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

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-β1-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 α-SMA, a myofibroblast marker, and fibronectin, a representative ECM component, in a dose-dependent manner in TGF-β1-induced NPDFs. 1,25(OH)(2)D(3) suppressed activated Smad2/3 in time-course. Up-regulation of α-SMA, fibronectin and phosphorylation of Smad2/3 by TGF-β1 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 α-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 α-SMA gene expression. Treatment with 1,25(OH)(2)D(3) also significantly suppressed TGF-β1-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-β1 signaling pathways in NPDFs.