Abstract
BackgroundOsteonecrosis 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.MethodsPrimary 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.ResultsPAI-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.ConclusionThe 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.
Highlights
Osteonecrosis of the femoral head is a common complication of high-dose glucocorticoid treatment
Plasminogen activator inhibitor-1 (PAI-1) and adiponectin mRNA expression regulated by dexamethasone or simvastatin PAI-1 and adiponectin mRNA expression in bone marrow adipocytes were examined by reverse transcription-polymerase chain reaction (RT-PCR)
PAI-1 mRNA expression was significantly up-regulated by 388% (P = 0.002) with dexamethasone and down-regulated by 45% (P = 0.002) with simvastatin, as compared to control levels (Figure 1A), while adiponectin mRNA expression was 95% with dexamethasone, and 125% with simvastatin (Figure 1B)
Summary
Osteonecrosis of the femoral head is a common complication of high-dose glucocorticoid treatment. We previously reported that adipokines and dexamethasone induced PAI-1 secretion from bone marrow adipocytes. Osteonecrosis of the femoral head (ONFH) is a common complication of high-dose glucocorticoid treatment. Steroids, such as glucocorticoids, have diverse activities throughout the body in multiple organs, and numerous disorders have been linked to hypercortisolism. Plasminogen activator inhibitor-1 (PAI-1), one of the adipokines secreted by adipocytes [13,14], suppresses fibrinolysis by binding tissue-type plasminogen activator (t-PA), and a relationship between PAI-1 and thrombosis or hypercoagulation has been suggested. We previously reported about dexamethasone-induced PAI-1 secretion from human bone marrow adipocytes [19]
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