Parathyroid hormone reprograms M1/M2 macrophage fate to regulate alveolar bone remodeling during orthodontic tooth...

Orthodontic tooth movement (OTM) initiates sterile inflammation within the periodontal ligament, wherein macrophage polarization serves as a pivotal regulatory node of alveolar bone remodeling. Parathyroid hormone (PTH) possesses potent immunomodulatory and osteogenic properties; however, its impact on macrophage heterogeneity under mechanical stress remains incompletely understood. In this study, a co-culture system of human periodontal ligament cells (hPDLCs) and THP-1-derived macrophages was established and exposed to cyclic tensile stress, with or without PTH (1-34) treatment and pharmacological activation of the NLRP3 inflammasome using nigericin. Quantitative analyses revealed that mechanical loading induced early apoptosis in hPDLCs (3.2-fold increase vs. control, P < 0.001), elevated the M1 macrophage subset (CD68⁺CD11b⁺) by 2.7-fold (P < 0.001), and reduced M2 macrophages (CD68⁺CD206⁺) by 58% (P < 0.001). Concurrently, osteogenic markers BMP-2, OPG, and RUNX2 were markedly downregulated (P < 0.001), while pro-inflammatory mediators TNF-α, IL-1β, and iNOS were significantly upregulated (P < 0.001). PTH intervention reversed these alterations-restoring osteogenic protein expression to near-baseline levels (P < 0.001) and increasing anti-inflammatory IL-10 production (P < 0.001)-while shifting macrophage polarization toward the reparative M2 phenotype. These immunomodulatory effects were abolished by NLRP3 activation (P < 0.01). Importantly, these findings parallel clinical observations that PTH accelerates oral wound healing following tooth extraction or periodontal surgery by fostering a regenerative M2-dominant microenvironment and enhancing bone formation. In conclusion, PTH reprograms mechanical stress-induced M1 macrophages into an M2 reparative phenotype via inhibition of the NLRP3 inflammasome, thereby augmenting osteogenic transcription and curbing inflammatory bone resorption. Targeted modulation of the PTH-NLRP3 axis may constitute a translatable strategy to expedite OTM, mitigate adverse tissue reactions, and optimize clinical orthodontic protocols while minimizing iatrogenic complications.