Transforming growth factor-β1 and hypoxia inducible factor-1α at synergistically inhibit the osteogenesis of periodontal ligament stem cells

Periodontal ligament stem cells (PDLSCs) exhibit potential for osteogenesis in vitro and in vivo and are a candidate cell type for periodontal regeneration for the treatment of periodontitis. However, periodontitis is accompanied by hypoxia, and it is not clear how hypoxia affects the osteogenesis of PDLSCs. In this study, we found that the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and transforming growth factor-beta 1 (TGF-beta 1) is enhanced in the osteogenesis of PDISCs under nonhypoxic conditions. TGF-beta 1 can induce the stabilization of HIF-1 alpha through the phosphorylation of mothers against decapentaplegic homolog 3 (Smad3) in PDLSCs, and in turn, HIF-1 alpha inhibits the mRNA and protein expression of TGF-beta 1 and inhibits the phosphorylation of Smad3 in PDLSCs. In addition, both HIF-1 alpha and TGF-beta 1 reduce the expression of crucial osteogenic gene runt-related transcription factor 2 (RUNX2) and the mineralization of PDLSCs in normoxia. In conclusion, our results showed that TGF-beta 1 can induce the stabilization of HIF-1 alpha in PDLSCs under nonhypoxic conditions, that HIF-1 alpha can negatively regulate the TGF-beta 1/Smad3 signal pathway in PDLSCs, and that TGF-beta 1 and HIF-1 alpha can synergistically inhibit the osteogenesis of PDLSCs.