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Vitamin D Inhibits TGF-β1-Induced Myofibroblast Differentiation and Extracellular Matrix Production Via Smad2/3 Signaling Pathway in Nasal Polyp-Derived Fibroblasts
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A5738 - Vitamin D Inhibits TGF-β1-Induced Myofibroblast Differentiation and Extracellular Matrix Production Via Smad2/3 Signaling Pathway in Nasal Polyp-Derived Fibroblasts
Author Block: J. Shin1, H. Yang2, S. Lee3, J. Park2, H. Lee1; 1Department of Otorhinolaryngology-Head and Neck Surgery, Korea University, College of Medicine, Seoul, Korea, Republic of, 2Department of Biomedical Science, Korea University, College of Medicine, Seoul, Korea, Republic of, 3Institute for Medical Devices Translation Clinical Trial Support Center, Korea University Guro Hospital, Seoul, Korea, Republic of.
Purpose: Nasal polyps are associated with chronic inflammation of the mucous membranes in the nose and paranasal sinuses and involved in extracellular matrix (ECM) accumulation. Vitamin D has a wide range of antifibrotic properties, including anti-inflammation, anti-proliferation, anti-apoptosis, and anti-epithelial-mesenchymal transition properties. This study aimed to determine whether vitamin D affects the myofibroblast differentiation and extracellular matrix synthesis and to investigate the mechanism of action of vitamin D in nasal polyp-derived fibroblasts (NPDFs). Methods: To investigate the potential role of vitamin D (1,25(OH)2D3) in preventing the development of nasal polyps, we examined the effect of vitamin D on myofibroblast differentiation and ECM production in TGF-β1-induced NPDFs and elucidated the mechanisms underlying the inhibitory effect. 1,25(OH)2D3 significantly reduced the expression levels of α-SMA, a myofibroblast marker, and fibronectin, a representative ECM component, in a dose-dependent manner in TGF-β1-NPDFs. Results: 1,25(OH)2D3 suppressed activated Smad2/3 in time-course. Up-regulation of α-SMA, fibronectin and phosphorylation of Smad2/3 by TGF-β1 were unaffected by 1,25(OH)2D3 in NPDFs after vitamin D receptor specific siRNA transfection. We confirmed inactivation of Smad2/3 and reduced level of α-SMA and fibronectin expression by the Smad2/3 specific inhibitor, SIS3. Furthermore, acetylation of histone H3 was compromised by 1,25(OH)2D3, leading to inhibition of collagen 1A1, collagen 1A2 and α-SMA gene expression. Treatment with 1,25(OH)2D3 also significantly suppressed TGF-β1-enhanced contractility and motility in a contraction assay and Transwell migration assay. Finally, 1,25(OH)2D3 had a similar effect in ex vivo organ cultures of nasal polyps. Conclusions: Our results suggest that 1,25(OH)2D3 might be an effective therapy for treating nasal polyps by reducing myofibroblast differentiation and ECM production mediated by Smad2/3-dependent TGF-β1 signaling pathways in NPDFs.
Author Block: J. Shin1, H. Yang2, S. Lee3, J. Park2, H. Lee1; 1Department of Otorhinolaryngology-Head and Neck Surgery, Korea University, College of Medicine, Seoul, Korea, Republic of, 2Department of Biomedical Science, Korea University, College of Medicine, Seoul, Korea, Republic of, 3Institute for Medical Devices Translation Clinical Trial Support Center, Korea University Guro Hospital, Seoul, Korea, Republic of.
Purpose: Nasal polyps are associated with chronic inflammation of the mucous membranes in the nose and paranasal sinuses and involved in extracellular matrix (ECM) accumulation. Vitamin D has a wide range of antifibrotic properties, including anti-inflammation, anti-proliferation, anti-apoptosis, and anti-epithelial-mesenchymal transition properties. This study aimed to determine whether vitamin D affects the myofibroblast differentiation and extracellular matrix synthesis and to investigate the mechanism of action of vitamin D in nasal polyp-derived fibroblasts (NPDFs). Methods: To investigate the potential role of vitamin D (1,25(OH)2D3) in preventing the development of nasal polyps, we examined the effect of vitamin D on myofibroblast differentiation and ECM production in TGF-β1-induced NPDFs and elucidated the mechanisms underlying the inhibitory effect. 1,25(OH)2D3 significantly reduced the expression levels of α-SMA, a myofibroblast marker, and fibronectin, a representative ECM component, in a dose-dependent manner in TGF-β1-NPDFs. Results: 1,25(OH)2D3 suppressed activated Smad2/3 in time-course. Up-regulation of α-SMA, fibronectin and phosphorylation of Smad2/3 by TGF-β1 were unaffected by 1,25(OH)2D3 in NPDFs after vitamin D receptor specific siRNA transfection. We confirmed inactivation of Smad2/3 and reduced level of α-SMA and fibronectin expression by the Smad2/3 specific inhibitor, SIS3. Furthermore, acetylation of histone H3 was compromised by 1,25(OH)2D3, leading to inhibition of collagen 1A1, collagen 1A2 and α-SMA gene expression. Treatment with 1,25(OH)2D3 also significantly suppressed TGF-β1-enhanced contractility and motility in a contraction assay and Transwell migration assay. Finally, 1,25(OH)2D3 had a similar effect in ex vivo organ cultures of nasal polyps. Conclusions: Our results suggest that 1,25(OH)2D3 might be an effective therapy for treating nasal polyps by reducing myofibroblast differentiation and ECM production mediated by Smad2/3-dependent TGF-β1 signaling pathways in NPDFs.
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