Article

Dual roles of QOA-8a in antiosteoporosis: a combination of bone anabolic and anti-resorptive effects

Authors: Jing WU1,2, Qi SHEN1, Wei CUI1, Yu ZHAO1, Yue HUAI1, Yu-chao ZHANG1, Bei-hua BAO1, Chen-xi LIU1, Qing JIANG2, Jian-xin LI1
1 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
2 Medical School of Nanjing University, Nanjing 210093, China
Corresponding to: Jian-xin LI: lijxnju@nju.edu.cn,
DOI: 10.1038/aps.2017.63
Received: 25 January 2017
Accepted: 13 April 2017
Advance online: 17 August 2017

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.
Keywords: QOA-8a; oleanolic acid; antiosteoporosis; osteoclasts; osteoblasts; OVX rat model; bone mineral density; dual-energy X-ray absorptiometry; microcomputed tomography