A Novel RANKL/RANK Inhibitor IMB-R38 Inhibits Osteoporosis Through Regulating Bone Metabolism

作者：Yuyan Zhang, Xinwei Wei, Ren Sheng, Guijun Yang, Xiaowan Han, Jingrui Wang, Chao Liu, Shunwang Li, Lijuan Lei, Weilian Jiang, Yang Lun, Shuyi Si, Jing Zhang, Ying Xu · 发表于：International Journal of Molecular Sciences · 年份：2025 · DOI：10.3390/ijms262412151 · 被引用次数：3 · 研究领域：Bone Metabolism and Diseases、Bone health and osteoporosis research、NF-κB Signaling Pathways

Osteoporosis is a systemic skeletal disease that severely impairs the health of the elderly population. The interaction between the receptor activator of the NF-κB ligand (RANKL) and its receptor RANK is critical for osteoclast differentiation and function. Therefore, targeting the RANKL/RANK interaction represents a promising strategy for osteoporosis. In this study, we employed a newly established yeast two-hybrid system based on RANKL/RANK interaction and identified IMB-R38, a novel benzamide compound that dose-dependently blocked RANKL/RANK interaction by inhibiting the growth of AH109 cells harboring pAD-RANKL/pBD-RANK plasmids in quadruple-dropout medium. IMB-R38 significantly suppressed osteoclast differentiation, disrupted F-actin ring formation, and downregulated the expression of osteoclast-specific genes, including NFATc1 and MMP9 in RANKL-induced RAW264.7 macrophages. IMB-R38 also promoted osteoblast differentiation by upregulating the expression of osteogenic genes. Importantly, in a dexamethasone (DXM)-induced osteoporotic zebrafish model, IMB-R38 significantly increased bone mineralization, with anti-osteoporosis efficacy superior to that of alendronate sodium (Alen). RT-qPCR assays showed that IMB-R38 significantly upregulated the mRNA expression of osteogenesis genes (Bmp2, Runx2a, Runx2b, Sp7, Alp, and Oc) while markedly downregulating that of the osteoclastogenesis genes (Mmp9, Mmp13, and Mmp2) compared with the DXM group. Mechanistically, an SPR assay conf...