Vitamin D attenuates myofibroblast differentiation and extracellular matrix accumulation in nasal polyp-derived fibroblasts through smad2/3 signaling pathway

Abstract

To investigate the potential role of vitamin D (1,25(OH)(2)D-3) in preventing the development of nasal polyps, we examined the effect of vitamin D on myofibroblast differentiation and extracellular matrix (ECM) production in TGF-beta 1-induced nasal polyp-derived fibroblasts (NPDFs) and elucidated the mechanisms underlying its inhibitory effect. 1,25(OH)(2)D-3 significantly reduced expression levels of alpha-SMA, a myofibroblast marker, and fibronectin, a representative ECM component, in a dose-dependent manner in TGF-beta 1-induced NPDFs. 1,25(OH)(2)D-3 suppressed activated Smad2/3 in time-course. Up-regulation of alpha-SMA, fibronectin and phosphorylation of Smad2/3 by TGF-beta 1 was unaffected by 1,25(OH)(2)D-3 in NPDFs after vitamin D receptor-specific siRNA transfection. We confirmed that the Smad2/3-specific inhibitor SIS3 inactivated Smad2/3 and reduced alpha-SMA and fibronectin expression. Furthermore, acetylation of histone H3 was compromised by 1,25(OH)(2)D-3, leading to inhibition of collagen 1A1, collagen 1A2 and alpha-SMA gene expression. Treatment with 1,25(OH)(2)D-3 also significantly suppressed TGF-beta 1-enhanced contractility and motility in a contraction assay and Transwell migration assay. Finally, 1,25(OH)(2)D-3 had a similar effect in ex vivo organ cultures of nasal polyps. Taken together, our results suggest that 1,25(OH)(2)D-3 might be an effective therapy for nasal polyps by reducing myofibroblast differentiation and ECM production mediated by Smad2/3-dependent TGF-beta 1 signaling pathways in NPDFs.