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Simvastatin suppresses dexamethasone-induced secretion of plasminogen activator inhibitor-1 in human bone marrow
Kazutaka Sakamoto1, Makoto Osaki, Akira Hozumi
1Department of Orthopaedic Surgery, Graduate School of Biomedical Science, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, Nagasaki 852-8501, Japan. mosaki@nagasaki-u.ac.jp.
Insights
Simvastatin effectively reduces plasminogen activator inhibitor-1 (PAI-1) secretion from bone marrow adipocytes. This finding suggests simvastatin may prevent steroid-induced osteonecrosis of the femoral head by inhibiting PAI-1.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Osteonecrosis of the femoral head is a complication of high-dose glucocorticoid treatment, potentially linked to intravascular thrombosis.
- Plasminogen activator inhibitor-1 (PAI-1), an adipokine, suppresses fibrinolysis and has been associated with steroid-induced osteonecrosis.
- Previous research indicated adipokines and dexamethasone induce PAI-1 secretion from bone marrow adipocytes.
Purpose of the Study:
- To investigate the effects of simvastatin on PAI-1 secretion from human bone marrow adipocytes in vitro.
- To determine if simvastatin can counteract dexamethasone-induced PAI-1 secretion.
Main Methods:
- Human bone marrow adipocytes were isolated from patients undergoing hip replacement surgery.
- Cells were cultured with or without dexamethasone and/or simvastatin.
- PAI-1 mRNA expression and protein secretion were quantified using real-time RT-PCR and ELISA, respectively.
Main Results:
- Dexamethasone significantly upregulated PAI-1 mRNA expression and secretion.
- Simvastatin significantly downregulated PAI-1 mRNA expression and secretion.
- Simvastatin pre-treatment reversed dexamethasone-induced PAI-1 secretion by 89%.
Conclusions:
- Simvastatin suppresses PAI-1 expression and secretion in bone marrow adipocytes.
- Simvastatin may prevent steroid-induced osteonecrosis of the femoral head by inhibiting PAI-1 secretion.
- The findings support a potential therapeutic role for simvastatin in managing steroid-induced osteonecrosis.
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.
Conclusion:
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.
