title: Activation of FGF receptors is a new mechanism by which strontium ranelate induces osteoblastic cell growth.
abstract: OBJECTIVE
  Strontium ranelate (SrRan) is an anti-osteoporotic treatment that reduces the risk of vertebral and hip fractures. Recent in vitro studies suggest that the effect of strontium ranelate on osteoblastic cell growth likely involves two processes including activation of the calcium sensing receptor (CaSR) and a yet undefined mechanism. In the present study, we investigated the CaSR-independent molecular mechanism by which SrRan stimulates osteoblast growth.
  
  
  METHODS
  MC3T3-E1 and primary osteoblastic cells, specific inhibitors of receptor tyrosine kinases (RTK) and western blot analysis were used to characterize the CaSR-independent mechanism in osteoblastic cells.
  
  
  RESULTS
  A selective inhibitor of FGF receptor but not other RTK inhibitors markedly blunted cell growth induced by SrRan in osteoblastic cells. Associated with this observation, SrRan induced rapid activation of FGFR signaling pathways such as PLCγ, FRS2, Akt, ERK1,2 and p38. FGFR-dependent stimulation of osteogenic cell growth was also observed with other cations but not with neomycin, a selective CaSR agonist. Also, in cultured conditions used in this study, MC3T3-E1 cells and primary osteoblasts did not express the CaSR.
  
  
  CONCLUSIONS
  data presented in this study suggest that activation of FGFRs is a new potential mechanism by which strontium can stimulate osteoblastic cell growth. Activation of FGFR-dependent cell growth is also observed in response to other cations suggesting that activation of FGF receptors is a new cation sensing mechanism in osteoblasts.
authors.affiliation: Service of Bone Diseases, Department of Rehabilitation and Geriatrics, University Hospital of Geneva, Geneva, Switzerland. Joseph.Caverzasio@unige.ch
authors.forename: Joseph
authors.initials: J
authors.lastname: Caverzasio
authors.forename: Cyril
authors.initials: C
authors.lastname: Thouverey
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013876:Thiophenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; C488187:FRS2alpha protein, mouse; D008565:Membrane Proteins; D009942:Organometallic Compounds; D044169:Receptors, Calcium-Sensing; D017468:Receptors, Fibroblast Growth Factor; D013876:Thiophenes; C081587:strontium ranelate; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases