A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

Abstract

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.

Keywords: Lrp5/Lrp6; Wnt signaling; mouse models; skeletal phenotypes; β-catenin.

Figure 1

Overview of Wnt/β-catenin signaling. Production and secretion of Wnt ligands is dependent on the Porcupine-dependent lipid modification of Wnt and the presence of Wntless to facilitate the transport of lipid-modified Wnt to the plasma membrane (10). Once secreted, Wnt proteins bind to a receptor complex that includes either Lrp5 or Lrp6 and a member of the Frizzled family of seven-transmembrane receptors (3). In the absence of a Wnt ligand, a multiprotein complex, which includes GSK3, Axin, and APC, facilitates Casein kinase 1 (CKI)-primed and GSK3-dependent phosphorylation of β-catenin, targeting it for proteolytic degradation via the E3-ubiquitin ligase β-TrCP (11). Activation of the Wnt receptor complex leads to the activation of Dishevelled (Dvl) and the phosphorylation of the cytoplasmic domain of Lrp5/6 leading to the recruitment of Axin to the plasma membrane. This inhibits the processes, which induce the degradation of β-catenin, leading to increased accumulation in the cytoplasm. β-catenin can subsequently enter the nucleus where it can bind to members of the LEF/TCF family and activate target gene transcription via the recruitment of factors such as BCL9, Pygopus, and Parafibromin (a component of the PAF complex) to target gene promoters (12), (13). In the absence of β-catenin nuclear localization, TCF/LEF proteins can associate with members of the Groucho family to facilitate transcriptional repression. β-catenin also plays a key role in mediating cellular adhesion via its interactions with Cadherins. Finally, several extracellular inhibitors of this process, such as Dkks, Sost, and potentially Kremen, can negatively regulate the formation of the Wnt receptor complex.