Sclerostin and Vascular Pathophysiology

Abstract

There is cumulating evidence for a contribution of Wnt signaling pathways in multiple processes involved in atherosclerosis and vascular aging. Wnt signaling plays a role in endothelial dysfunction, in the proliferation and migration of vascular smooth muscle cells (VSMCs) and intimal thickening. Moreover, it interferes with inflammation processes, monocyte adhesion and migration, as well as with foam cell formation and vascular calcification progression. Sclerostin is a negative regulator of the canonical Wnt signaling pathway and, accordingly, the consequence of increased sclerostin availability can be disruption of the Wnt signalling cascade. Sclerostin is becoming a marker for clinical and subclinical vascular diseases and several lines of evidence illustrate its role in the pathophysiology of the vascular system. Sclerostin levels increase with aging and persist higher in some diseases (e.g., diabetes, chronic kidney disease) that are known to precipitate atherosclerosis and enhance cardiovascular risk. Current knowledge on the association between sclerostin and vascular diseases is summarized in this review.

Keywords: Wnt; aging; atherosclerosis; calcification; cardiovascular; chronic kidney disease; diabetes mellitus; sclerostin.

Figure 1

Canonical Wnt pathway. In the active state, Wnt ligands (Wnt) form a complex with the receptors low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) and Frizzled (Fz). Disheveled (Dsh) is then able to bind to Fz. Dsh forms a complex with glycogen synthase kinase 3ß (GSK3ß), GSK3 binding protein (GBP), axin and adenomatous polyposis coli (APC). This protects ß-catenin from proteasomal degradation. ß-catenin translocates into the nucleus and interacts with the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to promote gene transcription. In the inactive state, inhibitors of this system, such as Sclerostin (SCL), prevent the formation of the Wnt-Fz-LRP5/6 complex. ß-catenin is degraded by proteasomes after GSK3ß-mediated phosphorylation, so the signal is stopped.

Figure 2

Sclerostin in the vascular system. SCL is produced by osteocytes at bone level and may drive the paracrine effect. SCL also spills over the circulation and may contribute to vascular pathophysiology (e.g., atherosclerosis, arterial stiffness and vascular calcification). SCL is also up-regulated in calcifying vascular smooth muscle cells at the vascular level. SCL = sclerostin. Arrows indicate the spill over of sclerostin from the sites where it is produced into circulation and the related factors or diseases associated with higher sclerostin circulating levels.