INTS7-ABCD3 Interaction Stimulates the Proliferation and Osteoblastic Differentiation of Mouse Bone Marrow Mesenchymal Stem Cells by Suppressing Oxidative Stress

Yubo Liu; Xiao Yu; Anquan Huang; Xiangxin Zhang; Yijun Wang; Wei Geng; Renjie Xu; Suoyuan Li; Hui He; Bo Zheng; Guangxiang Chen; Yaozeng Xu

doi:10.3389/fphys.2021.758607

INTS7-ABCD3 Interaction Stimulates the Proliferation and Osteoblastic Differentiation of Mouse Bone Marrow Mesenchymal Stem Cells by Suppressing Oxidative Stress

Front Physiol. 2021 Nov 22:12:758607. doi: 10.3389/fphys.2021.758607. eCollection 2021.

Authors

Yubo Liu^{1

2}, Xiao Yu², Anquan Huang², Xiangxin Zhang², Yijun Wang¹, Wei Geng¹, Renjie Xu², Suoyuan Li², Hui He², Bo Zheng^{3

4}, Guangxiang Chen², Yaozeng Xu¹

Affiliations

¹ Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, China.
² Department of Orthopaedics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
³ State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, China.
⁴ State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.

Abstract

Increased adipocyte and decreased osteoblast differentiation, combined with the ectopic proliferation of bone marrow mesenchymal stem cells (BM-MSCs), represent the primary causes of osteoporosis. The dysregulation of numerous intracellular bioactive factors is responsible for the aberrant differentiation and growth of BM-MSCs. In this study, we focused on a new stimulative factor, integrator complex subunit 7 (INTS7), and its cooperative protein ATP-binding cassette subfamily D member 3 (ABCD3)/high-density lipoprotein-binding protein (HDLBP) in mouse BM-MSCs. We aimed to uncover the effects of the INTS7-ABCD3/HDLBP interaction on BM-MSC biological behaviors and the potential mechanism underlying these effects. Functional in vitro experiments showed that the suppression of the INTS7-ABCD3 interaction rather than HDLBP could impair BM-MSC proliferation and induce cell apoptosis. Moreover, Alizarin Red S and Oil Red O staining, respectively, revealed that INTS7 and ABCD3 knockdown but not HDLBP knockdown could decrease osteoblastic differentiation and accelerate the adipogenic differentiation of BM-MSCs. Mechanistically, reactive oxygen species (ROS) and histone γ-H2AX quantities significantly increased, whereas the levels of antioxidants declined due to INTS7 and ABCD3 inhibition in BM-MSCs. These findings indicated that the suppression of oxidative stress could be involved in the INTS7/ABCD3 co-regulatory mechanisms for BM-MSC proliferation and differentiation, identifying new potential candidates for osteoporosis therapy.

Keywords: ABCD3; INTS7; adipogenic differentiation; bone marrow mesenchymal stem cells (BM-MSCs); osteoblastic differentiation; oxidative stress; proliferation.