@article{APS9722,
author = {Jing WU and Qi SHEN and Wei CUI and Yu ZHAO and Yue HUAI and Yu-chao ZHANG and Bei-hua BAO and Chen-xi LIU and Qing JIANG and Jian-xin LI},
title = {Dual roles of QOA-8a in antiosteoporosis: a combination of bone anabolic and anti-resorptive effects},
journal = {Acta Pharmacologica Sinica},
volume = {39},
number = {2},
year = {2018},
keywords = {},
abstract = {Abstract
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 IC50 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-1·d-1, 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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/9722}
}