paradigm shift, because in the past researchers have thought that the disease was due to a fault in the structural integrity of the joint cartilage - that perhaps there was some inadequacy in the way it was manufactured. But it now seems that there is some active process going on, some abnormal behavior by cells, that accounts for the destruction of cartilage in osteoarthritis."

Loughlin and colleagues, together with collaborators at the University of California at San Diego, report their findings in the June 21, 2004, issue of the Proceedings of the National Academy of Sciences in a paper titled "Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females."

The teams have been collaborating for several years to pinpoint variants of genes that predispose people to osteoarthritis. In 2000, they carried out a genome-wide linkage analysis to determine genes inherited by people with osteoarthritis. That allowed them to identify several regions of the human genome that were of interest - but each contained several hundred genes.

They report their analysis of one of those regions, found on chromosome 2q, in the current PNAS paper. When they came to the FRZB gene, which encodes the secreted frizzled-related protein 3, they stumbled across something unusual. Although most people had the same wild-type gene, others had inherited one of two possible polymorphisms that had the effect of altering the amino acid sequence of the protein.

"This is quite interesting," Loughlin said, "because both variants lead to substitution of very important, highly conserved arginine residues with other amino acids that have completely different functions."

They subsequently observed that women with osteoarthritis of the hip were more likely to have inherited one of the two variant FRZB genes than female controls.

Their next experiments involved transfecting the variant FRZB genes into cells in culture, to find out if the function of those genes was different to that of wild-type FRZB.

In normal cells, FRZB binds to a molecule called wnt, preventing it from binding to its cell-surface receptor. Such binding sends signals into the cell, which results in the transcription of new genes and the manufacture of new proteins.

"We found that the variant FRZB was no longer able to interfere with wnt binding to its receptor," Loughlin said. "Although these experiments were not done in cartilage cells, what this means is that in people with variant FRZB, these cells are going to be responding completely differently compared with those in whom FRZB is working normally."

The team now is planning to study the metabolism of chondrocytes from people with variant FRZB in more detail. Loughlin said: "We want to see what genes are turned on. We will be investigating whether there is increased production of metalloproteinases, for example, when wnt signaling is switched on. These are small enzymes that can degrade cartilage."

Another line of inquiry will be to find out whether cartilage responds differently to load in people with variant FRZB.

"Our hypothesis is that cartilage cells may not be communicating with each other in the correct way, or may not be communicating with their environment correctly, with the result that cartilage breaks down," Loughlin said. "It may be possible one day to develop drugs to target the signaling molecules and make the cells communicate with each other in the correct way. Ultimately, it may be possible to screen people for development of osteoarthritis, and perhaps recommend that they do a particular exercise regimen or take drugs to slow the progress of the disease, if we can develop these."

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