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. 2014 Jun;6(3):79–91. doi: 10.1177/1759720X14523500

Figure 2.

Figure 2.

Wnt pathway, sclerostin, and DKK1; effects of monoclonal antibodies on bone.

(a) Scl and DKK1 bind Wnt coreceptors LRP5/6 to inhibit Wnt binding and signaling to decrease bone formation. Scl and DKK1 bind the first β-sheet of LRP5 and LRP6 to inhibit Wnt-1 signaling. DKK1 also binds the third β-sheet to inhibit Wnt-3a signaling. DKK1 and Scl can also utilize coreceptors, such as Kremen-1 or -2 receptors, to augment Wnt inhibitory activity resulting in the internalization of the complex. (b) Scl-Ab and DKK1-Ab prevent the interaction of these molecules with LRP5 and LRP6, thereby allowing Wnt-1 and Wnt-3a to bind the first and third β-sheet of LRP5/6, respectively. Actions of these antibodies on bone are summaries. Wnt proteins (either Wnt-1 or Wnt-3a) form a complex with FRZ receptors and LRP5/6 to transduce an intracellular signal leading to increased bone formation. (For an in-depth review see Ke et al. [2012]). DKK1, Dickkopf-related protein 1; DKK1-Ab, Dickkopf-1 antibody; FRZ, frizzled; LRP, lipoprotein receptor-related protein; Scl, sclerostin; Scl-Ab, sclerostin antibody.