Role of Sclerostin in Cardiovascular Disease

Abstract

Sclerostin is most recognized for its role in controlling bone formation but is also expressed in the heart, aorta, coronary, and peripheral arteries. This review summarizes research on sclerostin’s role in cardiovascular disease. Rodent studies have found sclerostin to be expressed at sites of arterial calcification. In contrast, aortic sclerostin was reported to be downregulated in a mouse model of abdominal aortic aneurysm, and transgenic upregulation or administration of sclerostin was found to prevent abdominal aortic aneurysm and atherosclerosis formation. Sclerostin deficiency was reported to stimulate cardiac rupture in one rodent model. In humans, 7 of 11 studies reported a significant association between high serum sclerostin and high carotid intima media thickness. Ten of 15 studies reported a significant association between high serum sclerostin and severe arterial calcification. Twelve of 14 studies reported a significant association between high serum sclerostin and high arterial stiffness or atherosclerosis severity. Four of 9 studies reported a significant association between high serum sclerostin and high risk of cardiovascular events. A meta-analysis of randomized controlled trials suggested that administration of the sclerostin blocking antibody romosozumab did not significantly increase the risk of major adverse cardiovascular events (risk ratio, 1.14 [95% CI, 0.83–1.57]; P =0.54) or cardiovascular death (risk ratio, 0.92 [95% CI, 0.53–1.59]; P =0.71). Human genetic studies reported variants predisposing to low arterial sclerostin expression were associated with a high risk of cardiovascular events. Overall, past research suggests a cardiovascular protective role of sclerostin but findings have been inconsistent, possibly due to variations in study design, the unique populations and models studied, and the heterogeneous methods used.

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“…Therefore, sclerostin may protect against vascular inflammation, aortic aneurysm, and atherosclerosis in selected animal models. 40 – 42 Consequently, inhibition of sclerostin by romosozumab could theoretically lead to increased vascular calcification. 37 , 43 …”

“…The association between serum level of sclerostin and surrogate markers of cardiovascular dysfunction/cardiovascular outcomes has been investigated and has yielded inconsistent findings. 42 The conflicting results were related to variations in study design, differences between study populations and animal models, and heterogeneous methods used to investigate this association. 42 For example, in a cohort of patients with chronic kidney disease, aortic calcifications were noted in patients with higher sclerostin levels.…”

“… 42 The conflicting results were related to variations in study design, differences between study populations and animal models, and heterogeneous methods used to investigate this association. 42 For example, in a cohort of patients with chronic kidney disease, aortic calcifications were noted in patients with higher sclerostin levels. However, in multivariate analysis, the association was inversed.…”

“… 46 Studies investigating the association of serum sclerostin and aortic valve, coronary, or aortic calcification have yielded positive associations, negative associations, and no correlation. 42 Golledge and Thanigaimani reviewed 14 studies examining the association between serum sclerostin concentration and arterial stiffness or atherosclerosis severity. 12 studies reported positive associations, while one study reported a negative association, and one study reported no association.…”

“…12 studies reported positive associations, while one study reported a negative association, and one study reported no association. 42 …”