Osteoclast-specific HIF-1α regulates hypoxia-associated bone remodeling during orthodontic tooth movement.

OBJECTIVE: To investigate the role of osteoclast-specific HIF-1α in orthodontic tooth movement and to explore the underlying molecular mechanisms. METHODS: A controlled experimental study was performed using a murine OTM model and osteoclast-specific HIF-1α conditional knockout mice (HIF-1αfl/fl; Ctsk-Cre). In vitro osteoclast differentiation assays were conducted using RAW264.7 cells under hypoxic or hypoxia-mimetic conditions. Tooth movement distance and trabecular bone parameters were assessed by micro-computed tomography. Histological staining (H&E and TRAP), immunofluorescence, quantitative PCR and Western blotting were used to evaluate osteoclast number and the expression of HIF-1α and transferrin receptor (TFRC). Small interfering RNA was used to examine the functional role of TFRC. RESULTS: Osteoclast activity increased during OTM and was associated with reduced local oxygen levels and HIF-1α stabilization. Osteoclast-specific deletion of HIF-1α reduced tooth movement distance, decreased osteoclast numbers and increased trabecular bone volume. HIF-1α upregulated TFRC expression under hypoxic conditions, and TFRC silencing attenuated osteoclast differentiation. Pharmacological stabilization of HIF-1α enhanced tooth movement in wild-type mice. CONCLUSIONS: Osteoclast-intrinsic HIF-1α contributes to force-induced bone remodeling and promotes osteoclast differentiation n through a TFRC-associated pathway. Modulation of hypoxia-responsive mechanisms may provide a potential approach to influence orthodontic treatment outcomes.