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.
Highlights
Sclerostin is a 190-residue secreted glycoprotein that is predicted to contain a cysteine-knot motif and is a member of the DAN/Cerberus protein family [1] (Fig. 1)
In patients with the rare inherited bone disorder, sclerosteosis, which is characterized by exceptionally high bone density [2], have recently been found to be homozygous for a defective sclerostin gene (SOST) [3, 4], and a similar high bone mass phenotype has been reported in sclerostin knock-out mice [5]
We have recently reported an increased serum sclerostin levels (Fig. 4) and that serum sclerostin were closely associated with serum phosphate and fibroblast growth factor 23 (FGF23) levels and treatment with vitamin D in hemodialysis patients with low serum Parathyroid hormone (PTH) levels [44]
Summary
Sclerostin is a 190-residue secreted glycoprotein that is predicted to contain a cysteine-knot motif and is a member of the DAN/Cerberus protein family [1] (Fig. 1). Wnt ligands bind to cell surface receptor complexes that are comprised of Frizzled and low-density lipoprotein receptor-related protein (LRP) family members [14, 15]. In addition to being dependent on the local expression of specialized Wnt ligands, regulation of the canonical Wnt pathway is dependent on the relative expression of inhibitors that bind to either Wnts themselves (Frizzled-related proteins, FRPs) or to one of the LRP co-receptors, such as sclerostin or Dickkopf-related protein 1 (Dkk). Sclerostin blocks Wnt signaling pathway in osteoblasts by binding to LRP-5/6 receptors [19]. Osteocytes regulate bone formation via the Wnt signaling pathway by secreting sclerostin and Dkk1 [21]. Parathyroid hormone (PTH) is known to bind directly to cells of the osteoblast/osteocyte lineage and promote increased RANKL expression, which leads to osteoclast activation. The effect of intermittent PTH administration is transient, because RANKL actions are balanced by the subsequent rising levels of its
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