Han Xiaowan, Gong Shiqiang, Li Ni, Wang Xiao, Liu Peng, Xu Yanni, He Xiaobo, Jiang Wei, Si Shuyi
NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.
Front Pharmacol. 2019 Mar 11;10:103. doi: 10.3389/fphar.2019.00103. eCollection 2019.
The ratio of osteoprotegerin (OPG) to the receptor activator of NF-κB ligand (RANKL) is a key determinant in the regulation of bone metabolism. The study was performed to screen novel anti-osteoporotic drugs regulating OPG/RANKL ratio and evaluate their effect on bone metabolism. According to the screening results and results, we found a small molecule, E09241, significantly increased the ratio of OPG/RANKL by mainly increasing OPG expression. Our studies showed that E09241 increased the alkaline phosphatase (ALP) activity of mouse osteoblasts, promoted mineralization, and increased the expression of osteogenic differentiation-related genes. In addition, we observed that E09241 inhibited RANKL-induced osteoclast differentiation and reduced the expression of osteoclast differentiation-related proteins nuclear factor of activated T cells c1 (NFATc1) and matrix metalloproteinase 9 (MMP-9). More importantly, E09241 exerted therapeutic protection against bone loss in ovariectomized rats . This protective effect was confirmed to be achieved by inhibiting bone resorption and promoting bone formation . Mechanistically, E09241 regulates OPG expression through canonical Wnt/β-catenin signaling. Our findings suggest that E09241 is a promising small-molecule compound for treating osteoporosis with a dual effect on osteoblasts and osteoclasts.
骨保护素（OPG）与核因子κB受体活化因子配体（RANKL）的比值是骨代谢调节的关键决定因素。本研究旨在筛选调节OPG/RANKL比值的新型抗骨质疏松药物，并评估其对骨代谢的影响。根据筛选结果，我们发现一种小分子化合物E09241，它主要通过增加OPG表达来显著提高OPG/RANKL的比值。我们的研究表明，E09241可提高小鼠成骨细胞的碱性磷酸酶（ALP）活性，促进矿化，并增加成骨分化相关基因的表达。此外，我们观察到E09241可抑制RANKL诱导的破骨细胞分化，并降低破骨细胞分化相关蛋白活化T细胞核因子c1（NFATc1）和基质金属蛋白酶9（MMP-9）的表达。更重要的是，E09241对去卵巢大鼠的骨质流失具有治疗保护作用。这种保护作用通过抑制骨吸收和促进骨形成得以证实。从机制上讲，E09241通过经典的Wnt/β-连环蛋白信号通路调节OPG表达。我们的研究结果表明，E09241是一种有前景的小分子化合物。它对成骨细胞和破骨细胞具有双重作用，有望用于治疗骨质疏松症。
