Lipid Droplets Disturb Bone Homeostasis And Impair Osseointegration In Hyperlipidemia

Hyperlipidemia impairs osseointegration and interferes the effect of implant restoration, and this study aimed to investigate the molecular mechanisms of lipid droplet accumulation induced by hyperlipidemia on disturbing bone homeostasis. The animal experimental procedures were approved by the Medical Ethics Committee of Stomatological Hospital, Shandong University, Jinan, China. Twenty-four 6-week-old male C57BL/6J mice were used to construct normal or hyperlipidemia femoral implant model. Wnt3a or NAC were locally injected into the distal femur in hyperlipidemia mice for assessing changes of osseointegration, lipid droplet accumulation, and osteogenesis-osteoclasis balance by Micro-CT, hard tissue slicing and staining, H&E staining, TRAP staining, as well as immunofluorescence staining. Additionally, the relationship between lipid droplets and oxidative damage in BMMSCs cultured on titanium sheets surface were detected. In vivo, the osteogenesis-related ROS/Wnt/β-catenin pathway was downregulated and the osteoclasis-related ROS/RANKL/NF-κB pathway was upregulated in hyperlipidemia mice, compared with normal mice. In addition, local application of NAC could alleviate endoplasmic reticulum stress and mitochondrial dysfunction in situ, yet failed to reduce lipid droplet accumulation in peri-implant tissue. In vitro, the intracellular level of GSH/GSSG, MDA, ATP and the mean fluorescence intensity of BODIPY, GRP78, DCFH-DA in high-fat medium were significantly different with those in normal condition, and the effect of intermittent application of NAC was short-lived. Lipid droplet accumulation is the primary cause for inducing oxidative damage, disturbing osteogenesis-osteoclasis balance, and impairing osseointegration in hyperlipidemia.