Punicalagin alleviates senile osteoporosis by inhibiting the senescence of bone mesenchymal stem cells via NRF2/HO-1 pathway.

<h4>Background</h4>The senescence(definition) and abnormal osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) are important causes of senile osteoporosis. Punicalagin (PUN), a natural polyphenol extracted from pomegranate peel, has demonstrated antioxidant activity in preclinical studies. This study aims to investigate the inhibitory effect of PUN on the aging of BMSCs and its therapeutic effect on senile osteoporosis.<h4>Methods</h4>The senescence of BMSCs were induced by hydrogen peroxide (H₂O₂) to assess the therapeutic effect of PUN. Intracellular reactive oxygen species measurements, the senescence β-galactosidase staining, western blotting, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were conducted to evaluate the senescence of BMSCs. Alkaline phosphatase staining, Alizarin red S staining, western blotting, and RT-qPCR were performed to assess the osteogenic differentiation of senescent BMSCs. Transcriptome sequencing was conducted to explore the underlying mechanism. In vivo, the therapeutic effects of PUN were investigated in aging rats with senile osteoporosis.<h4>Results</h4>PUN reversed the senescence of BMSCs and promoted the osteogenic differentiation in a dose-dependent manner. Mechanistically, PUN activated the nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway to protect BMSCs from oxidative stress. In aging rats with senile osteoporosis, intraperitoneal injection of PUN can promote osteogenesis and reduce aging-related bone loss in vivo.<h4>Conclusion</h4>PUN alleviates senile osteoporosis by inhibiting the senescence of BMSCs via NRF2/HO-1 pathway, representing a candidate therapeutic drug for aging-related bone diseases.