%0 Journal Article
%T Dual roles of QOA-8a in antiosteoporosis: a combination of bone anabolic and anti-resorptive effects
%A Bei-hua Bao
%A Chen-xi Liu
%A Jian-xin Li
%A Jing Wu
%A Qi Shen
%A Qing Jiang
%A Wei Cui
%A Yu Zhao
%A Yu-chao Zhang
%A Yue Huai
%J Archive of "Acta Pharmacologica Sinica".
%D 2018
%R 10.1038/aps.2017.63
%X 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 ¦Ìmol/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
%K QOA-8a
%K oleanolic acid
%K antiosteoporosis
%K osteoclasts
%K osteoblasts
%K OVX rat model
%K bone mineral density
%K dual-energy X-ray absorptiometry
%K microcomputed tomography
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800470/