Pigment Epithelium-Derived Factor (PEDF) Protects Osteoblastic Cell Line from Glucocorticoid-Induced Apoptosis via PEDF-R.

Shengcheng Yao,Xin Zheng,Hongyan Dong,Fengchao Zhao,Kaijin Guo,Maji Sun,Yingnan Zhang,Xiaoyu Wang

doi:10.3390/ijms17050730

Abstract

Pigment epithelial-derived factor (PEDF) is known as a widely expressed multifunctional secreted glycoprotein whose biological actions are cell-type dependent. Recent studies demonstrated that PEDF displays cytoprotective activity in several cell types. However, it remains unknown whether PEDF is involved in glucocorticoid-induced osteoblast death. The aim of this study was to examine the role of PEDF in osteoblast survival in response to dexamethasone, an active glucocorticoid analogue, and explore the underlying mechanism. In the present study, dexamethasone (DEX) was used to induce MC3T3-E1 pre-osteoblast apoptosis. PEDF mRNA and protein levels and cell apoptosis were determined respectively. Then PEDF receptor (PEDF-R)- and lysophosphatidic acid (LPA)-related signal transductions were assessed. Here we show that DEX down-regulates PEDF expression, which contributes to osteoblast apoptosis. As a result, exogenous recombinant PEDF (rPEDF) inhibited DEX-induced cell apoptosis. We confirmed that PEDF-R was expressed on MC3T3-E1 pre-osteoblast membrane and could bind to PEDF which increased the level of LPA and activated the phosphorylation of Akt. Our results suggest that PEDF attenuated DEX-induced apoptosis in MC3T3-E1 pre-osteoblasts through LPA-dependent Akt activation via PEDF-R.

Highlights

Glucocorticoids (GCs) are frequently used for the management of inflammation and autoimmune disorders
MC3T3-E1 pre-osteoblasts were exposed to a wide range of DEX concentrations for 24 h; in addition, 10 ́5 mol/L DEX was assessed at different time points
According to CCK-8 assay (Figure 1A,B), cell death rates were increased with doses and prolonged DEX treatments, in agreement with data obtained for primary osteoblasts and other osteoblastic cell lines [5]

Summary

Introduction

Glucocorticoids (GCs) are frequently used for the management of inflammation and autoimmune disorders. Among the severe acute respiratory syndrome patients, approximately 39% develop osteonecrosis within a few months of GC treatment [2]. Previous studies reported changes in the bone microenvironment [3], the underlying molecular mechanisms of GC-induced side effects are still not fully understood. Bone remodeling regulates the bone metabolism through the maintenance of the balance between resorption and formation. Previous studies found that GCs could inhibit bone marrow-derived mesenchymal stem cell proliferation, promote adipogenic differentiation and induce osteoblast apoptosis [4,5,6], breaking the balance between bone resorption and formation. The majority of GC effects depend greatly on the glucocorticoid receptor (GR). The molecular mechanisms underlying GC-induced apoptosis remain undefined, hindering the treatment and prevention of GC-induced adverse effects on the skeleton

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