Osteoporosis is a disease that significantly influences life expectancy and quality in humans. Oxidative stress may stimulate bone marrow osteoclast differentiation and inhibit osteoblast (OB) differentiation. OB proliferation and differentiation are affected by the forkhead box O (FoxO)1/β‑catenin signaling pathway. The osteogenic differentiation of mesenchymal stem cells (MSCs) may be promoted by silent information regulator type‑1 [sirtuin (SIRT)1]. However, the molecular mechanism of SIRT1 regulation of osteogenic differentiation of MSCs remains unclear, and further elucidation is needed. The present study investigated the role of SIRT1 in the FoxO1/β‑catenin signaling pathway in oxidative stress and its mechanism in the osteoblastic progenitor cell line (MC3T3‑E1). The results demonstrated that OB apoptosis and elevated oxidative stress in cells were simulated by H2O2, which was inhibited by moderate SIRT1 overexpression through reducing the oxidative stress. Further studies revealed that FOXO1 and β‑catenin pathway activity was downregulated by SIRT1 and eventually resulted in inhibition of target genes, including the proapoptotic gene B cell lymphoma‑2 interacting mediator of cell death, DNA repair gene growth arrest and DNA damage inducible protein 45 and the OB differentiation suppressor gene peroxisome proliferator activated receptor (PPAR)‑γ. Furthermore, β‑catenin and PPAR‑γ were inhibited by SIRT1. Overall, the results of the present study suggest that moderate overexpression of SIRT1 (~3‑fold of normal level) may directly or indirectly inhibit apoptosis of OBs via the FOXO1 and β‑catenin signaling pathway.
Keywords: SIRT1; osteoblast; osteoporosis; FoxO1; β‑catenin; Gadd45; PPAR‑γ.