Age-Related Bone Loss: A Role for Functional Genetic Variants Affecting a Critical Bone Signalling Pathway?

Bone remodelling maintains bone structure and function through resorption of old bone by osteoclasts and replacement with new bone by osteoblasts. Aging is associated with progressive bone loss, especially in post-menopausal women, largely due to excessive osteoclast activity. Formation and activation of osteoclasts is critically regulated by the signalling pathway downstream from Receptor Activator of Nuclear Factor kB (RANK) [1]. Genome-wide association studies have implicated genetic variation in multiple components of the RANK signalling pathway in regulation of bone mineral density (BMD) in cross-sectional studies [2]; however, no data is yet available on the effect of these variants on age-related bone loss, and functional variants have not been identified.

In this study, 25 genes encoding key components of the RANK signalling pathway will be screened in 50 women with high BMD and 50 with low BMD to identify novel common functional polymorphisms. Polymorphisms of interest will be genotyped in two well-characterised cohorts of post-menopausal women and examined for association with BMD and rate of bone loss. Functional consequences of variants on activation of the RANK signalling pathway and on osteoclast formation, function and survival will then be assessed using model cell systems and assays in routine use within our laboratories.