Metformin alleviates hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts through inhibiting the TLR4 signaling pathway.

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.

• Authors: Lifeng Zheng, Ximei Shen, Junjian Ye, Yun Xie, Sunjie Yan
• Journal: Life sciences (Life Sci) Vol. 216 Pg. 29-38 (Jan 01 2019) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 30414431 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Bone Morphogenetic Protein 2
• Hypoglycemic Agents
• NF-kappa B
• Recombinant Proteins
• Tlr4 protein, mouse
• Tlr4 protein, rat
• Toll-Like Receptor 4
• Transforming Growth Factor beta
• recombinant human bone morphogenetic protein-2
• Metformin

Topics

• Animals
• Apoptosis (drug effects)
• Bone Density (drug effects)
• Bone Morphogenetic Protein 2 (genetics)
• Cell Differentiation (drug effects)
• Cell Line
• Diabetes Mellitus, Experimental (drug therapy, physiopathology)
• Down-Regulation (drug effects)
• Hyperglycemia (complications, drug therapy)
• Hypoglycemic Agents (pharmacology)
• Male
• Metformin (pharmacology)
• Mice
• NF-kappa B (metabolism)
• Osteoblasts (drug effects, pathology)
• Rats
• Rats, Sprague-Dawley
• Recombinant Proteins (genetics)
• Signal Transduction (drug effects)
• Toll-Like Receptor 4
• Transforming Growth Factor beta (genetics)
• Up-Regulation (drug effects)