Tetrathiomolybdate alleviates osteoporosis by activating the PI3K/Akt signaling axis

Abstract

To investigate the role and possible mechanisms of tetrathiomolybdate (TTM) in ovariectomy (OVX)-induced osteoporotic mice. Eighteen 12-week-old C57BL/6 female mice were randomized into three groups: sham-operated group (Sham group, n = 6), OVX-induced osteoporosis (OP) group (OP group, n = 6), and OVX-induced OP+TTM gavage-treated group (OP+TTM group, n = 6). The mice body weight results and abdominal fat macroscopic view showed significant improvement in obesity in the OP+TTM group of mice as compared to those in the OP group. HE staining and micro-CT scanning results demonstrated that mice in the OP+TTM group showed milder bone loss than those in the OP group. The results of TRAP staining also supported these findings. In addition, serum lipid profiling and immunohistochemical staining showed that compared with mice in the OP group, mice in the OP+TTM group had significantly lower serum levels of triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), as well as PPARγ and FABP4 protein expression in the femur. Further, the results of transcriptome sequencing analysis indicated that the differential genes between OP+TTM and OP groups were mainly enriched in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Immunofluorescence assay preliminarily confirmed that the expression of p-PI3K and p-Akt proteins was significantly elevated in the femur of mice in the OP+TTM group, especially in the bone marrow cavity. Taken together, we reported for the first time that TTM ameliorated obesity and inhibited bone loss in OP mice, which may be related to the activation of PI3K/Akt signaling.

Keywords

• tetrathiomolybdate
• osteoporosis
• bone formation
• pi3k/akt signaling
• ovariectomy
• cuproptosis