Hypoxia dissociates HDAC6/FOXO1 complex and aggregates them into nucleus to regulate autophagy and osteogenic differentiation

Abstract Objective This research aimed to elucidate the molecular mechanisms underlying the periodontitis‐associated bone loss, with particular emphasis on the contributory role of hypoxic microenvironment in this process. Background Periodontitis generally causes alveolar bone loss and is often associated with a hypoxic microenvironment, which affects bone homeostasis. However, the regulating mechanism between hypoxia and jaw metabolism remains unclear. Hypoxia triggers autophagy, which is closely related to osteogenic differentiation, but how hypoxia‐induced autophagy regulates bone metabolism is unknown. HDAC6 and FOXO1 are closely related to bone metabolism and autophagy, respectively, but whether they are related to hypoxia‐induced bone loss and their internal mechanisms is still unclear. Methods Established rat nasal obstruction model and hypoxia cell model. Immunohistochemistry was performed to detect the expression and localization of HDAC6 and FOXO1 proteins, analysis of autophagic flux and transmission electron microscopy was used to examine the autophagy level and observe the autophagosomes, co‐immunoprecipitation and chromatin immunoprecipitation were preformed to investigate the interaction of HDAC6 and FOXO1. Results Hypoxia causes increased autophagy and reduced osteogenic differentiation in rat mandibles and BMSCs, and blocking autophagy can attenuate hypoxia‐induced osteogenic differentiation decrease. Moreover, hypoxia dissociated the FOXO1‐HDAC6 complex and accumulated them in the nucleus. Knocking down of FOXO1 or HDAC6 alleviated hypoxia‐induced autophag y elevation or osteogenic differentiation reduction by binding to related genes, respectively. Conclusion Hypoxia causes mandibular bone loss and autophagy elevation. Mechanically, hypoxia dissociates the FOXO1‐HDAC6 complex and aggregates them in the nucleus, whereas HDAC6 decreases osteogenic differentiation and FOXO1 enhances autophagy to inhibit osteogenic differentiation.