Cilostazol ameliorates high glucose-induced osteoblast dysfunction by modulating mitogen-activated protein kinase signaling and the OPG/RANKL axis

Diabetic osteopathy, characterized by impaired bone formation and increased fracture risk, is a complication of diabetes mellitus, with chronic hyperglycemia-induced oxidative stress contributing to osteoblast dysfunction. Cilostazol (CLZ) is a selective phosphodiesterase 3 inhibitor; however, its effects on bone cell function under metabolic stress remain unclear. The present study investigated the effects of CLZ on osteoblast function and the mitogen-activated protein kinase (MAPK) signaling network under oxidative stress induced by high glucose (HG) and glucose oxidase (GOx) in MC3T3-E1 osteoblastic cells. Osteogenic marker expression and MAPK signaling were evaluated by western blotting, while osteoblast differentiation was assessed using alkaline phosphatase and Alizarin Red S assays. Exposure to 50 mM HG and 5 mU/ml GOx markedly suppressed key osteogenic markers, including bone morphogenetic protein 2 and 7, Runt-related transcription factor 2, Osterix and collagen type I α1 chain, decreased osteoprotegerin (OPG) expression and increased receptor activator of NF-κB ligand (RANKL) expression. However, CLZ (0.1 and 1 µM) restored the expression of these osteogenic factors, increased OPG expression, decreased RANKL expression and restored alkaline phosphatase activity and mineralized nodule formation. CLZ treatment was associated with increased p38 and ERK phosphorylation and decreased JNK phosphorylation in HG/GOx-treated cells. These findings suggest that CLZ may attenuate HG/GOx-induced osteoblast dysfunction through modulation of MAPK signaling and the OPG/RANKL axis. However, further in vivo studies are required to determine its translational relevance in diabetic bone healing.