Sclerostin Antibody Therapy for the Treatment of Osteoporosis: Clinical Prospects and Challenges

Figure 1

(a) Canonical Wnt signalling involves binding of Wnt to LRP5/6 and its coreceptor Frizzled resulting in the phosphorylation of LRP5/6 thus permitting Axin to bind to the receptor complex. Formation of this complex leads to inhibition of GSK3β which prevents degradation of β-catenin. Accumulation of cytosolic β-catenin leads to nuclear translocation where it activates target gene promoters which result in increased bone mass. (b) Sclerostin inhibition of the Wnt-canonical pathway in osteogenesis. Sclerostin binding to LRP receptor 5/6 prevents Wnt binding and formation of the Frizzled-LRP complex and thus Axin remains unphosphorylated. Downstream effects include activation of GSK3β resulting in phosphorylation of cytosolic β-catenin, thus targeting it for degradation. In the absence of β-catenin accumulation and subsequent nuclear translocation, osteogenesis is prevented.

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