The role of the Wnt signaling pathway in osteoblast commitment and differentiation.
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.
Department of Endocrinology and Metabolism, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.
Maria P
MP
Yavropoulou
John G
JG
Yovos
D000818:Animals; D015519:Bone Density; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D002454:Cell Differentiation; D003600:Cytosol / Q000737:chemistry; D051157:Frizzled Receptors / Q000502:physiology; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000502:physiology; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology*; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D019485:Bone Morphogenetic Proteins; D051157:Frizzled Receptors; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; D011973:Receptors, LDL; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins