AGEs/RAGE Promote Osteogenic Differentiation in Rat Bone Marrow-Derived Endothelial Progenitor Cells via MAPK Signaling.

Yuping Wang,Yong Liu,Gang Yuan,Yanzheng He,Guochun Qiu,Chunxia Jiang,Kaiqiang Xu,Qingchun Hou,Zhongming Shang,Raffaella Mastrocola

doi:10.1155/2022/4067812

Abstract

Systemic vascular impairment is the most common complication of diabetes. Advanced glycation end products (AGEs) can exacerbate diabetes-related vascular damage by affecting the intima and media through a variety of mechanisms. In the study, we demonstrated that AGEs and their membrane receptor RAGE could induce the differentiation of EPCs into osteoblasts under certain circumstances, thereby promoting accelerated atherosclerosis. Differentiation into osteoblasts was confirmed by positive staining for DiI-acetylated fluorescently labeled low-density lipoprotein and FITC-conjugated Ulex europaeus agglutinin. During differentiation, expression of receptor for AGE (RAGE) was significantly upregulated. This upregulation was attenuated by transfection with RAGE-targeting small interfering (si)RNA. siRNA-mediated knockdown of RAGE expression significantly inhibited the upregulation of AGE-induced calcification-related proteins, such as runt-related transcription factor 2 (RUNX2) and osteoprotegerin (OPG). Additional experiments showed that AGE induction of EPCs significantly induced ERK, p38MAPK, and JNK activation. The AGE-induced upregulation of osteoblast proteins (RUNX2 and OPG) was suppressed by treatment with a p38MAPK inhibitor (SB203580) or JNK inhibitor (SP600125), but not by treatment with an ERK inhibitor (PD98059), which indicated that AGE-induced osteoblast differentiation from EPCs may be mediated by p38MAPK and JNK signaling, but not by ERK signaling. These data suggested that AGEs may bind to RAGE on the EPC membrane to trigger differentiation into osteoblasts. The underlying mechanism appears to involve the p38MAPK and JNK1/2 pathways, but not the ERK1/2 pathway.

Highlights

Diabetes is one of the most common chronic diseases in the world
Advanced glycation end products (AGEs) have been shown to induce the differentiation of human periodontal ligament stem cells into osteoblasts [8], indicating that they may have potential to promote the differentiation of endothelial progenitor cells (EPCs) into osteoblasts during the process of diabetes-related vascular injury
Transfection with siRAGE prevented AGE-induced differentiation of osteoblasts from EPCs, as the protein expression levels of calcification-related proteins (OPG and RUNX2) were significantly decreased in the siRAGEtreated cells compared with those in the AGEs and EV +AGE groups (Figure 5(e)). These results suggested that AGEs promote osteogenic differentiation of EPCs via receptor for AGE (RAGE)

Summary

Introduction

In 2019, 8.8% of the adult population (463 million people) was reported to have diabetes [1]. Systemic vascular impairment is the most common complication of diabetes and is one of the leading causes of mortality in diabetic patients. The incidence of vascular complications was significantly increased in patients with diabetes compared with those without diabetes [3, 4]. AGEs are reported to significantly promote the development of atherosclerosis through signaling mediated by receptor for AGE (RAGE) [5]. AGEs have been shown to induce the differentiation of human periodontal ligament stem cells into osteoblasts [8], indicating that they may have potential to promote the differentiation of EPCs into osteoblasts during the process of diabetes-related vascular injury

Objectives

Methods

Conclusion