Control of Bone Homeostasis by the Wnt Inhibitor Sclerostin

Abstract

Wnt signaling is an important osteogenic pathway regulating skeletal development and maintenance, and sclerostin is a potent extracellular inhibitor of this process. New anabolic skeletal therapies are needed to treat osteoporosis in the aging population, and pre-clinical and clinical studies demonstrate that targeting sclerostin with neutralizing antibodies releases an inhibitory brake on osteogenic Wnt signaling, promoting new bone formation and suppressing bone resorption to ultimately increase net bone mass. In this article, we review recent evidence regarding the regulation of sclerostin production in vivo under normal and disease states and summarize recent findings regarding the efficacy, mechanism of action, and potential complications of sclerostin-targeting therapies (i.e., sclerostin-neutralizing antibodies) in the treatment of skeletal disorders. While recent studies have revealed a great deal of information regarding sclerostin’s biological effects and regulatory patterns, much remains to be learned about the role of this molecule in the skeleton and other body systems