title: Protein geranylgeranylation controls collagenase expression in osteoarthritic cartilage.
abstract: OBJECTIVE
  Statins possess anti-inflammatory properties. This study was undertaken to characterize the mechanism of action of statin drugs on collagenase expression in primary human osteoarthritic cartilage tissue.
  
  
  METHODS
  Human articular chondrocytes and cartilage explants from osteoarthritic donors were exposed to simvastatin in the presence or absence of interleukin-1 beta (IL-1beta). Collagenase expression was determined by quantifying levels of matrix metalloproteinase 13 (MMP-13) and MMP-1 mRNA and MMP-13 protein. The mechanism of statin action was tested by addition of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) or by using inhibitors of farnesyl transferase (FT) and geranylgeranyl transferase (GGT-1).
  
  
  RESULTS
  Treatment of osteoarthritic chondrocytes with simvastatin decreased mRNA levels of MMP-13 and MMP-1 whether under basal conditions or during stimulation with IL-1beta. MMP-13 protein secreted into the culture media was also decreased. Genes involved in cartilage synthesis (type II collagen and aggrecan) were not down-regulated by simvastatin. Exogenous addition of GGPP completely reversed the statin-mediated decrease in MMP-13 mRNA and protein levels whereas FPP partially reversed the statin-mediated effect. An inhibitor of GGT-1 mimicked the simvastatin-mediated reduction in MMP-13 expression by chondrocytes. Finally, consistent with impacts on MMP-13 and MMP-1 expression, simvastatin as well as the GGT-1 inhibitor both blocked type II collagen degradation in primary human articular cartilage explants.
  
  
  CONCLUSIONS
  These results suggest that statins modulate chondrocyte metabolism by reducing prenylation of key signaling molecules that control the expression of collagen-degrading enzymes. Our results strongly support the hypothesis that protein prenyltransferases including geranylgeranyl transferase regulate chondrocyte collagenase expression in osteoarthritis.
authors.affiliation: Pfizer Global Research and Development, Chesterfield, MO 63017, USA. fsverdrup@charter.net
authors.forename: Francis M
authors.initials: FM
authors.lastname: Sverdrup
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Yates
authors.forename: Lillian E
authors.initials: LE
authors.lastname: Vickery
authors.forename: Jon A
authors.initials: JA
authors.lastname: Klover
authors.forename: Lily R-H
authors.initials: LR
authors.lastname: Song
authors.forename: Charles P
authors.initials: CP
authors.lastname: Anglin
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Misko
mesh_terms: D000704:Analysis of Variance; D002358:Cartilage, Articular / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects*; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects* / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D017364:Collagenases