Genes involved in cell signaling implicated in OA

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Genes involved in cell signaling implicated in OA

June 14, 2004 Nainggolan

Rheumawire

Berlin, Germany - British scientists at the EULAR 2004 meeting reported

a new twist in the genetics of osteoarthritis (OA) last week.

Dr Loughlin (Oxford University, UK) said that although it was known

that genetic variations account for up to 50% of OA, it was previously

assumed that the defective genes responsible were linked to the

structure of the joints [1].

But the new work by his team implicates genes expressed by adult

articular chondrocytes that are involved in cell signalinga finding that

may have important implications, as it may be easier to intervene at

this level than if the genetic risk were in the genes that code for the

structure, he said.

In addition, the researchers found that " the genes predisposing to knee,

hip, and hand osteoarthritis are different, " Loughlin told a press

conference in Berlin. " There does not appear to be any overlap between

these skeletal sites; they seem to be genuinely distinct, " he noted,

adding that " epidemiologists have suspected this since the 1990s, but

this very new data confirm it. "

Loughlin and his team looked for susceptibility genes for OA after

identifying several genomic regions harboring such loci in a previous

genomewide linkage scan among women, who are known to be more prone to

OA.

" We looked at whether the siblings of women who have the disease have

inherited certain alleles to try to narrow down the process, " he

explained, " but it was still a long and arduous process. "

Candidate genes were targeted based on their expression in joint tissue

or on a known role in skeletal development or homeostasis. The genes

were then subject to genetic association and functional analyses.

" We uncovered that the genes involved are the ones that affect the way

the chondrocytes talk to each other, " he noted.

His team identified 3 genessecreted frizzled-related protein 3 gene

(sFRP3) on chromosome 2; bone morphogenetic protein gene (BMP5) on

chromosome 6; and the interleukin 4 receptor gene (IL4R) on chromosome

16all of which code for proteins involved in cell signaling and are

expressed by adult articular chondrocytes.

" It seems more likely, therefore, that aberrant effects on cell

signaling and cartilage homeostasis are the areas in which OA genetic

susceptibility is acting, " said Loughlin.

" If you inherit 1 or more copies of these genes you have up to a

fourfold increased risk of OA, " he explained.

There may be hope on the horizon, however, he said. " The proteins

produced by these genes have a relatively short half-life, so perhaps

this is a point at which we could intervene and somehow make the protein

normal, " he suggested.

But he admitted that any potential therapy was years away and that

currently there is very little advice that could be given to anyone

found to have these genes, other than the obvious, such as keeping

weight down. Also, there is currently no commercial test to look for

these 3 genes, he noted.

Loughlin et al also found a significant association with another

genetype IX collagen gene (COL9A1) on chromosome 6but this codes for a

structural protein rather than being involved in cell signaling, he told

rheumawire.

Sources

Loughlin J, Ferreira A, Southam et al. Osteoarthritis

genetic susceptibility--cell-signaling genes are major culprits.

Presented at: EULAR 2004; Berlin, Germany; June 9-12, 2004. Abstract

OP0123.

Riyazi N, Huizinga TWJ, De Craen AR, et al.

Identification of three new genetically determined risk factors for

osteoarthritis (OA): High levels of interleukin (IL)-1 ² and IL-receptor

antagonist (IL-1Ra) and low IL-10 production. Presented at: EULAR 2004;

Berlin, Germany; June 9-12, 2004. Abstracts OP0139 and THU0056.

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Mayo Clinic in Rochester

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s Hopkins Medicine

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