Metformin promotes osteogenic differentiation and prevents hyperglycaemia-induced osteoporosis by suppressing PPAR. expression

Metformin can prevent hyperglycaemia-induced osteoporosis and decrease the bone fracture rate, but the mechanism has not been fully elucidated. To reveal the mechanism by which metformin affects hyperglycaemiainduced osteoporosis, we treat a mouse osteoporosis cell model with metformin and find that osteoblast mineralization increases and PPAR gamma expression decreases. Single-cell mRNA sequencing analysis show that PPAR gamma is highly expressed in the bone tissue of osteoporosis patients, which highlights the role of PPAR gamma in osteoporosis. Furthermore, we find that PPAR gamma is the effector through which metformin prevents osteoporosis. We further examine the mechanism of PPAR gamma regulation and reveal that metformin regulates PPAR gamma expression through the AMPK pathway and that PPAR gamma affects osteoblasts through the endoplasmic reticulum stress (ERS) pathway gamma Moreover, we verify the association between the effect of metformin on bone metabolism and the expression of PPAR gamma in high-fat diet-induced diabetic rats. Thus, we identify and functionally validate that metformin prevents hyperglycaemia-induced osteoporosis by regulating the AMPK-PPAR gamma-ERS axis.