Hyperlipidemia Impairs Osseointegration via the ROS/Wnt/β-Catenin Pathway

Abstract

The influence of hyperlipidemia on titanium implant osseointegration and the underlying mechanisms is not well understood. This study investigates the changes in osseointegration and explores the potential mechanisms in hyperlipidemia conditions. 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 the titanium surface in high-fat medium. Results showed that hyperlipidemia led to poor osseointegration in both types of mice in vivo, and high-fat medium impaired the osteogenic differentiation of primary osteoblasts on the titanium surface in vitro. In addition, high-fat medium caused significant overproduction of reactive oxygen species (ROS) and inhibition of the Wnt/β-catenin pathway in osteoblasts. Both N-acetyl-L-cysteine (NAC, an ROS antagonist) and Wnt3a (an activator of the Wnt/β-catenin pathway) attenuated the poor osteogenic ability of osteoblasts. In addition, NAC reactivated the Wnt/β-catenin pathway in osteoblasts under high-fat stimulation. These results demonstrate that hyperlipidemia impairs osseointegration via the ROS/Wnt/β-catenin pathway and provide support for the ROS or Wnt/β-catenin pathway as a promising therapeutic target for the development of novel drugs or implant materials to improve the osseointegration of implants in hyperlipidemic patients.

In Sickness and in Health: The Oxygen Reactive Species and the Bone

“…The implant itself will behave differently in the presence of the disease-induced microenvironment changes, namely by increased metal ion leaching ( Arteaga et al, 2021 ). Hyperlipidemia, frequently present in diabetic patients and in several other diseases, as well as a primary condition, causes overproduction of ROS in vitro , interfering with the Wnt/β-Catenin pathway and causing osteoblast dysfunction; in vivo , poor bone formation at the bone-implant interface was observed ( Wang Y. N. et al, 2021 ). Overproduction of ROS may also cause eNOS uncoupling, and a shift from NO production to O 2 − , contributing to oxidative distress.…”

“…NAD + -dependent Sirtuin1 deacetylates FoxOs and β-catenin, increasing Wnt pathway expression in osteoblast progenitors ( Kim and Park., 2021 ). ROS interference in osteoblastogenesis and osteoclastogenesis is also present in pathological conditions such as osteoporosis and arthritis ( Agidigbi and Kim, 2019 ; Wang Y. N. et al, 2021 ).…”

T‐2 toxin‐induced femur lesion is accompanied by autophagy and apoptosis associated with Wnt/β‐catenin signaling in mice

“…Decreased RNA expression of β-catenin leads to diminishing the expression of osteoblastic genes. 52 Thus, in our study, the reduction of Wnt/β-catenin signaling target genes (RUNX2 and COL-I) caused…”

“…Meanwhile, decreased mRNA expressions of β‐catenin and TCF‐4 inhibited target genes expression. Wnt/β‐catenin signaling has been proven to be inhibited by ROS on bone lesion, hepatocellular carcinoma, and myocardial infarction 49–51 . Thus, we speculated that ROS was a reason for the inhibition of Wnt/β‐catenin signaling in T‐2 toxin‐exposed femur.…”

Gingipain-Responsive Thermosensitive Hydrogel Loaded with SDF-1 Facilitates In Situ Periodontal Tissue Regeneration

“…Live/dead cell staining was performed to observe the cell viability following the standard protocols (Sigma-Aldrich, St. Louis, MO, USA). In addition, cellular actin filaments and nuclei were visualized respectively by staining with rhodamine phalloidin (Millipore Sigma, USA) and 4′,6-diamidino-2-phenylindole (DAPI; Millipore Sigma, USA), as reported previously . All fluorescent images in this article were obtained with a fluorescence microscope (Leica, Germany).…”