The Wnt signaling pathway plays key roles in differentiation and development and alterations in this signaling pathway are causally associated with numerous human diseases.While several laboratories were examining roles for Wnt signaling in skeletal development during the 1990s,interest in the pathway rose exponentially when three key papers were published in 2001-2002.One report found that loss of the Wnt co-receptor,Low-density lipoprotein related protein-5(LRP5),was the underlying genetic cause of the syndrome Osteoporosis pseudoglioma(OPPG).OPPG is characterized by early-onset osteoporosis causing increased susceptibility to debilitating fractures.Shortly thereafter,two groups reported that individuals carrying a specific point mutation in LRP5(G171V)develop high-bone mass.Subsequent to this,the causative mechanisms for these observations heightened the need to understand the mechanisms by which Wnt signaling controlled bone development and homeostasis and encouraged significant investment from biotechnology and pharmaceutical companies to develop methods to activate Wnt signaling to increase bone mass to treat osteoporosis and other bone disease.In this review,we will briefly summarize the cellular mechanisms underlying Wnt signaling and discuss the observations related to OPPG and the high-bone mass disorders that heightened the appreciation of the role of Wnt signaling in normal bone development and homeostasis.We will then present a comprehensive overview of the core components of the pathway with an emphasis on the phenotypes associated with mice carrying genetically engineered mutations in these genes and clinical observations that further link alterations in the pathway to changes in human bone.
展开▼
