Sclerostin and bone : the role of the SOST gene in osteoporosis and fragility fractures in Malta

Abstract

INTRODUCTION: Sclerostin is an important regulator of the bone remodelling cycle acting as an inhibitor of the canonical Wnt signalling pathway, resulting in reduced bone mass. The aim of the study was to identify known or novel SOST variants associated with osteoporosis and fracture susceptibility in the Malta Osteoporotic Fracture Study (MOFS).

MATERIALS AND METHODS: Sanger sequencing of the SOST exons and their intronic flanking regions, together with the promoter and 3’untraslated region (UTR) was performed in 200 individuals having normal and low bone mineral density (BMD).

RESULTS: A total of 10 known and 3 novel variants were identified including: rs851055, rs140960915, rs117857467, rs59613373, rs17882143, rs768384322, rs199560099, rs17883310, rs17881550, rs17886183, c.220+134(T>C), c*331(A>G) and c*390(C>A). Preliminary logistic regression with regards to the rs851055 promoter variant (G>A), indicate that homozygosity for the A allele was associated with a protective effect on BMD at the lumbar spine, LS (Age adjusted Odds ratio: 0.1 [95% confidence interval 0.03-0.8]) and total hip, TH (OR: 0.3 [0.1-1.0]). The rs17881550 3’ UTR insertion (-/G) also showed a protective effect on LS BMD (OR 0.1 [0.03-0.7]), TH (OR 0.2 [0.04-0.9]), and also with fracture risk (OR 0.2 [0.05-0.9]) in women with the homozygous mutant genotype compared to women with the homozygous wild-type genotype.

CONCLUSION: Observations suggest that the rs851055 and rs17881550 variants might be affecting transcriptional activation or epigenetic mechanisms resulting in altered Sclerostin function. All variants will be replicated in the entire MOFS collection to determine association with BMD and fracture susceptibility at different anatomical sites.