Nutritional activation of the Nrf2-Pth1r axis by pyrroloquinoline quinone enhances peak bone mass and potentiates teriparatide in osteoporosis.

Peak bone mass (PBM) critically determines lifelong skeletal health. We showed that dietary supplementation with pyrroloquinoline quinone (PQQ) - a water-soluble bioactive compound that activates nuclear factor erythroid 2-related factor 2 (Nrf2) signaling - during pregnancy or post-weaning enhances PBM acquisition in wild-type mice, subsequently attenuating age-related bone loss and improving mechanical strength. Mechanistically, PQQ-activated Nrf2 binds directly to the parathyroid hormone 1 receptor (Pth1r) promoter, upregulating its transcription and augmenting PTH-induced osteogenesis. Pth1r overexpression rescues the impaired osteogenesis of Nrf2-deficient bone marrow mesenchymal stem cells (BMSCs). Teriparatide's (PTH 1-34) anabolic effects are markedly compromised in Nrf2-deficient mice and human BMSCs, underscoring Nrf2's essential role in PTH-mediated bone formation. Notably, PQQ and PTH 1-34 co-administration synergistically enhances skeletal anabolism in aged mice beyond PTH 1-34 monotherapy. These results establish the PQQ-Nrf2-Pth1r axis as a key regulator of bone mass accrual and suggest PQQ as a promising adjunct to teriparatide for osteoporosis.