[HTML][HTML] Bone morphogenetic protein (BMP)-4 and BMP-7 regulate differentially transforming growth factor (TGF)-β1 in normal human lung fibroblasts (NHLF)

S Pegorier, GA Campbell, AB Kay, CM Lloyd - Respiratory research, 2010 - Springer
S Pegorier, GA Campbell, AB Kay, CM Lloyd
Respiratory research, 2010Springer
Background Airway remodelling is thought to be under the control of a complex group of
molecules belonging to the Transforming Growth Factor (TGF)-superfamily. The Bone
Morphogenetic Proteins (BMPs) belong to this family and have been shown to regulate
fibrosis in kidney and liver diseases. However, the role of BMPs in lung remodelling remains
unclear. BMPs may regulate tissue remodelling in asthma by controlling TGF-β-induced
profibrotic functions in lung fibroblasts. Methods Cell cultures were exposed to TGF-β1 alone …
Background
Airway remodelling is thought to be under the control of a complex group of molecules belonging to the Transforming Growth Factor (TGF)-superfamily. The Bone Morphogenetic Proteins (BMPs) belong to this family and have been shown to regulate fibrosis in kidney and liver diseases. However, the role of BMPs in lung remodelling remains unclear. BMPs may regulate tissue remodelling in asthma by controlling TGF-β-induced profibrotic functions in lung fibroblasts.
Methods
Cell cultures were exposed to TGF-β1 alone or in the presence of BMP-4 or BMP-7; control cultures were exposed to medium only. Cell proliferation was assessed by quantification of the incorporation of [3H]-thymidine. The expression of the mRNA encoding collagen type I and IV, tenascin C and fibronectin in normal human lung fibroblasts (NHLF) was determined by real-time quantitative PCR and the main results were confirmed by ELISA. Cell differentiation was determined by the analysis of the expression of α-smooth muscle actin (α-SMA) by western blot and immunohistochemistry. The effect on matrix metalloproteinase (MMP) activity was assessed by zymography.
Results
We have demonstrated TGF-β1 induced upregulation of mRNAs encoding the extracellular matrix proteins, tenascin C, fibronectin and collagen type I and IV when compared to unstimulated NHLF, and confirmed these results at the protein level. BMP-4, but not BMP-7, reduced TGF-β1-induced extracellular matrix protein production. TGF-β1 induced an increase in the activity of the pro-form of MMP-2 which was inhibited by BMP-7 but not BMP-4. Both BMP-4 and BMP-7 downregulated TGF-β1-induced MMP-13 release compared to untreated and TGF-β1-treated cells. TGF-β1 also induced a myofibroblast-like transformation which was partially inhibited by BMP-7 but not BMP-4.
Conclusions
Our study suggests that some regulatory properties of BMP-7 may be tissue or cell type specific and unveil a potential regulatory role for BMP-4 in the regulation of lung fibroblast function.
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