Sclerostin: current knowledge and future perspectives

Abstract

In recent years study of rare human bone disorders has led to the identification of important signaling pathways that regulate bone formation. Such diseases include the bone sclerosing dysplasias sclerosteosis and van Buchem disease, which are due to deficiency of sclerostin, a protein secreted by osteocytes that inhibits bone formation by osteoblasts. The restricted expression pattern of sclerostin in the skeleton and the exclusive bone phenotype of good quality of patients with sclerosteosis and van Buchem disease provide the basis for the design of therapeutics that stimulate bone formation. We review here current knowledge of the regulation of the expression and formation of sclerostin, its mechanism of action, and its potential as a bone-building treatment for patients with osteoporosis.

Fig. 1

Chronological portraits of a patient with sclerosteosis from the age of 3 years onward. She was born with syndactyly at both hands and developed facial palsy, deafness, facial distortion, and maxillary overgrowth during childhood. By the age of 30, she had developed proptosis and elevated intracranial pressure due to overgrowth of the calvaria. Craniectomy was performed, but she died nevertheless because of elevated intracranial pressure at the age of 54 years (description of this case was previously published by Epstein et al. [13])

Fig. 2

Schematic model of the mechanism of action of sclerostin in bone remodeling and modeling. In remodeling a, sclerostin produced and secreted by newly embedded osteocytes may be transported to the bone surface, where it inhibits osteoblastic bone formation and prevents overfilling of the BMU. In modeling b, sclerostin may serve two actions. First, it may keep bone lining cells in a state of quiescence and prevent, thereby, initiation of de novo bone formation. In addition, sclerostin produced and secreted by newly embedded osteocytes may inhibit osteoblastic bone formation, as in a BMU (reproduced from van Bezooijen et al. [8])

Fig. 3

Schematic model of antagonized canonical Wnt signaling. Canonical Wnt signaling involves the formation of complexes of Wnts with Frizzled receptors and LRP5/6 coreceptors, resulting in the accumulation of β-catenin in the cytoplasm and translocation into the nucleus. The antagonist Dkk1 inhibits canonical Wnt signaling by the formation of complexes with LRP5/6 and Kremen, resulting in the removal of LRP5/6 from the membrane. Dkk1 binds to the first and third β-propellers of LRP5/6. The antagonist sclerostin inhibits canonical Wnt signaling by binding to probably the first β-propeller of LRP5/6. Whether sclerostin requires a cofactor like Kremen for Dkk1 to exert its antagonistic effect remains to be established (reproduced from van Bezooijen et al. [8])

Fig. 4

Schematic model for the regulation of the control of bone formation by sclerostin. Sclerostin may exert its inhibitory effect on bone formation by preventing the activation of lining cells as well as the inactivation of active osteoblasts. Glucocorticoids stimulate sclerostin expression and, thereby, inhibit bone formation, whereas intermittent PTH and loading inhibit sclerostin expression in osteocytes and, thereby, stimulate bone formation