卡非佐米通过靶向PSME1/2激活Wnt/β-catenin信号缓解骨质疏松症

Abstract

Osteoporosis (OP) is characterized by decreased bone mineral density and impaired bone strength. Carfilzomib (CFZ) is a new-generation proteasome inhibitor and has been found to affect bone metabolism . However, the effect and mechanism of CFZ on OP has not been investigated systematically. In this study, we found that protein levels of proteasome activator subunit 1/2 (PSME1/2) increased in OP, and accumulated mostly in osteoblasts and osteoclasts . Treatment with PSME1/2 recombinant protein inhibited osteogenesis and promoted osteoclast formation in vitro . Also, PSME1/2 inhibited the expression of β-catenin protein, resulting in limitation of Wnt/β-catenin signaling. CFZ inhibited PSME1 and PSME2 proteasome activities and increased β-catenin protein level, resulting in the translocation of β-catenin to the nucleus and activation of canonical Wnt/β-catenin signaling, further promoting osteogenesis and inhibiting osteoclastic differentiation. In vivo , we conducted ovariectomy (OVX) to create a model of OVX-induced postmenopausal OP in mice. When analyzed by micro-CT scanning, enhancement of bone mineral density, bone volume, trabecular number, and thickness was seen in the CFZ-treated mice. Also, we noticed increased osteogenesis and decreased osteoclastogenesis, diminished expression of PSME1 and PSME2 and activated Wnt/β-catenin signaling in bone sections from OP mice treated with CFZ. Overall, our data indicated that PSME1/2 may serve as new targets for the treatment of OP, and targeting PSME1/2 with CFZ provides a candidate therapeutic molecule for postmenopausal OP.