Wnt signaling pathways and the biology of sclerostin.Notes: (A) Canonical Wnt signaling: in the absence of sclerostin, Wnt binds to LRP 5/6 and its co-receptor, frizzled

Wnt signaling pathways and the biology of sclerostin.Notes: (A) Canonical Wnt signaling: in the absence of sclerostin, Wnt binds to LRP 5/6 and its co-receptor, frizzled. This results in phosphorylation of the cytoplasmic tail of LRP 5/6, which allows axin to bind the receptor complex Axin binding leads to inhibition of GSK-3β, which normally functions to target β-catenin for degradation. Therefore, cytoplasmic levels of β-catenin increase and are translocated to the nucleus, where they bind to DNA binding proteins and activate target gene promoters. This results in osteoblast differentiation, proliferation and survival and hence, increased bone formation. (B and C) Loss-of-function of LRP5 and Wnt prevent canonical Wnt signaling: Loss-of-function of LRP5 and Wnt prevent formation of the active Wnt-LRP 5/6-frizzled complex and prevent Wnt signaling. The cytoplasmic tail of LRP 5/6 remains unphosphorylated. Therefore, axin does not bind the receptor complex. GSK-3β activity is uninhibited and therefore leads to phosphorylation of β-catenin, targeting it for degradation. Cytoplasmic levels of β-catenin decrease. Therefore, there is less translocation of the protein to the nucleus. Target gene promoters of the Wnt signaling pathway are not activated. This results in decreased bone formation and increased bone resorption and hence, skeletal fragility and fractures. (D) Inhibition of canonical Wnt signaling by sclerostin: sclerostin is secreted by osteocytes. It binds to LRP 5/6, which prevents Wnt from binding to LRP 5/6 and its co-receptor, frizzled. Therefore, Wnt signaling is inhibited. Through the mechanisms described above (B and C), this results in decreased bone formation and increased bone resorption.

Publication

Sclerostin inhibition: a novel therapeutic approach in the treatment of osteoporosis. (2015) Arti D Shah, et al. Int J Womens Health. 2015;7:565-580. Figure: F1. All organisms Homo sapiens Rattus norvegicus Macaca fascicularis Mus musculus Drosophila melanogaster

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