Metformin promotes osteogenic differentiation and prevents hyperglycaemia-induced osteoporosis by suppressing PPARγ 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 hyperglycaemia-induced osteoporosis, we treat a mouse osteoporosis cell model with metformin and find that osteoblast mineralization increases and PPARγ expression decreases. Single-cell mRNA sequencing analysis show that PPARγ is highly expressed in the bone tissue of osteoporosis patients, which highlights the role of PPARγ in osteoporosis. Furthermore, we find that PPARγ is the effector through which metformin prevents osteoporosis. We further examine the mechanism of PPARγ regulation and reveal that metformin regulates PPARγ expression through the AMPK pathway and that PPARγ affects osteoblasts through the endoplasmic reticulum stress (ERS) pathway. Moreover, we verify the association between the effect of metformin on bone metabolism and the expression of PPARγ in high-fat diet-induced diabetic rats. Thus, we identify and functionally validate that metformin prevents hyperglycaemia-induced osteoporosis by regulating the AMPK-PPARγ-ERS axis.