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: Wnt signaling; mouse models; Lrp5/Lrp6; β-catenin; skeletal phenotypes Bone Research (2013) 1: 27-71. doi: 10.4248/BR201301004 Overview of Wnt signal transductionWnts are a family of 19 mammalian proteins characterized by a conserved pattern of cysteine residues( 1). Wnts can activate several signaling pathways after binding to their cognate receptors, however, the bulk of this review will focus on the best characterized of these pathways, the so-called canonical pathway (Figure 1). This pathway results in the stabilization of the β-catenin protein and subsequent transactivation of target genes (2). It is initiated by Wnt ligands binding to a receptor complex that includes a member of the Frizzled (Fzd) family of seven-transmembrane receptors and either Lrp5, or the related Lrp6 protein(3). Engagement of this complex results in the phosphorylation of the cytoplasmic domain of Lrp5 or Lrp6, creating a binding site for the Axin protein.In the absence of an upstreamsignal, Axin exists in a multiprotein complex that also includes Adenomatous polyposis coli (APC) and the serine/ threonine protein kinase, Glycogen synthase kinase 3 α/β. This complex facilitates β-catenin for GSK3-dependent phosphorylation, targeting it for ubiquitin-depen- 28 dent proteolysis. Binding of Axin to phosphoryl...

Signaling pathways regulating cartilage growth plate formation and activity

“…Members of the Dikkopf (DKK) family, secreted Frizzled-related proteins (sFRP), and Wnt inhibitory factor 1 (WIF-1), act as antagonists of Wnt signaling [55]. Mouse genetic studies have shown that Wnt signaling is intimately involved in the development of many tissues and organs, and both gain- and loss-of-function mutations in Wnt signaling cause various human diseases, including bone diseases [56] [57, 58]. …”

“…Multiple Wnt ligands signal through non-canonical pathways, including the planar cell polarity (PCP) and the Wnt/Ca 2+ pathways [57]. Non-canonical Wnt signaling has been implicated in promoting chondrocyte differentiation due to its ability to inhibit canonical Wnt signaling.…”

“…Such transcriptional cofactors, although they do not have identifiable DNA-binding domains themselves, can interact with key transcription factors such as Sox9, Runx2, and key signaling downstream effectors, such as Smads, to regulate chondrocyte differentiation and skeletal development in a spatio-temporal manner. In this regard, β-catenin serves as a prime example as a crucial transcriptional co-activator that plays essential roles at multiple steps of growth plate formation [57]. Overall, various transcription co-factors often interpret various developmental signaling pathways in an exquisite fashion, serving as a crucial bridge between upstream signaling cues and downstream events in the nucleus [1].…”

Aerobic Glycolysis in Osteoblasts

“…Wnt signaling has emerged as a major promoter of bone accretion 38 . Recently, Wnt proteins were shown to reprogram cellular glucose metabolism during osteoblast differentiation 39 .…”

C-kit induces epithelial-mesenchymal transition and contributes to salivary adenoid cystic cancer progression

“…Both TGF-β and Wnt signal pathways have been implicated in cancer progression and EMT [18]. TGF-β1 has been shown to highly express in ACC patient samples and SACC-LM cell line and induced Smad2 phosphorylation and promoted the migration and invasion of SACC-83 cells [19].…”