title: Direct effects of osteoprotegerin on human bone cell metabolism.
abstract: OBJECTIVE
  Osteoprotegerin (OPG) affects bone metabolism by intercepting the RANK-RANKL interaction which prevents osteoclastic differentiation and consequently reduces bone resorption. Different bone phenotypes of mice overexpressing OPG and of mice with knockdown of receptor activator of NF-kappaB (RANK) or RANK-ligand (RANKL) suggest that the mechanism of action of the OPG-RANKL-RANK system in regulating bone remodeling is not completely understood. Furthermore, OPG increases bone mass and density independently from reduced osteoclastogenesis which is consistent with the possibility that OPG may directly affect bone metabolism beyond its known role as decoy receptor for RANKL.
  
  
  METHODS
  We treated primary human osteoblastic cells with OPG and inhibitory anti-RANKL antibodies and measured cellular ALP activity, in vitro mineralization, vitronectin receptor protein expression and ERK phosphorylation. We also analyzed the mRNA co-expression of ALP and OPG ex vivo in bone biopsies from acute and old stable vertebral fractures.
  
  
  RESULTS
  OPG directly increased ALP activity and in vitro mineralization of HOC, enhanced expression of the vitronectin receptor thereby increasing adherence of HOC to vitronectin and stimulated ERK phosphorylation. All OPG-mediated effects could be prevented by RANKL antibodies or RANKL-siRNA transfection and MAPK inhibitor PD98059 reduced the stimulatory effect of OPG on integrin alphav expression. In acutely fractured vertebrae OPG and ALP mRNA expression was significantly increased compared to stable vertebral fractures. In conclusion, OPG exerts direct osteoanabolic effects on HOC metabolism via RANKL in addition to its well described role as decoy receptor for RANKL.
authors.affiliation: Department of Medicine I and Clinical Chemistry, Division of Osteology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Grundt
authors.forename: Ingo Alexander
authors.initials: IA
authors.lastname: Grafe
authors.forename: Ute
authors.initials: U
authors.lastname: Liegibel
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sommer
authors.forename: Peter
authors.initials: P
authors.lastname: Nawroth
authors.forename: Christian
authors.initials: C
authors.lastname: Kasperk
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D010011:Osteocytes / Q000187:drug effects* / Q000378:metabolism; D053244:Osteoprotegerin / Q000494:pharmacology*; D053245:RANK Ligand / Q000378:metabolism; D016103:Spinal Fractures / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; D053244:Osteoprotegerin; D053245:RANK Ligand; D000469:Alkaline Phosphatase