The relationship between inhibitors of the Wnt signalling pathway (Dickkopf-1(DKK1) and sclerostin), bone mineral density, vascular calcification and arterial stiffness in post-menopausal women

Abstract

Epidemiological studies have shown an association between bone loss/osteoporosis and vascular calcification (VC). Recent studies have implicated the Wnt signalling pathway in the pathogenesis of VC. We investigated the association between circulating concentrations of Wnt inhibitors; DKK1 and sclerostin with bone mineral density (BMD), abdominal aortic calcification (AAC) and arterial stiffness in post-menopausal women. One hundred and forty six post-menopausal women aged (mean [SD]) 61.5[6.5] years were studied. Sclerostin and DKK1 were measured in serum. BMD was measured at the lumbar spine (LS), femoral neck (FN), total hip (TH). AAC was detected by Vertebral Fracture Assessment (VFA) imaging and quantified using an 8- and 24- point scoring methods. Arterial stiffness was determined by aortic pulse wave velocity (PWV). A significant positive correlation was observed between sclerostin and BMD at the FN (r=0.166, p=0.043) and TH (r=0.165, p=0.044). The association remained significant at the FN (p=0.045) and TH (p=0.026) following adjustment for confounders. No significant correlation was observed between DKK1 and BMD. In contrast, there was a significant negative correlation between log DKK1 and AAC (24-point score: r=−0.25, p=0.008 and 8-point score: r=−0.21, p=0.024). Subjects with AAC score of 1 or less had significantly higher DKK1 (p=0.01). The association between DKK1 and AAC remained significant following correction for age, blood pressure, cholesterol (24-point score: p=0.017, 8-point score: p=0.044). In adjusted linear regression analysis, sclerostin was positively associated with AAC (24-point score: p=0.048, 8-point score: p=0.031). Subjects with a PWV>9m/s had significantly higher sclerostin than those with PWV <9m/s: 23.8[12.3], vs 29.7 [14] pmol/l, p=0.03). No association was observed between DKK1 and PWV. The opposite association between AAC and the 2 Wnt signaling inhibitors is of interest and merits further investigations. Future longitudinal studies are needed to establish the precise role of sclerostin and DKK1 in the pathogenesis of VC.