Abstract

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.