Enhanced osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis: a study based on a three-dimensional biomimetic environment

Guan Zheng,Xiaohua Wu,Huiyong Shen,Zhongyu Xie,Peng Wang,Hongjun Su,Guiwen Ye,Jinteng Li,Su’An Tang,Shan Wang,Ming Li,Wenjie Liu,Yanfeng Wu,Shuizhong Cen,Yuxi Li

doi:10.1038/s41419-019-1586-1

Abstract

The mechanism of pathological osteogenesis in Ankylosing spondylitis (AS) is largely unknown. Our previous studies demonstrated that the imbalance between BMP-2 and Noggin secretion induces abnormal osteogenic differentiation of marrow-derived mesenchymal stem cells (MSCs) from AS patients in a two-dimensional culture environment. In this study, HA/β-TCP scaffolds were further used as a three-dimensional (3D) biomimetic culture system to mimic the bone microenvironment in vivo to determine the abnormal osteogenic differentiation of AS-MSCs. We demonstrated that when cultured in HA/β-TCP scaffolds, AS-MSCs had a stronger osteogenic differentiation capacity than that of MSCs from healthy donors (HD-MSCs) in vitro and in vivo. This dysfunction resulted from BMP2 overexpression in AS-MSCs, which excessively activated the Smad1/5/8 and ERK signalling pathways and finally led to enhanced osteogenic differentiation. Both the signalling pathway inhibitors and siRNAs inhibiting BMP2 expression could rectify the enhanced osteogenic differentiation of AS-MSCs. Furthermore, BMP2 expression in ossifying entheses was significantly higher in AS patients. In summary, our study demonstrated that AS-MSCs possess enhanced osteogenic differentiation in HA/β-TCP scaffolds as a 3D biomimetic microenvironment because of BMP2 overexpression, but not Noggin. These results provide insights into the mechanism of pathological osteogenesis, which can aid in the development of niche-targeting medications for AS.

Highlights

Ankylosing spondylitis (AS) is a common autoimmune disease that affects the axial skeleton, and one of its critical pathogenic features is new bone formation at local sites of entheses[1], which is confined to the periosteal bone compartment, outside the cortical bone lining
The intensity of Alkaline phosphatase (ALP) staining in HA/β-TCP gradually increased during osteogenic differentiation
In this study, we demonstrated that AS-mesenchymal stem cells (MSCs) had a stronger capacity for osteogenic differentiation than HD

Summary

Introduction

Ankylosing spondylitis (AS) is a common autoimmune disease that affects the axial skeleton, and one of its critical pathogenic features is new bone formation at local sites of entheses[1], which is confined to the periosteal bone compartment, outside the cortical bone lining. Mesenchymal stem cells (MSCs) are one of the most important kinds of multipotential stem cells and possess strong immunoregulatory and trilineage differentiation abilities[5]. Dysfunction of the osteogenic differentiation ability of MSCs contributes to bone metabolism disorders in rheumatic diseases[7]. For. Official journal of the Cell Death Differentiation Association. Zheng et al Cell Death and Disease (2019)10:350 example, mesenchymal progenitors increased, decreased osteoblast differentiation is progressive with disease development in Interleukin-1 receptor antagonist knock-out mice, which spontaneously develop RA-like disease[8]. Several histopathologic studies in AS patients prove that endochondral new bone formation during bone erosion involves a series of events from chondrocyte apoptosis to colonization of preosteoblasts, differentiation of the preosteoblasts to osteolasts and bone matrix secretion[10]. MSCs as progenitor cells may play an important role in pathophysiological processes

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Conclusion