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Involvement of WNT/β-catenin Signaling in the Treatment of Osteoporosis

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Abstract

Osteoblast differentiation is predominantly regulated by the WNT/β-catenin signaling (canonical WNT pathway), which, together with bone morphogenetic proteins, acts as the master regulator of osteogenesis. The recent characterization of the canonical WNT pathway in the regulation of bone modeling and remodeling provided important insights for our understanding of the pathophysiology of a number of conditions and of the mechanism of action of hormones or drugs with important effect on bone metabolism. This review is mainly focused on the growing therapeutic implications of these new findings. WNT/β-catenin signaling plays a key role in bone tissue by determining the differentiation of stem cells into mature osteoblasts rather than into chondrocytes and adipocytes. Its regulation is predominantly driven by the production of two WNT signaling antagonists: sclerostin (SOST) and Dickkopf-related protein 1 (DKK1). The most proximate regulator of SOST expression by osteocytes and its serum levels is bone mechanical load. SOST expression is increased with advancing age, by glucocorticoid treatment and during treatment with antiresorptive agents such as bisphosphonates and denosumab, while it is decreased by parathyroid hormone excess or administration of estrogens. Correlation between DKK1 serum levels and bone formation in various pathological conditions or during osteoporosis treatment has been reported. Inhibitors of the negative regulators of WNT/β-catenin signaling (“inhibiting the endogenous inhibitors”) are potential candidates for the prevention and treatment of bone loss. Inactivating monoclonal antibodies against SOST appears to be the most attractive strategy because SOST is the only component of the WNT pathway expressed almost exclusively by osteocytes.

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The authors are participating in the Amgen phase 3 trial of the anti-SOST antibodies.

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  1. Department of Medicine, Rheumatology Section, Policlinico Borgo Roma, University of Verona, Piazzale Scuro, 10, 37134, Verona, Italy

    Maurizio Rossini, Davide Gatti & Silvano Adami

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  1. Maurizio Rossini
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  2. Davide Gatti
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  3. Silvano Adami
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Correspondence to Silvano Adami.

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Rossini, M., Gatti, D. & Adami, S. Involvement of WNT/β-catenin Signaling in the Treatment of Osteoporosis. Calcif Tissue Int 93, 121–132 (2013). https://doi.org/10.1007/s00223-013-9749-z

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