Effects of metformin on knee joint capsule fibrosis in a diabetic mouse model
Toichiro Naito1, Yoshiaki Yamanaka1, Kotaro Tokuda1
1Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Aims:
The antidiabetic agent metformin inhibits fibrosis in various organs. This study aims to elucidate the effects of hyperglycaemia and metformin on knee joint capsule fibrosis in mice.
Methods:
Eight-week-old wild-type (WT) and type 2 diabetic (db/db) mice were divided into four groups without or with metformin treatment (WT met(-/+), Db met(-/+)). Mice received daily intraperitoneal administration of metformin and were killed at 12 and 14 weeks of age. Fibrosis morphology and its related genes and proteins were evaluated. Fibroblasts were extracted from the capsules of 14-week-old mice, and the expression of fibrosis-related genes in response to glucose and metformin was evaluated in vitro.
Results:
The expression of all fibrosis-related genes was higher in Db met(-) than in WT met(-) and was suppressed by metformin. Increased levels of fibrosis-related genes, posterior capsule thickness, and collagen density were observed in the capsules of db/db mice compared with those in WT mice; these effects were suppressed by metformin. Glucose addition increased fibrosis-related gene expression in both groups of mice in vitro. When glucose was added, metformin inhibited the expression of fibrosis-related genes other than cellular communication network factor 2 (Ccn2) in WT mouse cells.
Conclusion:
Hyperglycaemia promotes fibrosis in the mouse knee joint capsule, which is inhibited by metformin. These findings can help inform the development of novel strategies for treating knee joint capsule fibrosis.
Insights
Metformin, an antidiabetic drug, effectively inhibits knee joint capsule fibrosis in mice. This study demonstrates that hyperglycemia promotes fibrosis, while metformin treatment mitigates these effects.
Area of Science:
- Biomedical research
- Pharmacology
- Fibrosis research
Background:
- Metformin is known to inhibit fibrosis across various organs.
- Knee joint capsule fibrosis is a significant clinical concern.
Purpose of the Study:
- To investigate the impact of hyperglycemia and metformin on knee joint capsule fibrosis in a mouse model.
- To elucidate the molecular mechanisms underlying metformin's antifibrotic effects in this context.
Main Methods:
- Utilized wild-type and type 2 diabetic (db/db) mice, treated with or without metformin.
- Assessed fibrosis markers, including gene and protein expression, capsule thickness, and collagen density.
- Conducted in vitro experiments using mouse fibroblasts to evaluate responses to glucose and metformin.
Main Results:
- Diabetic mice exhibited significantly higher fibrosis-related gene expression and collagen density compared to wild-type mice.
- Metformin treatment suppressed fibrosis markers in diabetic mice.
- In vitro, glucose exacerbated fibrosis-related gene expression, an effect largely inhibited by metformin, except for CCN2.
Conclusions:
- Hyperglycemia is a key driver of knee joint capsule fibrosis in mice.
- Metformin demonstrates potent antifibrotic properties in the knee joint capsule, offering potential therapeutic benefits.
- Findings support the development of metformin-based strategies for treating knee joint capsule fibrosis.
