title: The cross-talk between osteoclasts and osteoblasts in response to strontium treatment: involvement of osteoprotegerin.
abstract: BACKGROUND
  The mechanism for the uncoupling effects of Sr on bone remains to be evaluated. Osteoblasts play important roles in osteoclastogenesis through regulating receptor activated nuclear factor kappa B (RANK) ligand (RANKL) and osteoprotegerin (OPG) expression. We hypothesize that OPG plays an important role in the cross-talk between osteoclasts and osteoblasts in response to Sr treatment.
  
  
  METHODS
  MC3T3E1 cells were treated with Sr chloride (0-3 mM) and conditioned media were collected at 24h after the treatment. The effect of conditioned media on osteoclastogenesis was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and bone resorption pits analysis. OPG and RANKL mRNA expressions in osteoblastic cells and protein secretion in the conditioned media were analyzed with real-time PCR and ELISA assay, respectively. The role of OPG in Sr-mediated inhibition of osteoclastogenesis was further evaluated with anti-OPG antibody in pre-osteoclastic cells. The role of OPG in Sr-mediated uncoupling effects on osteoporotic bone was evaluated by an animal study. Ovariectomized rats were oral administrated with vehicle or Sr chloride for two months supplemented with anti-IgG antibody (control) or anti-OPG antibody. The effects of OPG neutralization after Sr treatment on bone metabolism were analyzed by microCT, bone histomorphometry and biochemical analysis.
  
  
  RESULTS
  The conditioned media derived from Sr-treated osteoblastic cells exerted a dose-dependent inhibitory effect on osteoclastic differentiation and resorptive activity in pre-osteoclastic cells. OPG mRNA expression and protein secretion in osteoblastic cells were significantly increased after Sr treatment. Neutralization with anti-OPG antibody abolished the inhibitory effect of conditioned media on RANKL-induced osteoclastogenesis. The uncoupling effects of Sr treatment on trabecular bone were evidenced by greater bone volume and trabecular number, greater osteoid surface and bone formation rate, while less osteoclast surface. These effects were attenuated by the OPG neutralization by anti-OPG antibody injection.
  
  
  CONCLUSIONS
  The evidences from the in vitro and in vivo studies suggested that OPG played an important role in the uncoupling effect of Sr on bone metabolism, possibly by acting as a cross-talk molecule between osteoclasts and osteoblasts in response to Sr treatment.
authors.affiliation: Department of Spine Surgery, Shenzhen People's Hospital, Jinan University School of Medicine, Shenzhen, China.
authors.forename: Songlin
authors.initials: S
authors.lastname: Peng
authors.forename: X Sherry
authors.initials: XS
authors.lastname: Liu
authors.forename: Shishu
authors.initials: S
authors.lastname: Huang
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Li
authors.forename: Haobo
authors.initials: H
authors.lastname: Pan
authors.forename: Wanxin
authors.initials: W
authors.lastname: Zhen
authors.forename: K D K
authors.initials: KD
authors.lastname: Luk
authors.forename: X Edward
authors.initials: XE
authors.lastname: Guo
authors.forename: W William
authors.initials: WW
authors.lastname: Lu
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001862:Bone Resorption / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism*; D010052:Ovariectomy; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013324:Strontium / Q000494:pharmacology* / Q000627:therapeutic use; D013977:Tibia / Q000187:drug effects / Q000473:pathology
chemical_list: D045930:Anabolic Agents; D057134:Antibodies, Neutralizing; D017077:Culture Media, Conditioned; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D013324:Strontium