State Key Laboratory of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
Medical School of Nanjing University, Nanjing 210093, China.
Acta Pharmacol Sin. 2018 Feb;39(2):230-242. doi: 10.1038/aps.2017.63. Epub 2017 Aug 17.
Osteoporotic treatments have largely depended on antiresorptive or anabolic drugs; but the former also suppresses new bone formation, and the latter only includes human parathyroid hormone. There is no drug that has a dual effect to inhibit bone resorption and to stimulate bone formation simultaneously. Here, we report a small molecule, a quinoxaline derivative of oleanolic acid (QOA-8a) that plays such dual roles in osteoblasts and osteoclasts in the treatment of osteoporosis. Osteoclast differentiation was induced by incubation of primary mouse bone marrow-derived macrophages in the presence of RANKL and M-CSF, treatment with QOA-8a dose-dependently inhibited the osteoclast formation with an IC value of 0.098 μmol/L. QOA-8a also directly acted on osteoblasts, and stimulated new bone formation in murine calvarial bones in vitro and in vivo. In an OVX rat model, administration of QOA-8a (1, 5 mg·kg·d, po) for 16 weeks effectively prevented OVX-induced bone loss, accompanied by decreased serum levels of the bone resorption marker CTX-1 and increased serum levels of osteoblast marker N-MID-OT. Meaningfully, our preliminary study revealed that QOA-8a down-regulated the ERK1/2 signal in osteoclasts and up-regulated the signal in osteoblasts. QOA-8a showed dual functions in both animal and human osteoclastogenesis and osteoblastogenesis. Our results demonstrate that QOA-8a might serve as a lead compound with a dual function of bone anabolic and anti-resorptive effects in the development of anti-osteoporosis agents.
骨质疏松症的治疗主要依赖于抗吸收或合成代谢药物；但前者也会抑制新骨形成，而后者仅包括人甲状旁腺激素。目前还没有一种药物具有同时抑制骨吸收和刺激骨形成的双重作用。在这里，我们报告了一种小分子，即齐墩果酸的喹喔啉衍生物（QOA-8a），它在成骨细胞和破骨细胞中具有双重作用，可用于治疗骨质疏松症。破骨细胞分化是通过在存在 RANKL 和 M-CSF 的情况下孵育原代小鼠骨髓来源的巨噬细胞来诱导的，用 QOA-8a 处理可剂量依赖性地抑制破骨细胞形成，IC 值为 0.098 μmol/L。QOA-8a 还直接作用于成骨细胞，刺激体外和体内鼠颅骨骨的新骨形成。在 OVX 大鼠模型中，QOA-8a（1、5 mg·kg·d，po）给药 16 周可有效预防 OVX 引起的骨丢失，同时降低血清骨吸收标志物 CTX-1 的水平和增加成骨标志物 N-MID-OT 的水平。有意义的是，我们的初步研究表明，QOA-8a 下调破骨细胞中的 ERK1/2 信号，并上调成骨细胞中的信号。QOA-8a 在动物和人破骨细胞和成骨细胞分化中均具有双重功能。我们的结果表明，QOA-8a 可能作为一种具有骨合成代谢和抗吸收作用双重功能的先导化合物，用于开发抗骨质疏松药物。
