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.