Wnt and the Wnt signaling pathway in bone development and disease

Abstract

Wnt signaling affects both bone modeling, which occurs during development, and bone remodeling, which is a lifelong process involving tissue renewal. Wnt signals are especially known to affect the differentiation of osteoblasts. In this review, we summarize recent advances in understanding the mechanisms of Wnt signaling, which is divided into two major branches: the canonical pathway and the noncanonical pathway. The canonical pathway is also called the Wnt/β-catenin pathway. There are two major noncanonical pathways: the Wnt-planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt-Ca² pathway). This review also discusses how Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists affect both the bone modeling and bone remodeling processes. We also review the role of Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists in bone as demonstrated in mouse models. Disrupted Wnt signaling is linked to several bone diseases, including osteoporosis, van Buchem disease, and sclerosteosis. Studying the mechanism of Wnt signaling and its interactions with other signaling pathways in bone will provide potential therapeutic targets to treat these bone diseases.

Figure 1

The Wnt pathway and its interactions with other pathways in bone. (a)Wnt signaling and the TGF-β/BMP-Smad pathway influence each other during bone development. The Wnt pathway participates in R-Smad degradation and so does the Bmp pathway in β-catenin degradation. (b. c)The Wnt canonical pathway: Wnt proteins, following their binding to a frizzled receptor and a Lrp co-receptor (most likely LRP6), activate the canonical Wnt signaling pathway. These receptors transduce a signal to several intracellular proteins that include Dishevelled (Dsh), glycogen synthase kinase-3β(GSK-3), Axin, Adenomatous Polyposis Coli(APC), and the transcriptional regulator, β-catenin. This results in the translocation to nucleus of β-catenin, β-catenin’s association with members of the Lef1/Tcf family of nuclear proteins, and activation of a specific program of gene expression. (d) Wnt interacts with PTH1R, decreases wnt antagonists, Sost, WIF1 and Dkk expression, and sustains β-catenin stabilization. (e, f) The Wnt noncanonical pathway. The Ca²⁺ pathway and PCP pathway affect osteoblastogenesis and osteoclastogenesis.

Figure 2

The role of the canonical Wnt, Ihh, Bmp and PTH/PTHrP signaling pathways in regulating the differentiation of mesenchymal precursors. The Wnt canonical pathway and Ihh, Bmp, PTH/PTHrP pathways control the commitment of mesenchymal precursors and also the differentiation of osteoblasts/osteocytes. Though these processes, they regulate the osteoblastogenesis and bone remodeling.