The emerging role of IMD 0354 on bone homeostasis by suppressing osteoclastogenesis and bone resorption but without affecting bone formation

摘要

Osteoporosis is caused by an imbalance between bone formation and bone resorption. Receptor activator of nuclear factor-κB ligand (RANKL) promotes the activity and differentiation of osteoclasts via activating the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. IMD 0354 is a selective molecular inhibitor of inhibitor of NF-κB kinase subunit beta (IKKβ) and effective for treatment of acute and subacute inflammatory diseases through the suppression of NF-κB activation. However, the effect of IMD 0354 on bone homeostasis is unknown. In this study, we demonstrated that IMD 0354 significantly attenuated ovariectomy-induced bone loss and inhibited osteoclastogenesis in mice, whereas bone formation was not affected. Additionally, IMD 0354 dramatically inhibited osteoclast differentiation and function induced by RANKL and macrophage colony-stimulating factor in bone marrow monocytes as verified by tartrate-resistant acid phosphatase (TRAP) staining as well as bone resorption assay in vitro. Subsequently, we found that activation of NF-κB signaling and the ERK/c-Fos axis were blunted during osteoclast formation induced by RANKL. Transcription factors nuclear factor of activated T cells c1 (NFATc1) and c-Fos were suppressed with the decreased expression of osteoclast-related genes by IMD 0354. Our findings suggest that IMD 0354 could be a potential preventive and therapeutic drug for osteoporosis.