miRNA-92a-3p regulates osteoblast differentiation in patients with concomitant limb fractures and TBI via IBSP/PI3K-AKT inhibition

Liangcong Hu; Jing Liu; Hang Xue; Adriana C Panayi; Xudong Xie; Ze Lin; Tiantian Wang; Yuan Xiong; Yiqiang Hu; Chengcheng Yan; Lang Chen; Abudula Abududilibaier; Wu Zhou; Bobin Mi; Guohui Liu

doi:10.1016/j.omtn.2021.02.008

miRNA-92a-3p regulates osteoblast differentiation in patients with concomitant limb fractures and TBI via IBSP/PI3K-AKT inhibition

Mol Ther Nucleic Acids. 2021 Feb 15:23:1345-1359. doi: 10.1016/j.omtn.2021.02.008. eCollection 2021 Mar 5.

Authors

Affiliations

¹ Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
² Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston 02215, USA.
³ Department of Emergency, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.

Abstract

Patients who sustain concomitant fractures and traumatic brain injury (TBI) are known to have significantly quicker fracture-healing rates than patients with isolated fractures. The mechanisms underlying this phenomenon have yet to be identified. In the present study, we found that the upregulation of microRNA-92a-3p (miRNA-92a-3p) induced by TBI correlated with a decrease in integrin binding sialoprotein (IBSP) expression in callus formation. In vitro, overexpressing miRNA-92a-3p inhibited IBSP expression and accelerated osteoblast differentiation, whereas silencing of miRNA-92a-3p inhibited osteoblast activity. A decrease in IBSP facilitated osteoblast differentiation via the Phosphatidylinositol 3-kinase/threonine kinase 1 (PI3K/AKT) signaling pathway. Through luciferase assays, we found evidence that IBSP is a miRNA-92a-3p target gene that negatively regulates osteoblast differentiation. Moreover, the present study confirmed that pre-injection of agomiR-92a-3p leads to increased bone formation. Collectively, these results indicate that miRNA-92a-3p overexpression may be a key factor underlying the improved fracture healing observed in TBI patients. Upregulation of miRNA-92a-3p may therefore be a promising therapeutic strategy for promoting fracture healing and preventing nonunion.

Keywords: fracture; healing; miRNA; traumatic brain injury.