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MicroRNA-130b regulates scleroderma fibrosis by targeting peroxisome proliferator-activated receptor γ
Hui Luo1, Honglin Zhu, Bin Zhou
1Department of Rheumatology, Xiangya Hospital, Central South University , Changsha, Hunan , P. R. China.
Objectives:
To investigate the role of microRNA-130b (miR-130b) in systemic sclerosis (SSc) skin fibrosis and its regulatory effect on peroxisome proliferator-activated receptor γ (PPARγ).
Methods:
miR-130b was identified from microarray analyses in our previous studies. The expression of miR-130b, PPARγ, and fibrosis-related genes were determined by real-time PCR analysis. PPARγ protein levels were detected by immunohistochemistry and Western blot. Cells were transfected with microRNA mimics/inhibitor/scramble of miR-130b using Lipofectamine. Luciferase reporter gene assays were used to identify the direct target of miR-130b. Transforming growth factor β (TGF-β) was used for stimulation.
Results:
The expression of miR-130b was significantly upregulated and level of PPARγ was decreased in the dermis of the SSc skin biopsy samples and fibroblasts. Similar to human SSc, the same expression patterns of miR-130b, PPARγ, and fibrosis-related genes were observed in the bleomycin-induced skin fibrosis model; TGF-β induced the expression of miR-130b and fibrosis-related genes expression, but downregulated the expression of PPARγ. Overexpression of miR-130b in normal or SSc skin fibroblasts significantly decreased, and accordingly, knockdown of miR-130b increased the levels of PPARγ and fibrosis-related genes. In the reporter gene assay, cotransfection with miR-130b mimics significantly decreased the relative luciferase activity, which suggested a direct regulation of PPARγ by miR-130b.
Conclusions:
These studies demonstrated that miR-130b played important profibrotic roles in SSc fibrosis, and enhanced TGF-β signaling through negative regulation of PPARγ expression. MiR-130b may be a potential therapeutic target in SSc fibrosis.
Insights
MicroRNA-130b (miR-130b) promotes systemic sclerosis (SSc) skin fibrosis by downregulating peroxisome proliferator-activated receptor γ (PPARγ). Inhibiting miR-130b may offer a therapeutic strategy for SSc fibrosis.
Area of Science:
- Dermatology
- Molecular Biology
- Fibrosis Research
Background:
- Systemic sclerosis (SSc) is characterized by skin fibrosis.
- The role of microRNAs in SSc pathogenesis is increasingly recognized.
- Peroxisome proliferator-activated receptor γ (PPARγ) is implicated in fibrotic processes.
Purpose of the Study:
- To investigate the role of microRNA-130b (miR-130b) in SSc skin fibrosis.
- To determine the regulatory effect of miR-130b on PPARγ expression in SSc.
Main Methods:
- Microarray analysis to identify miR-130b.
- Real-time PCR, immunohistochemistry, and Western blot to assess gene and protein expression.
- Cell transfection with miR-130b mimics/inhibitors.
- Luciferase reporter gene assays to confirm direct targeting.
Main Results:
- miR-130b was upregulated, and PPARγ was downregulated in SSc skin and fibroblasts.
- Bleomycin-induced fibrosis model mirrored these expression patterns.
- Transforming growth factor β (TGF-β) upregulated miR-130b and fibrosis genes while downregulating PPARγ.
- miR-130b directly targeted and downregulated PPARγ, promoting fibrosis.
Conclusions:
- miR-130b plays a profibrotic role in SSc by negatively regulating PPARγ.
- Enhanced TGF-β signaling is mediated by miR-130b's suppression of PPARγ.
- miR-130b represents a potential therapeutic target for SSc fibrosis.
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