Polymorphism in signal transduction is a major route through which osteoarthritis susceptibility is acting

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Abstract
In the last year there has been considerable success in the identification of genes harbouring susceptibility for primary osteoarthritis. This report brings the reader up-to-date by focusing on three of the more compelling finds. A UK group reported an association of the FRZB gene with hip osteoarthritis in females. FRZB codes for secreted frizzled-related protein 3, an antagonist of Wnt signalling. The Wnt signal transduction pathway is critical for normal development and is also active in adult tissues. Secreted frizzled-related protein 3 helps to maintain articular cartilage and the associated alleles at FRZB reduce the activity of this important protein. A Japanese group has reported an association of the asporin gene ASPN with knee and hip osteoarthritis and an association of the calmodulin 1 gene CALM1 with hip osteoarthritis. Asporin is a cartilage extracellular protein that regulates the activity of transforming growth factor-β. Calmodulin is an intracellular protein that interacts with a number of proteins involved in signal transduction. The associated alleles at ASPN and CALM1 reduce the ability of chondrocytes to express the genes encoding aggrecan and type II collagen. Since these are essential structural components of articular cartilage, the ASPN and CALM1 associations are predicted to adversely affect the maintenance of cartilage. The FRZB, ASPN and CALM1 results are compelling and highlight that polymorphism in signal transduction pathways is a major component of osteoarthritis susceptibility. This is an exciting observation since signal transduction pathways are malleable and therefore potentially amenable to intervention and modification.