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Simvastatin Suppresses Osteoblastic Expression of Cyr61 and Progression of Apical Periodontitis through Enhancement of the Transcription Factor Forkhead/Winged Helix Box Protein O3a
- Source :
- Journal of Endodontics. 39:619-625
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
Abstract
- Introduction In this study, the role of transcription factor Forkhead/winged helix box protein O3a (FoxO3a) in Cyr61 expression and its modulation by simvastatin were investigated in cultured murine osteoblasts and a rat model of induced apical periodontitis. We also examined the effects of simvastatin on the synthesis of chemokine CCL2 and chemotaxis of macrophages in vitro . Methods We assessed tumor necrosis factor (TNF)-α–stimulated expression of Cyr61 and phosphorylated inactive FoxO3a (p-FoxO3a) in MC3T3-E1 murine osteoblasts by Western analysis. Forced expression of FoxO3a by lentiviral-based gene transduction was performed, and its effect on Cyr61 expression was evaluated. The modulation of CCL2 secretion and macrophage chemotaxis by simvastatin were examined by enzyme-linked immunosorbent assay and transwell migration assay, respectively. In a rat model of induced apical periodontitis, the relation between disease progression and osteoblastic expression of Cyr61, p-FoxO3a, and CCL2 and macrophage recruitment were studied by radiographic and immunohistochemistry analyses. Results Western blot analysis showed enhanced expression of Cyr61 and p-FoxO3a after TNF-α treatment in a time-dependent manner. Simvastatin significantly counteracted the actions of TNF-α. Forced expression of FoxO3a reduced TNF-α–stimulated Cyr61 synthesis. Simvastatin and FoxO3a diminished TNF-α–induced CCL2 secretion and macrophage recruitment, whereas Cyr61 partially restored the stimulating action. In rat periapical lesions, simvastatin significantly attenuated bone resorption, reduced osteoblastic expressions of Cyr61, p-FoxO3a, and CCL2, and suppressed macrophage recruitment. Conclusions Simvastatin may alleviate periapical lesions by enhancing FoxO3a activity to suppress the synthesis of Cyr61 in osteoblasts. Moreover, the downstream effector mechanism of Cyr61 may involve CCL2 production and macrophage recruitment.
- Subjects :
- Simvastatin
Chemokine
medicine.medical_specialty
Alveolar Bone Loss
Biology
CCL2
Cell Line
Macrophage chemotaxis
Rats, Sprague-Dawley
Mice
Internal medicine
medicine
Animals
General Dentistry
Transcription factor
Chemokine CCL2
Osteoblasts
Tumor Necrosis Factor-alpha
Chemotaxis
Macrophages
Forkhead Box Protein O3
Forkhead Transcription Factors
3T3 Cells
Radiography, Dental, Digital
Rats
Cell biology
Disease Models, Animal
Endocrinology
Disease Progression
biology.protein
Tumor necrosis factor alpha
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Periapical Periodontitis
Cysteine-Rich Protein 61
medicine.drug
Subjects
Details
- ISSN :
- 00992399
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- Journal of Endodontics
- Accession number :
- edsair.doi.dedup.....ba34621815332a7568698f36072a770c