SMAD4 and pulmonary arterial hypertension: The truncating mutation of SMAD9 was identified in familial PAH patients, and genetic variants in SMAD1 and SMAD4 were identified as a causative factor for IPAH.71, 72 Interestingly, the pathological results from a SMAD9 knockout mouse model strongly support the functional involvement of SMAD genes in the progression of human PAH.56 It was demonstrated that the translation of SMAD genes is epigenetically modified by multiple sets of miRNAs in various cell types such as endothelial and vascular smooth muscle cells, as well as mesenchymal stem cells, for bone differentiation.