TGF-β1 is a central pro-fibrotic cytokine in stricturing Crohn’s disease. Its affects are normally inhibited by increased Smad7 expression. We have shown that Smad7 is silenced in stricturing Crohn’s disease by TGF-β1 activated, Smad3-dependent expression of miR-21 resulting in sustained Smad3 activity and increased collagen I production. Smad7 expression can also be silenced by CpG island methylation or its protein levels diminished by deacetylation which allows E3 ubiquitin ligase-dependent proteosomal degradation via Smurf1/2.