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Metformin alleviates hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts through inhibiting the TLR4 signaling pathway
- Source :
- Life sciences. 216
- Publication Year :
- 2018
-
Abstract
- Aims Metformin was found to protect against hyperglycemia-induced injury in osteoblasts, but the cellular mechanisms involved remain unclear. Therefore, the aim of this study was to determine the effect of metformin on hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts and to explore its relationships with the TLR4 signaling pathway. Main methods A mouse osteoblast cell line, MC3T3-E1, and a diabetic rat model were used to survey the protective effects of metformin on hyperglycemia-induced injury. TLR4 expression was altered using small interfering (si)RNA and lentivirus-mediated TLR4 overexpression. LPS was used as a specific TLR4 activator, and CLI-095 was used as a TLR4 inhibitor. Key findings Metformin improved osteoblast differentiation, reduced apoptosis in hyperglycemic osteoblasts, and inhibited TLR4, MyD88 and NF-κB expression in a dose-dependent manner. Down-regulating the expression or inhibiting the activity of TLR4 enhanced these protective effects of metformin on osteoblast differentiation, cell viability and cell apoptosis in hyperglycemic conditions, whereas up-regulating the expression or activating the activity of TLR4 had the opposite effects. Activating NF-κB suppressed the protective effects of metformin, while inhibiting NF-κB activity had the opposite effects. Metformin increased ALP and OCN secretion, enhanced BMP-2 expression, improved bone mineral density (BMD), and decreased TLR4, MyD88 and NF-κB levels in the femur tissues of diabetic rats. Significance Taken together our experimentation support the hypothesis that metformin may alleviate hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts by inhibiting the TLR4/MyD88/NF-κB signaling pathway.
- Subjects :
- 0301 basic medicine
Male
endocrine system diseases
Bone Morphogenetic Protein 2
Down-Regulation
Apoptosis
030226 pharmacology & pharmacy
General Biochemistry, Genetics and Molecular Biology
Cell Line
Diabetes Mellitus, Experimental
Rats, Sprague-Dawley
03 medical and health sciences
Mice
0302 clinical medicine
Bone Density
Transforming Growth Factor beta
medicine
Animals
Hypoglycemic Agents
Secretion
Viability assay
General Pharmacology, Toxicology and Pharmaceutics
Osteoblasts
Activator (genetics)
Chemistry
NF-kappa B
nutritional and metabolic diseases
Osteoblast
Cell Differentiation
General Medicine
Metformin
Recombinant Proteins
Rats
Up-Regulation
Toll-Like Receptor 4
030104 developmental biology
medicine.anatomical_structure
Hyperglycemia
Cancer research
TLR4
Signal transduction
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 18790631
- Volume :
- 216
- Database :
- OpenAIRE
- Journal :
- Life sciences
- Accession number :
- edsair.doi.dedup.....b898af2f57f37f79036ccfaf83e634c0