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The present study aimed to examine the effects of isopsoralen against postmenopausal osteoporosis in an ovariectomized rat model. The ovariectomized rats were treated with three days 10 mg/kg isopsoralen or with three days 20 mg/kg isopsoralen. Alkaline phosphatase, the oxidative stress indicators and caspase-3/9 were measured using ELISA assay kits. Reverse transcription-quantitative polymerase chain reaction was used to measure collagen type I (Col I), osteocalcin and osteoprotegerin mRNA levels. Wnt,β-catenin and peroxisome proliferators-activated receptor γ (PPAR-γ) were analyzed using western blot analysis. Isopsoralen suppressed mature adipocyte differentiation of C2C12 cells, inhibited serum calcium and urinary calcium levels, and reduced the structural scores of articular cartilage and cancellous bone in the proximal tibia metaphysis of mice with postmenopausal osteoporosis. Isopsoralen also promoted the activity of alkaline phosphatase and the mRNA expression levels of Col 1, osterix and osteopontin in mice with postmenopausal osteoporosis. Oxidative stress and activities of caspase-3/9 in the mice with postmenopausal osteoporosis were effectively suppressed by isopsoralen treatment, which upregulated the protein expression of Wnt/β-catenin and downregulated the protein expression of PPAR-γ. These findings demonstrated that isopsoralen prevented osteoporosis through the regulation of PPAR-γ/WNT, inhibiting oxidative stress by targeting the PPAR-γ/WNT pathway. These results provide evidence of the potential targeted therapy for isopsoralen in the clinical treatment of postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]