Endocrine Abstracts

Wnts are a large family of carbohydrate- and lipid-modified growth factors that mediate essential biological processes such as embryogenesis, morphogenesis and organogenesis. These proteins bind to a membrane receptor complex comprised of a frizzled (FZD) G-protein-coupled receptor and a low-density lipoprotein (LDL) receptor-related protein (LRP). The formation of this ligand-receptor complex initiates a number of signaling cascades that includes the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation and remodeling. Clinical studies have found that mutations in LRP-5 are associated with bone mineral density and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components including Wnt-10b, LRP-5 and -6, secreted frizzled-related protein-1 and -4, dickkopf-1 and -2, Sclerostin, axin-2, beta-catenin and T-cell factor-1 have shown that canonical signaling modulates almost all aspects of osteoblast physiology including proliferation, differentiation, function, mineralization, apoptosis and mechanosensory perception as well as coupling to osteoclasts. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3beta support the importance of the canonical pathway in modulation bone formation. Moreover, well-established bone forming agents like bone morphogenetic proteins and parathyroid hormone have been demonstrated to intersect and utilize components of Wnt signaling pathways. Future research in this swiftly expanding area of skeletal biology should focus on understanding Wnt/FZD specificity in the control of bone cell physiology, the role of noncanonical pathways in bone remodeling, the interplay between Wnt signaling and other bone metabolic pathways and direct actions of Wnts on cells of the osteoclast lineage.