Identification of PKM2 as a pyroptosis-related key gene aggravates senile osteoporosis via the NLRP3/Caspase-1/GSDMD signaling pathway

Backgrounds: Senile osteoporosis-alternatively labeled as skeletal aging-encompasses age -induced bone deterioration and loss of bone microarchitecture. Recent studies have indicated a potential association between senile osteoporosis and chronic systemic inflammation, and pyroptosis in bone marrow -derived mesenchymal stem cells is speculated to contribute to bone loss and osteoporosis. Therefore, targeting pyroptosis in stem cells may be a potential therapeutic strategy for treating osteoporosis. Methods: Initially, we conducted bioinformatics analysis to screen the GEO databases to identify the key gene associated with pyroptosis in senile osteoporosis. Next, we analyzed the relationship between altered proteins and clinical data. In vitro experiments were then performed to explore whether the downregulation of PKM2 expression could inhibit pyroptosis. Additionally, an aging -related mouse model of osteoporosis was established to validate the efficacy of a PKM2 inhibitor in alleviating osteoporosis progression. Results: We identified PKM2 as a key gene implicated in pyroptosis in senile osteoporosis patients through bioinformatics analysis. Further analyses of bone marrow and stem cells demonstrated significant PKM2 overexpression in senile osteoporosis patients. Silencing PKM2 expression inhibited pyroptosis in senile stem cells, of which the osteogenesis potential and angiogenic function were also primarily promoted. Moreover, the results in vivo demonstrated that administering PKM2 inhibitors suppressed pyroptosis in senile osteoporosis mice and mitigated senile osteoporosis progression. Conclusion: Our study uncovered PKM2, a key pyroptosis marker of bone marrow mesenchymal stem cells in senile osteoporosis. Shikonin, a PKM2 inhibitor, was then identified as a potential drug candidate for the treatment of osteoporosis.