NEW YORK (Reuters Health) - Polymorphisms in the frizzle-related protein 3 gene (FRZB) confer susceptibility to hip osteoarthritis in females, according to a report in the June 21st issue PNAS early edition.
“Identifying the basic causes of any disease always sheds light on that disease,” lead author Dr. John Loughlin from University of Oxford, UK told Reuters Health. “We have identified common variants that are associated with osteoarthritis in females.”
Dr. Loughlin and colleagues used microsatellite targeting of eight candidate genes in a region on chromosome 2 previously linked to hip osteoarthritis to identify functional genetic variants associated with hip osteoarthritis in 378 families.
One polymorphism in FRZB was significantly associated with hip osteoarthritis, but only in female probands, the authors report. Although there was no gene-dose effect, the presence of the G allele at this locus was 50% more common among women with hip osteoarthritis than among women without hip osteoarthritis.
The polymorphism was within the region of FRZB that encodes frizzle-related protein 3 (sFRP3), the report indicates. Presence of the polymorphism was associated with diminished activity of sFRP3 in its normal role as an antagonist of wingless (wnt) signaling.
“The canonical wnt pathway is critical in skeletal and joint patterning in embryogenesis and recently has been implicated as a determining factor of mature adult bone mass,” the investigators explain.
“We believe the associated variants cause the protein encoded by FRZB (sFRP3) to lose some of its activity,” Dr. Loughlin said. “It may therefore be possible to return this activity to the cells or down-regulate the activity of molecules that have an effect opposite to FRZB.”
“Since FRZB/sFRP3 is involved in signal transduction,” Dr. Loughlin added, “we assume that the genes indirectly regulated by the activity of this protein may vary between those individuals with copies of the associated alleles and those without. We are planning on investigating a number of these ‘target’ genes.”
“Our finding is the first to implicate the wnt signaling pathway in osteoarthritis,” principal author Dr. Maripat Corr from University of California at San Diego, La Jolla told Reuters Health. “We need to investigate the anatomic ramifications of modest perturbations in this pathway.”
Proc Natl Acad Sci USA Early Edition 21 June 2004;doi:10.1073/pnas.0403456101.
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