The role of the Wnt signaling pathway in osteoblast commitment and differentiation

Abstract

Wnts are a large family of proteins that participate in an array of cellular biological processes such as embryogenesis, organogenesis and tumor formation. These proteins bind to membrane receptor complexes comprised of a frizzled (Fz) G-protein-coupled receptor and other membrane co-receptors forming molecular groups that initiate, at least, three different intracellular signaling cascades leading to nuclear generation of transcription factors which regulate various cellular events. These events result in selective cellular differentiation, reduction or inhibition of the apoptotic mechanisms or changes in the biologic behavior of various cell lines. During the last decade, canonical Wnt signaling has been shown to play a significant role in the control of osteoblastogenesis and bone formation. In several clinical cases, mutations have been found in the Wnt receptor complexes that are associated with changes in bone mineral density and fractures. Loss-of-function mutations in LRP5 receptors cause, osteoporosis-pseudoglioma syndrome, while gain-of-function mutations in the same group lead to high bone mass phenotypes. Furthermore, osteocytes secrete proteins such as sclerostin, which blocks the membrane complex activation by Wnt, resulting in inhibition of bone formation. Studies of knockout and transgenic mouse models for Wnt pathway components have demonstrated that canonical signaling regulates most aspects of osteoblast physiology including commitment, differentiation, bone matrix formation/mineralization and apoptosis as well as coupling to osteoclastogenesis and bone resorption. Future studies in this rapidly growing area of research can possibly lead to the identification of targets of pharmacological intervention useful in the management of osteoporosis. In the present review we summarized the current knowledge related to the various components of the Wnt signaling pathway, the ways they cooperate in inducing and directing transcriptional functions as well as the interacting points with the TGFbeta superfamily. We also outlined a probable working integrating model of the mechanism of bone formation.

Comparison of Phosphoinositide-Specific Phospholipase C Expression Panels of Human Osteoblasts Versus MG-63 and Saos Osteoblast-Like Cells

“…Great attention has been given to the wide number of signal transduction pathways acting in osteoblasts, which coordinate and regulate osteoblasts' complex contribution to bone remodeling. Various signal transduction pathways occurring in osteoblasts have been actively studied (39)(40)(41)(42)(43), with special regard to the systems related to complex calcium metabolism (44).…”

High cholesterol diet increases osteoporosis risk via inhibiting bone formation in rats

“…Genes involved in TGF-β/ BMP and Wnt pathways promote the differentiation of mesenchymal stem cells into osteoblasts and facilitate the proliferation and maturation of osteoblasts. They also regulate the differentiation of osteoblasts, the secretion of bone matrix and mineralization of the bone matrix [28][29][30] . Some genes involved in these pathways were also down-regulated in high cholesterol fed rats, which will lead to a suppression of differentiation, proliferation and maturation of osteoblasts, as well as decreased bone formation.…”

Mechanotransduction and Osteogenesis

“…There is exiguous information about Wnt pathways' relation to mechanotransduction. At the moment, it is known that (1) strain increases -catenin activation and translocation to the nucleus, probably via PI3K activation, or decreasing sclerostin expression, which is an inhibitor of the canonical Wnt signaling pathway; (2) strain increases Wnt1, Wnt3a, Wnt5a and Lrp5 receptor expression; (3) and Lrp5 receptor hyperexpression increases the cellular response to mechanical loading, and decreases the strain needed to stimulate bone cells response to mechanical stimulation (Bonewals & Johnson, 2008;Johnson, 2004;Lau et al, 2006;Olkku & Mahonen, 2008;Robling et al, 2008;Turner, 2006;Yavropoulou & Yovos, 2007). Fig.…”