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

To investigate the role of osteoclast-specific HIF-1α in orthodontic tooth movement and to explore the underlying molecular mechanisms.

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.

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.

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.