Wnt signaling and osteoblastogenesis.
Wnts are a large family of growth factors that mediate fundamental biological processes like embryogenesis, organogenesis and tumorigenesis. These proteins bind to a membrane receptor complex comprised of a frizzled (FZD) G-protein-coupled receptor (GPCRs) and a low-density lipoprotein (LDL) receptor-related protein (LRP). The formation of this ligand-receptor complex initiates a number of intracellular signaling cascades that includes the canonical/beta-catenin pathway, as well as several GPCR-mediated noncanonical pathways. In recent years, canonical Wnt signaling has been shown to play a substantial role in the control of bone formation. Clinical investigations have found that mutations in LRP-5 are associated with bone mineral density and fractures. For example, loss-of-function mutations in LRP-5 cause osteoporosis pseudoglioma syndrome, while gain-of-function mutations lead to high bone mass phenotypes. Studies of knockout and transgenic mouse models for Wnt pathway components like Wnt-10b, LRP-5/6, secreted frizzled-related protein-1, dickkopf-2, Axin-2 and beta-catenin have demonstrated that canonical signaling modulates most aspects of osteoblast physiology including proliferation, 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 should focus on elucidating Wnt/FZD specificity in the control of bone cell function, the role of noncanonical pathways in skeletal remodeling, and direct effects of Wnts on cells of the osteoclast lineage.
Bodine
Peter V N
PV
Women's Heath and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. bodinep@wyeth.com
Komm
Barry S
BS
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D060466:Axin Protein; D002113:Calcification, Physiologic / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D026502:LDL-Receptor Related Proteins / Q000502:physiology; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008565:Membrane Proteins / Q000502:physiology; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology* / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology; D010012:Osteogenesis; D011973:Receptors, LDL / Q000502:physiology; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
D060466:Axin Protein; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008565:Membrane Proteins; D011973:Receptors, LDL; D051153:Wnt Proteins; D051176:beta Catenin; C491761:AXIN2 protein, human; C405060:Dkk2 protein, mouse; C555482:LRP5 protein, human; C555475:LRP6 protein, human; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins