Palopegteriparatide

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.

Osteogenesis imperfecta (OI) is a genetically heterogenous disorder characterized by brittle bone and recurrent fractures. The majority of OI is clinically categorized into mild, moderate, severe, and perinatal lethal forms. A clinical study on the use of intermittent parathyroid hormone (PTH) as an anabolic therapy for OI found PTH was effective in mild, but not in individuals with moderate/severe OI. However, this sub-group analysis was relatively small and considered preliminary by the authors. Since then, research on PTH therapy in OI has focused on mild OI and no studies of PTH use in moderate/severe OI patients or animal models have been reported. In this work, we used the Aga2/+ mouse, an established autosomal dominant model of moderate/severe OI, to investigate whether PTH treatment has an effect on bone. In vitro, Aga2/+ osteoblasts were sensitive to PTH and exhibited similar transcriptional changes compared to WT. In vivo, PTH treatment improved lumbar trabecular bone, increased cortical bone area fraction in the mid-femur, and, in females, led to improved biomechanical properties. These results demonstrate the Aga2/+ model responded to PTH and support further investigation into whether PTH is effective in adult individuals with moderate/severe OI who have limited treatment options.