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.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No 21272114, 90913023). We thank the Shanghai Synchrotron Radiation Facility (SSRF) for the microcomputed tomography (μCT) analysis of bone. We thank Prof Shigetoshi KADOTA and Dr Feng LI from the University of Toyama, Japan, for the peripheral quantitative computed tomography (pQCT) analysis of bone.
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Wu, J., Shen, Q., Cui, W. et al. Dual roles of QOA-8a in antiosteoporosis: a combination of bone anabolic and anti-resorptive effects. Acta Pharmacol Sin 39, 230–242 (2018). https://doi.org/10.1038/aps.2017.63
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DOI: https://doi.org/10.1038/aps.2017.63
