title: Quinoxaline derivative of oleanolic acid inhibits osteoclastic bone resorption and prevents ovariectomy-induced bone loss.
abstract: OBJECTIVE
  Through bioassay-guided natural product research, it has been discovered that oleanolic acid and its glycosides possess an antibone resorption activity. Quinoxaline derivative of oleanolic acid (QOA-8a), a novel compound, is sourced from a structural modification of oleanolic acid. The aim of the present study was to evaluate the activities of QOA-8a on bone resorption in vitro and its osteoprotective effect in vivo.
  
  
  METHODS
  Osteoclast precursors and mature osteoclasts were used to assay antibone resorption activities in vitro. RAW264.7 cells cultured for 2 days in the presence of the receptor activator for nuclear factor κB ligand were used as osteoclast precursors. Mature osteoclasts were generated from either primary cultures of mouse bone marrow-derived macrophages or RAW264.7 cells. Eight-week-old female mice that underwent either ovariectomy or sham surgical operation were used for the evaluation of the osteoprotective effect of QOA-8a at doses of 0.1, 1, and 10 mg kg(-1) day(-1).
  
  
  RESULTS
  QOA-8a significantly inhibited the differentiation, formation, and bone resorptive activity of mature osteoclasts without cytotoxicity. QOA-8a selectively induced apoptosis at an early stage of mature osteoclasts at least via increasing the caspase-3 activity, but not osteoclast precursors. Furthermore, QOA-8a significantly prevented bone loss in ovariectomized mice without any hormone-like adverse effects, whereas the mice treated with 1 mg kg(-1) day(-1) kept the same bone mineral density level as that of the sham mice.
  
  
  CONCLUSIONS
  QOA-8a inhibits bone resorption without cytotoxicity and prevents bone loss without any hormone-like adverse effects. Although further investigations are necessary to elucidate the detailed molecular mechanisms, QOA-8a demonstrates great potential as a novel agent for the treatment of osteoporosis.
authors.affiliation: Key Lab of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yue
authors.initials: Y
authors.lastname: Huai
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.forename: Mei
authors.initials: M
authors.lastname: Geng
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Li
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy* / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects*; D010010:Osteoclasts / Q000187:drug effects*; D010052:Ovariectomy / Q000009:adverse effects; D011812:Quinuclidines / Q000494:pharmacology*
chemical_list: D011812:Quinuclidines