title: Statins regulate interleukin-1β-induced RANKL and osteoprotegerin production by human gingival fibroblasts.
abstract: OBJECTIVE
  Three-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase competitive inhibitors, or 'statins', are widely used for lowering cholesterol and thereby reducing the risk of a heart attack. Recent data suggest that statins influence metabolic bone activity by their actions on three molecules: RANKL; RANK; and osteoprotegerin (OPG), the soluble decoy receptor for RANKL. The purpose of this study was to evaluate OPG and RANKL production in resting and interleukin-1β (IL-1β)-activated human gingival fibroblasts (HGFs), and to determine the effect of statins on their production.
  
  
  METHODS
  Fibroblasts were pre-incubated with atorvastatin or simvastatin for 24h in serum-free medium, and then incubated with IL-1β for 6d. The concentration of OPG or RANKL in culture supernatants was measured by specific ELISA. Data were analyzed using analysis of variance and Scheffe's F procedure for post hoc comparison.
  
  
  RESULTS
  IL-1β (1×10(-8) m) stimulated a significant increase in the production of OPG on days 1, 3 and 6. There was a trend towards an increase in RANKL production as a result of stimulation with IL-1β. Both statins, at multiple concentrations, significantly increased the constitutive RANKL/OPG ratio. Only atorvastatin at the highest concentration (5×10(-6)  m) significantly increased the IL-1β-stimulated RANKL/OPG ratio.
  
  
  CONCLUSIONS
  IL-1β significantly increased OPG production by HGFs. The statins differed minimally in their effects on OPG and RANKL production by resting and IL-1β-activated HGFs. Both statins increased constitutive RANKL/OPG ratios, but generally not IL-1β-stimulated ratios. Thus, statins may influence the production of RANKL and OPG by HGFs to favor bone catabolism, under noninflammatory conditions.
authors.affiliation: Department of Periodontology, College of Dentistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA. sstein@uthsc.edu
authors.forename: S H
authors.initials: SH
authors.lastname: Stein
authors.forename: I N
authors.initials: IN
authors.lastname: Dean
authors.forename: S Y
authors.initials: SY
authors.lastname: Rawal
authors.forename: D A
authors.initials: DA
authors.lastname: Tipton
mesh_terms: D000069059:Atorvastatin; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004396:Coloring Agents; D016895:Culture Media, Serum-Free; D005347:Fibroblasts / Q000187:drug effects*; D005881:Gingiva / Q000166:cytology / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D053583:Interleukin-1beta / Q000494:pharmacology*; D053244:Osteoprotegerin / Q000032:analysis / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology / Q000633:toxicity; D053245:RANK Ligand / Q000032:analysis / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology / Q000633:toxicity; D013696:Temperature; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors
chemical_list: D004396:Coloring Agents; D016895:Culture Media, Serum-Free; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D053244:Osteoprotegerin; D011758:Pyrroles; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; D000069059:Atorvastatin; D019821:Simvastatin; C022616:thiazolyl blue