Osteogenic differentiation of periodontal ligament stem cells (PDLSCs) is limited in hypoxia, and HIF-1α is key to the response to hypoxia. However, its mechanisms remain largely unknown. This study discovered an osteogenesis-related gene sensitive to hypoxia in PDLSCs, and investigated the molecular mechanisms between HIF-1α and the gene. NOG , a gene that negatively regulates osteogenesis, was discovered by RNA-seq. Under normoxic conditions, HIF-1α overexpression led to enhanced expression of NOG /Noggin and inhibited the expression of osteogenesis-related genes, while inhibition of HIF-1α reversed this effect. The expression of HIF-1α, NOG /Noggin and the osteogenesis-related genes were detected by qRT-PCR or Western blot. Mechanistically, we verified that HIF-1α binds to the hypoxia response element (−1505 to −1502) in the promotor of NOG to enhance secretion of Noggin by chromatin immunoprecipitation and a dual-luciferase reporter assay. IHC staining findings in an animal model verified that Noggin-associated osteogenic differentiation was inhibited in hypoxia. NOG displayed a concordant relationship with HIF-1α, and secreted more with increasing of HIF-1α. Hypoxia stabilized HIF-1α, which bound to the HRE (−1505 to −1502) of the NOG promotor to enhance NOG transcription resulted in inhibiting osteogenic differentiation of PDLSCs. This study offers a promising therapy for periodontitis. [ABSTRACT FROM AUTHOR]