Osteogenesis Impairment by Oxidative Stress Via Wnt/β-Catenin Pathway at the Bone-Implant Interface: Critical Mechanisms and Potential Therapeutic Targets for Poor Osseointegration Under Hyperlipidemia Conditions

Abstract

The influence of hyperlipidemia on titanium implant osseointegration and the underlying mechanisms remain elusive. Here, we studied the effects of hyperlipidemia on osseointegration and the related mechanisms. In vivo, specialized titanium implants were implanted in the femurs of diet-induced or genetic hyperlipidemia mice. In vitro, primary murine osteoblasts were cultured on titanium surface. Results showed that hyperlipidemia led to poor bone formation on bone-implant interface in two types of mice in vivo. In vitro, high-fat medium caused significant overproduction of reactive oxygen species (ROS) and inhibiting of Wnt/β-catenin pathway in osteoblasts on titanium surface, inducing obvious cell dysfunction. Both N-acetyl-L-cysteine(NAC, a ROS antagonist) and Wnt3a(an activator of Wnt/β-catenin pathway) could effectively attenuated the poor osteogenic ability of osteoblasts. Besides, NAC reactivated the Wnt/β-catenin pathway in osteoblasts under high-fat stimulation. Our results suggested that the cellular oxidative stress leads to osteoblasts dysfunction via the Wnt/β-catenin pathway, which plays a critical role in the compromised implant osseointegration under hyperlipidemia conditions. These results demonstrated new insights into the negative effect of hyperlipidemia on osseointegration and also provided ROS or Wnt/β-catenin pathway as promising therapeutic targets for developing novel implant materials to accelerate the osseointegration of implants in hyperlipidemia patients.