P53 and Parkin co-regulate mitophagy in bone marrow mesenchymal stem cells to promote the repair of early steroid-induced osteonecrosis of the femoral head

Fei Zhang,Jianhua Wu,Zhihong Xie,Wentao Dong,Tao Wang,Wuxun Peng,Jian Zhang

doi:10.1038/s41419-020-2238-1

Fei Zhang, Jianhua Wu + Show 5 more

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https://doi.org/10.1038/s41419-020-2238-1

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Journal: Cell Death & Disease	Publication Date: Jan 1, 2020
Citations: 67	License type: open-access

Affiliation: Guiyang Medical University

Abstract

Survival and stemness of bone marrow mesenchymal stem cells (BMSCs) in osteonecrotic areas are especially important in the treatment of early steroid-induced osteonecrosis of the femoral head (ONFH). We had previously used BMSCs to repair early steroid-induced ONFH, but the transplanted BMSCs underwent a great deal of stress-induced apoptosis and aging in the oxidative-stress (OS) microenvironment of the femoral-head necrotic area, which limited their efficacy. Our subsequent studies have shown that under OS, massive accumulation of damaged mitochondria in cells is an important factor leading to stress-induced apoptosis and senescence of BMSCs. The main reason for this accumulation is that OS leads to upregulation of protein 53 (P53), which inhibits mitochondrial translocation of Parkin and activation of Parkin’s E3 ubiquitin ligase, which decreases the level of mitophagy and leads to failure of cells to effectively remove damaged mitochondria. However, P53 downregulation can effectively reverse this process. Therefore, we upregulated Parkin and downregulated P53 in BMSCs. We found that this significantly enhanced mitophagy in BMSCs, decreased the accumulation of damaged mitochondria in cells, effectively resisted stress-induced BMSCs apoptosis and senescence, and improved the effect of BMSCs transplantation on early steroid-induced ONFH.

Highlights

Effective treatment of early steroid-induced osteonecrosis of the femoral head (ONFH) is still a difficult and urgent problem in the field of orthopedics
The results showed that upregulation of Parkin and downregulation of protein 53 (P53) could further increase the number of mitophagic bodies in Bone marrow mesenchymal stem cell (BMSCs) on the basis of Parkin upregulation alone (Fig. 5g), and MitoTracker Green staining showed that damagedmitochondria content in the cells decreased (Fig. 5h, k–m)
ShP53 group, the new-bone tissue had completely matured, and the boundary between new and normal bone was not clear (Fig. 7b–g). These results suggested that upregulation of Parkin and downregulation of P53 to enhance mitophagy of BMSCs could effectively improve the reparative effect of BMSCs on early steroid-induced ONFH

Summary

Introduction

Effective treatment of early steroid-induced osteonecrosis of the femoral head (ONFH) is still a difficult and urgent problem in the field of orthopedics. Bone marrow mesenchymal stem cell (BMSCs) transplantation has been used to treat early steroid-induced ONFH1–3. Survival and stemness of BMSCs in the bone necrotic area are key to transplantation effectiveness[4,5,6,7]. After the femoral head suffers avascular necrosis, an oxidative-stress (OS) microenvironment forms in the osteonecrotic area[8,9,10]. Central to OS is the release by impaired mitochondria of excessive reactive oxygen species (ROS) and apoptosisinducing factors, which, in turn, increases telomere consumption, arrests the cell cycle, activates signaling pathways such as protein 53 (P53) and protein 38 mitogen-activated protein kinase (P38MAPK), and leads to cellular-stress-induced apoptosis and senescence[13,14,15].

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