The Role of Sclerostin in Bone and Ectopic Calcification

Abstract

Sclerostin, a 22-kDa glycoprotein that is mainly secreted by the osteocytes, is a soluble inhibitor of canonical Wnt signaling. Therefore, when present at increased concentrations, it leads to an increased bone resorption and decreased bone formation. Serum sclerostin levels are known to be increased in the elderly and in patients with chronic kidney disease. In these patient populations, there is a high incidence of ectopic cardiovascular calcification. These calcifications are strongly associated with cardiovascular morbidity and mortality. Although data are still controversial, it is likely that there is a link between ectopic calcification and serum sclerostin levels. The main question, however, remains whether sclerostin exerts either a protective or deleterious role in the ectopic calcification process.

Keywords: Wnt signaling; sclerostin; vascular calcification.

Figure 1

Overview of the actions of sclerostin in the bone. I: Inhibition of proliferation and differentiation of osteoprogenitor/pre-osteoblastic cells, as well as decreased activation of mature osteoblasts; II: decreased mineralization; III: increased apoptosis of the osteogenic cells; IV: maintenance of bone lining cells in their quiescent state; V: regulation of osteocyte maturation and osteocytic osteolysis; VI: stimulation of bone resorption.

Figure 2

Overview of activators and inhibitors of Wnt/β-catenin signaling pathway. BMP9: Bone-Morphogenetic Protein 9, BMP2: Bone-Morphogenetic Protein 2, Msx2: Msh homeobox 2, HMGB1: High Mobility Group Box 1, sFRP5: secreted Frizzled-Related Protein 5, PPARγ: Peroxisome Proliferator-Activated Receptor γ, PTH1R: Parathyroid Hormone 1 Receptor, SIRT1: Sirtuin1, MMP: Matrix Metalloproteinase, Runx2: Runt-related transcription factor 2, RANKL: Receptor Activator of Nuclear Factor Kappa-Β Ligand.

Figure 3

Hypothesized contribution of sclerostin in the calcification paradox. In a calcified artery, sclerostin is produced by transdifferentiated vascular smooth muscle cells [87,108]. It is hypothesized that this locally produced sclerostin can spill-over into the circulation, thereby contributing to increased serum sclerostin levels [87,134]. Via the circulation, this increased amount of sclerostin reaches the bone compartment, where it might be involved in the inhibition of bone formation/mineralization/turnover [87].