Peroxisome Proliferator-Activated Receptor α Facilitates Osteogenic Differentiation in MC3T3-E1 Cells via the Sirtuin 1-Dependent Signaling Pathway.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by lack of insulin and high glucose levels. T2DM can cause bone loss and fracture, thus leading to diabetic osteoporosis. Promoting osteogenic differentiation of osteoblasts may effectively treat diabetic osteoporosis. We previously reported that Sirtuin 1 (Sirt1), a NAD(+)-dependent deacetylase, promotes osteogenic differentiation through downregulation of peroxisome proliferator-activated receptor (PPAR) gamma. We also found that miR-132 regulates osteogenic differentiation by downregulating Sirt1 in a PPAR beta/delta-dependent manner. The ligand-activated transcription factor, PPAR alpha, is another isotype of the peroxisome proliferator-activated receptor family that helps maintain bone homeostasis and promot bone formation. Whether the regulatory role of PPAR alpha in osteogenic differentiation is mediated via Sirt1 remains unclear. In the present study, we aimed to determine this role and the underlying mechanism by using high glucose (HG) and free fatty acids (FFA) to mimic T2DM in MC3T3-E1 cells. The results showed that HG-FFA significantly inhibited expression of PPAR alpha, Sirt1 and osteogenic differentiation, but these effects were markedly reversed by PPAR alpha overexpression. Moreover, siSirt1 attenuated the positive effects of PPAR alpha on osteogenic differentiation, suggesting that PPAR alpha promotes osteogenic differentiation in a Sirt1-dependent manner. Luciferase activity assay confirmed interactions between PPAR alpha and Sirt1. These findings indicate that PPAR alpha promotes osteogenic differentiation via the Sirt1-dependent signaling pathway.