Figure 9.
Potential mechanisms involved in the reversal of the age-related decline in Wnt signaling by intermittent PTH. The increased levels of ROS and endogenous glucocorticoids that occur with advancing aging stimulate osteoblast apoptosis and inhibit Wnt signaling leading to decreased bone formation. Daily injections of PTH reduce oxidative stress, and increase Wnt signaling by activating LRP6 and by suppressing expression of Wnt antagonists such as sclerostin. By reducing oxidative stress and lipid oxidation, PTH-stimulated Wnt signaling in aged mice is further enhanced by reducing diversion of β-catenin to FoxOs, and by preventing PPARγ-mediated degradation of β-catenin. Activation of Akt by PTH may further lower activated FoxO levels. Ob, osteoblast; BFR, bone formation rate; GC, glucocorticoids; TCF/LEF, T cell factor/lymphoid enhancer factor; PTH1R, parathyroid hormone 1 receptor; Sost, the gene encoding sclerostin.