HIF-1α drives the transcription of NOG to inhibit osteogenic differentiation of periodontal ligament stem cells in response to hypoxia

• Published in: Experimental cell research 2022-10, Vol.419 (2), p.113324-113324, Article 113324
• Main Authors: Pan, Yingzi, Liu, Zhihua, Tang, Yaping, Tao, Jie, Deng, Fang, Lei, Yuzhu, Tan, Yan, Zhu, Shunyao, Wen, Xiujie, Guo, Ling, Li, Rulei, Deng, Manjing, Liu, Rui
• Format: Article
• Language: English
• Subjects: HIF-1α; Hypoxia; NOG; Noggin; Osteogenic differentiation; Periodontal ligament stem cells (PDLSCs)
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2022.113324

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.