Pyrroloquinoline quinone alleviates natural aging‐related osteoporosis via a novel MCM3‐Keap1‐Nrf2 axis‐mediated stress response and Fbn1 upregulation

Age‐related osteoporosis is associated with increased oxidative stress and cellular senescence. Pyrroloquinoline quinone (PQQ) is a water‐soluble vitamin‐like compound that has strong antioxidant capacity; however, the effect and underlying mechanism of PQQ on aging‐related osteoporosis remain unclear. The purpose of this study was to investigate whether dietary PQQ supplementation can prevent osteoporosis caused by natural aging, and the potential mechanism underlying PQQ antioxidant activity. Here, we found that when 6‐month‐old or 12‐month‐old wild‐type mice were supplemented with PQQ for 12 months or 6 months, respectively, PQQ could prevent age‐related osteoporosis in mice by inhibiting osteoclastic bone resorption and stimulating osteoblastic bone formation. Mechanistically, pharmmapper screening and molecular docking studies revealed that PQQ appears to bind to MCM3 and reduces its ubiquitination‐mediated degradation; stabilized MCM3 then competes with Nrf2 for binding to Keap1, thus activating Nrf2‐antioxidant response element (ARE) signaling. PQQ‐induced Nrf2 activation inhibited bone resorption through increasing stress response capacity and transcriptionally upregulating fibrillin‐1 (Fbn1), thus reducing Rankl production in osteoblast‐lineage cells and decreasing osteoclast activation; as well, bone formation was stimulated by inhibiting osteoblastic DNA damage and osteocyte senescence. Furthermore, Nrf2 knockout significantly blunted the inhibitory effects of PQQ on oxidative stress, on increased osteoclast activity and on the development of aging‐related osteoporosis. This study reveals the underlying mechanism of PQQ's strong antioxidant capacity and provides evidence for PQQ as a potential agent for clinical prevention and treatment of natural aging‐induced osteoporosis.