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Effects of different concentrations of metformin on osteoclast differentiation and apoptosis and its mechanism
Feng Bian1, Yufeng Zhang1, YuanLong Xie1
1Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, People's Republic of China.
Abstract:
This study aimed to investigate the effect of metformin on osteoclast differentiation and apoptosis. Low concentration of metformin inhibited osteoclast differentiation and downregulated the expression of TRAP, RANK, Cathepsink, NFATC-1, MMP-9 and TRAF-6. High concentration of metformin promoted osteoclast apoptosis and upregulated the expression of Bax/Bcl-2 and caspase-3; BV/TV, BS/TV, Tb.N and BMD were increased while Tp.Sp decreased in the group of intraperitoneal metformin+femoral intramedullary osteoclast injection (Met+OC) compared with the control group, 1 nM metformin downregulated Akt, p44/42 MAPK, JNK, p38 MAPK phosphorylation, 5 nM metformin down regulated ERK and Akt phosphorylation. These results suggest that a low concentration of metformin inhibits osteoclast differentiation through PI3K/Akt and MAPK/ERK signaling pathway; high concentrations of metformin promote osteoclast apoptosis through PI3K/Akt and ERK signaling pathway.
Insights
Metformin affects bone health by influencing osteoclasts. Low doses inhibit osteoclast differentiation, while high doses promote osteoclast apoptosis, impacting bone structure and density.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Osteoclasts are crucial for bone remodeling.
- Dysregulated osteoclast activity contributes to bone diseases.
- Metformin is a widely used antidiabetic drug with potential pleiotropic effects.
Purpose of the Study:
- To investigate the dual effects of metformin on osteoclast differentiation and apoptosis.
- To elucidate the underlying molecular mechanisms and signaling pathways involved.
Main Methods:
- In vitro studies on osteoclast differentiation.
- In vivo assessment of bone microarchitecture following metformin administration.
- Western blot analysis to evaluate protein phosphorylation in signaling pathways.
Main Results:
- Low metformin concentrations inhibited osteoclast differentiation markers (TRAP, RANK, NFATC-1, MMP-9).
- High metformin concentrations induced osteoclast apoptosis (Bax/Bcl-2, caspase-3).
- Metformin treatment improved bone parameters (BV/TV, BMD) and modulated signaling pathways (PI3K/Akt, MAPK).
Conclusions:
- Metformin exhibits concentration-dependent effects on osteoclasts.
- Low-dose metformin suppresses osteoclastogenesis via PI3K/Akt and MAPK/ERK pathways.
- High-dose metformin promotes osteoclast apoptosis through PI3K/Akt and ERK signaling.
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