Dual Effects of β‐TrCP2 Deletion in Bone Homeostasis: Suppression of Osteoclastogenesis and Enhancement of Osteoblast Activity

Abstract

OBJECTIVES: To elucidate role of beta-transducin repeat-containing protein 2 (β-TrCP2) in bone homeostasis for its potential as a therapeutic target for osteoporosis. METHODS: ) mice. Bone microarchitecture was assessed by micro-computed tomography, and osteoclast and osteoblast parameters by histomorphometry. Osteoclast resorptive activity was evaluated using dentine slice pit assays. Mechanisms regulating osteoclastogenesis were investigated by RNA sequencing, RT-qPCR, immunoprecipitation, and immunoblotting. Bone formation and injury-induced repair were assessed by dynamic histomorphometry and drill-hole defect model. Therapeutic potential was evaluated in ovariectomized WT and β-TrCP2KO mice. RESULTS: mice exhibited the increased bone mass and reduced osteoclast numbers compared to WT, but not β-TrCP1 KO mice. The β-TrCP2 KO bone marrow-derived myeloid cells were treated with RANKL. The activity and markers of osteoclast were decreased and interferon-β (IFN-β) was increased. Mechanistically, β-TrCP2-mediated IKKε ubiquitination and degradation is a critical event for enhancing IFN-β expression via IRF3 by RANKL or LPS stimulation. β-TrCP2 KO mice showed increased osteoblast differentiation and bone formation through β-catenin stabilization and upregulation of osteogenic genes. In post-osteoporosis induction therapeutic ovariectomized model, β-TrCP2 KO mice were protected from bone loss through both decreased osteoclast formation and enhanced osteoblast activity. CONCLUSION: β-TrCP2 regulates osteoclast formation by modulating IKKε-IRF3-IFN-β and NF-κB signaling pathway and influences osteoblast activity by β-catenin accumulation. This study suggests that β-TrCP2 has potential as a novel therapeutic target for osteoporosis.