Wnt signaling and the regulation of bone mass

Human genetic studies have firmly established a link between bone mass in humans and gain-of-function or loss-of-function mutations in a Wnt coreceptor, low-density lipoprotein receptor-related protein 5 (LRP5), or in the Wnt antagonist sclerostin, and several molecular genetic studies in mice have consistently confirmed the critical importance of the Wnt signaling pathway in skeletal biology and disease. In what may be a novel paradigm, the ubiquitous nature of LRP5/6 and Wnt signaling is counterbalanced by the bone-restricted and regulated expression of Wnt antagonists such as sclerostin and Dickkopf-1 (Dkk1) in adult tissues, offering new and potentially safe therapeutic means of intervention to stimulate bone formation.