title: Risedronate inhibits bone marrow mesenchymal stem cell adipogenesis and switches RANKL/OPG ratio to impair osteoclast differentiation.
abstract: BACKGROUND
  Osteoporosis is accompanied by an increase in bone marrow adipose tissue. Bone marrow adipogenesis has emerged as a therapeutic target for prevention of bone loss. Amino-bisphosphonates have been widely used for treatment of osteoporosis, but the mechanism through which amino-bisphosphonates inhibit osteoporosis remains unclear. The purpose of this study is to investigate the effects of bisphosphonates on bone marrow adipogenesis and the pro-osteoclastic factors produced by adipocytes in bone marrow microenvironment.
  
  
  METHODS
  Human mesenchymal stem cells were obtained and purified from six volunteer donors. Each sample of cells was treated by increasing concentrations of risedronate with or without adipogenic induction for 14 d, and then droplets of the differentiated adipocytes were analyzed. The level of receptor activator of nuclear factor-κB ligand and osteoprotegerin, as well as pro-osteoclastic inflammatory factors interleukin-1, interleukin-6, and tumor necrosis factor α produced by adipocytes were evaluated by Western blot and ELISA assay. Moreover, the effect of risedronate on the activity of mammalian target of rapamycin complex 1, a key Ser/Thr kinase for initiation of adipocyte differentiation, was investigated.
  
  
  RESULTS
  Risedronate not only dose-dependently inhibited the bone marrow adipogenesis from human mesenchymal stem cells but also suppressed receptor activator of nuclear factor-κB ligand, not osteoprotegerin, expression in differentiated adipocytes, as well as pro-osteoclastic inflammatory factors. Furthermore, the activity of mammalian target of rapamycin complex 1 was suppressed by risedronate.
  
  
  CONCLUSIONS
  Our findings that risedronate influences the crosstalk between bone marrow adipocyte-osteoclast represent a novel mechanism for the anti-osteoporotic effects of risedronate.
authors.affiliation: Department of Spine Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Xiao-Kai
authors.initials: XK
authors.lastname: Wang
authors.forename: Ping-Lin
authors.initials: PL
authors.lastname: Lai
authors.forename: Min-Jun
authors.initials: MJ
authors.lastname: Huang
authors.forename: Da-di
authors.initials: DD
authors.lastname: Jin
authors.forename: Zhao-Ming
authors.initials: ZM
authors.lastname: Zhong
authors.forename: Jian-Ting
authors.initials: JT
authors.lastname: Chen
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Bai
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D053244:Osteoprotegerin / Q000032:analysis*; D053245:RANK Ligand / Q000032:analysis*; D000068296:Risedronic Acid; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D050071:Bone Density Conservation Agents; D046912:Multiprotein Complexes; D053244:Osteoprotegerin; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000068296:Risedronic Acid; D012968:Etidronic Acid