Metformin Promotes Osteogenic Differentiation and Prevents Hyperglycaemia-Induced Osteoporosis by Suppressing PPARγ Expression
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Targeting nuclear receptors for diseases looks like needs to be understood better by all of us
Metformin improves osteoblast differentiation and suppresses PPARγ expression in osteoblasts exposed to glucotoxicity :
To examine the effect of metformin on osteoblasts, we treated the streptozotocin-induced osteoporosis cell model with different concentrations of metformin (25, 50, and 100 μM). The results showed that 50 and 100 μM metformin significantly increased mineralization in hyperglycaemic osteoblasts. In the 100 μM metformin treatment group, the protein level of PPARγ was significantly decreased, and the levels of p-AMPK and BMP-2 were increased . These findings indicate that metformin improves osteoblast differentiation and suppresses PPARγ expression in osteoblasts.
PPARγ is highly expressed in the bone tissue of osteoporosis patients.
To confirm that PPARγ is the specific effector molecule of osteoporosis, we analysed the expression level of PPARγ in human bone tissue using published single-cell mRNA sequencing datasets. We found that PPARγ was highly expressed in preosteoblasts (1970/5729 cells) but was rarely expressed in mature osteoblasts (201/1528 cells) and was not expressed in other cells, such as chondrocytes, neutrophils and endothelial cells ). In addition, we analysed the PPARγ protein levels in the bone tissue of 30 T2DM patients, including 20 osteoporosis patients and 10 healthy individuals. The results showed that the PPARγ protein levels in osteoporosis patients were significantly higher than those in healthy controls. Thus, these results suggest that PPARγ is highly expressed in the bone tissue of osteoporosis patients and may play an important role in osteogenic differentiation.
PPARγ mediates the effects of metformin through the AMPK pathway
We examined whether PPARγ affects the activity of metformin through the AMPK pathway. Dorsomorphin (compound C) is an AMPK inhibitor. After inhibiting the activity of AMPK, we found that the protective effect of metformin was reduced: compared with those in the HG+MF group, osteoblast viability and mineralization, the secretion of ALP and OCN , and the expression of BMP2 in the HG+MF+Compound C group were decreased. Compound C also weakened the inhibitory effect of metformin on the expressions of pAMPK, PPARγ, PERK, ATF4, and CHOP in hyperglycaemic osteoblasts. These findings suggest that PPARγ affects the activity of metformin through the AMPK pathway.
PPARγ plays an important role in metformin-mediated effect on hyperglycaemic osteoblasts.
To verify that metformin improves mineralization by affecting PPARγ, we altered the expression or activity of PPARγ in a metformin treatment assay. In this assay, we altered PPARγ levels through overexpression and RNAi-mediated knockdown. The results showed that downregulating PPARγ levels improved the metformin-mediated effect on hyperglycaemic osteoblasts; osteoblast viability and mineralization, the secretion of ALP and OCN, and the expression of BMP2 were increased. Conversely, the increased PPARγ level in osteoblasts weakened the metformin-mediated effect on hyperglycaemic osteoblasts.
Results : In this study, we demonstrated that metformin enhanced osteoblast differentiation and downregulated the protein level of PPARγ in an osteoporosis cell model. Increasing the activity of PPARγ weakened these effects of metformin, whereas inhibiting the activity of PPARγ had the opposite effect. Additionally, we found that metformin regulated PPARγ function through the AMPK pathway. PPARγ mediates the effect of metformin via the ERS pathway. Furthermore, we found a relationship between the effect of metformin on bone metabolism and the activity of PPARγ in diabetic rats.
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Seems like Berberine might be a safer way to accomplish this then, or Banaba Leaf extract standardised to Corosolic Acid
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@CurmudgeonApple They use same metabolic pathways and when combined they synergistic effect. Metformin + Berberine combination is superior to using only one medication.
