(D-Ala2)GIP Inhibits TNF-α-Induced Osteoclast Formation and Bone Resorption, and Orthodontic Tooth Movement

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) promotes insulin secretion, lowers blood glucose levels, and is increasingly linked to bone remodeling. Native GIP is quickly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), whereas (D-Ala²)GIP is a novel GIP analog engineered to resist DPP-4 degradation. Tumor necrosis factor-alpha (TNF-α), a key proinflammatory cytokine, promotes osteoclastogenesis and is notably upregulated during orthodontic tooth movement (OTM). This study aimed to evaluate the effects of (D-Ala²)GIP on TNF-α-induced osteoclast formation and bone resorption in vivo, as well as on OTM and related root resorption. Mice received daily supracalvarial injections of TNF-α with or without (D-Ala²)GIP for 5 days. The (D-Ala²)GIP-treated group showed significantly reduced osteoclast formation, bone resorption, and expression of osteoclastic markers TRAP and cathepsin K, compared to the group that received TNF-α alone. OTM was induced in mice by applying a nickel-titanium closed-coil spring, and mice were treated with either phosphate-buffered saline (PBS) or (D-Ala²)GIP every 2 days. After 12 days, the (D-Ala²)GIP-treated group showed significantly reduced tooth movement and fewer osteoclasts and odontoclasts on the compression side compared to the PBS control. These findings suggest that (D-Ala²)GIP inhibits OTM, potentially by suppressing TNF-α-driven osteoclastogenesis and bone resorption.