Role of sclerostin in the pathogenesis of chronic kidney disease-mineral bone disorder

Abstract

Sclerostin is a 190-amino-acid glycoprotein that is mainly secreted by osteocytes, and it decreases bone formation by inhibiting the terminal differentiation of osteoblasts and promoting their apoptosis. Sclerostin blocks the Wnt signaling pathway in osteoblasts by binding to low-density lipoprotein receptor-related protein 5/6 (LRP-5/6) receptors. We reviewed the literature detailing the role of sclerostin in the pathogenesis of chronic kidney disease-bone mineral disorder (CKD-MBD). Increased serum sclerostin levels may be correlated with increased serum levels of phosphate and fibroblast growth factor 23 (FGF23) in hemodialysis patients with relatively low parathyroid hormone levels. Decreased Wnt/β-catenin signaling occurs regardless of the overall changes in bone formation rates, suggesting that a reduction in the anabolic response may be a common feature of renal bone disorders; however, additional mechanisms may contribute to the diversity of osteodystrophy phenotypes. Recent clinical studies demonstrated that treatment with anti-sclerostin antibodies improved bone quality in the context of low but not high turnover renal osteodystrophy. Sclerostin also appears in the circulation, suggesting that it plays additional roles outside the skeleton under normal conditions and in disease states. The serum sclerostin levels in CKD patients are several times higher than in healthy subjects. Recent data suggest that the higher serum sclerostin levels are associated with increased fracture rates, but the relationship between sclerostin and cardiovascular disease is unclear. CKD stage-specific epidemiologic studies are needed to assess whether sclerostin elevations affect comorbidities associated with CKD-MBD.