Lipid droplet accumulation impairs osseointegration by disturbing the osteogenesis-osteoclasis balance on titanium implant surface in hyperlipidemia.

BACKGROUND: Effective osseointegration is a crucial factor for the success of implant restoration, and hyperlipidemia significantly impairs osseointegration. However, the underlying in vivo mechanisms remain unclear. This study aimed to investigate the impact and molecular mechanisms of lipid droplet accumulation on osteogenesis-osteoclasis balance on titanium (Ti) implant surface. METHODS: In vivo, hyperlipidemia mice receiving local injections of Wnt3a or N-acetyl-L-cysteine (NAC) in peri-implant tissue were used to assess 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 (IF) staining. The in situ oxidative damage of cells obtained from the extracted implant surfaces was detected by transmission electron microscopy and enzyme-linked immunosorbent assay. In vitro, bone marrow mesenchymal stem cells (BMMSCs) were cultured on Ti sheet with intermittent treatment of NAC. The relationship between lipid droplets and oxidative damage was detected by IF staining of BODIPY, GRP78, DCFH-DA, EdU, and the quantitative assay of GSH/GSSG, MDA, NAD(+)/NADH, ATP. RESULTS: Hyperlipidemia disrupted osseointegration via downregulating the osteogenesis-related ROS/Wnt/β-catenin pathway and simultaneously upregulating the osteoclasis-related ROS/RANKL/NF-κB pathway. NAC application alleviated endoplasmic reticulum stress and mitochondrial dysfunction but failed to reduce lipid droplet accumulation. The intracellular oxidative damage is positively correlated with the accumulation of lipid droplets induced by hyperlipidemia. CONCLUSION: Lipid droplet accumulation is the primary cause for inducing oxidative damage, disturbing osteogenesis-osteoclasis balance, and impairing osseointegration in hyperlipidemia. This study highlights that reducing lipid droplet accumulation may serve as a potential strategy to enhance Ti implant osseointegration in hyperlipidemia.