Ixazomib enhances parathyroid hormone-induced β-catenin/T-cell factor signaling by dissociating β-catenin from the parathyroid hormone receptor.

The anabolic action of PTH in bone is mostly mediated by cAMP/PKA and Wnt-independent activation of beta-catenin/T-cell factor (TCF) signaling. beta-Catenin switches the PTH receptor (PTHR) signaling from cAMP/PKA to PLC/PKC activation by binding to the PTHR. Ixazomib (Izb) was recently approved as the first orally administered proteasome inhibitor for the treatment of multiple myeloma; it acts in part by inhibition of pathological bone destruction. Proteasome inhibitors were reported to stabilize beta-catenin by the ubiquitin-proteasome pathway. However, how Izb affects PTHR activation to regulate beta-catenin/TCF signaling is poorly understood. In the present study, using CRISPR/Cas9 genome-editing technology, we show that Izb reverses beta-catenin-mediated PTHR signaling switch and enhances PTH-induced cAMP generation and cAMP response element-luciferase activity in osteoblasts. Izb increases active forms of beta-catenin and promotes beta-catenin translocation, thereby dissociating beta-catenin from the PTHR at the plasma membrane. Furthermore, Izb facilitates PTH-stimulated GSK3 beta phosphorylation and beta-catenin phosphorylation. Thus Izb enhances PTH stimulation of beta-catenin/TCF signaling via cAMP-dependent activation, and this effect is due to its separating beta-catenin from the PTHR. These findings provide evidence that Izb may be used to improve the therapeutic efficacy of PTH for the treatment of osteoporosis and other resorptive bone diseases.