title: Simvastatin suppresses dexamethasone-induced secretion of plasminogen activator inhibitor-1 in human bone marrow adipocytes.
abstract: BACKGROUND
  Osteonecrosis of the femoral head is a common complication of high-dose glucocorticoid treatment. Intravascular thrombosis is thought to be associated with the ischemic state of the femoral head. Plasminogen activator inhibitor-1 (PAI-1) is an adipokine, which are physiologically active substances secreted from visceral and subcutaneous adipocytes. PAI-1 suppresses fibrinolysis by binding tissue-type plasminogen activator. Several reports have described the relationship between PAI-1 and steroid-induced osteonecrosis of the femoral head, and the preventive effects of lipid-lowering agents (statins) against steroid-induced osteonecrosis of the femoral head. We previously reported that adipokines and dexamethasone induced PAI-1 secretion from bone marrow adipocytes. The purpose of the present study is to examine the effects of simvastatin on PAI-1 secretion from human bone marrow adipocytes in vitro.
  
  
  METHODS
  Primary bone marrow adipocytes were extracted from collagenase-treated bone marrow fluid obtained from the femoral necks of 40 patients (6 men, 34 women; age range, 52-81 years) undergoing hip joint replacement surgery. After suspended culture with or without dexamethasone or simvastatin, PAI-1 mRNA expression was assessed by real-time RT-PCR. Total PAI-1 protein secretion in culture medium was assessed by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  PAI-1 mRNA expression was up-regulated by 388% (P=0.002) with dexamethasone, and down-regulated by 45% (P=0.002) with simvastatin, as compared to control levels. Dexamethasone increased total PAI-1 secretion by 166% (P=0.001) and simvastatin decreased total PAI-1 secretion by 64% (P=0.002). No significant changes were observed in adiponectin mRNA expression and secretion by dexamethasone and simvastatin, while pre-treatment with simvastatin reversed dexamethasone induced PAI-1 secretion by 89%, as compared to control levels.
  
  
  CONCLUSIONS
  The present study confirmed the suppressive effects of simvastatin on PAI-1 expression and secretion from bone marrow adipocytes. Furthermore, pre-treatment with simvastatin reversed dexamethasone induced PAI-1 secretion. Simvastatin may thus exhibit preventive effects against steroid-induced osteonecrosis of the femoral head by suppressing PAI-1 secretion.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Biomedical Science, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, Nagasaki 852-8501, Japan. mosaki@nagasaki-u.ac.jp.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Osaki
authors.forename: Akira
authors.initials: A
authors.lastname: Hozumi
authors.forename: Hisataka
authors.initials: H
authors.lastname: Goto
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fukushima
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shindo
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005272:Femur Neck / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000633:toxicity*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; D005938:Glucocorticoids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051321:SERPINE1 protein, human; D003907:Dexamethasone; D019821:Simvastatin