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

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.

Hu’po Anshen Decoction Accelerated Fracture-Healing in a Rat Model of Traumatic Brain Injury Through Activation of PI3K/AKT Pathway

“…Activating PI3K/AKT pathway can not only promote the osteogenic differentiation of bone marrow stem cells ( Zhao et al, 2020 ) but also enhance the viability of osteoblasts ( Xie et al, 2020 ). In addition, the activation of the PI3K/AKT pathway is one of the mechanisms that the fracture healing rate of TBI patients is faster than that of single fracture patients ( Hu et al, 2021 ). Chlorogenic acid, the active ingredient of HPASD, has been reported to increase femoral bone mineral density and promote osteogenic differentiation of bone marrow stem cells by activating PI3K/AKT pathway ( Zhou et al, 2016 ), and Puerarin was proved to stimulate the human osteoblast differentiation and prevent osteoporosis by activating the PI3K/AKT ( Wang et al, 2013 ).…”

MicroRNA-223-3p is involved in fracture healing by regulating fibroblast growth factor receptor 2

“…Therefore, poor fracture healing remains a major clinical challenge. Current studies have proved that osteoblasts regulate new bone formation in fracture healing, and differentiate and proliferate under the influence of cytokines, hormones, growth factors, and other factors [ 17 ]. Although previous studies have confirmed that miR-497-5p [ 9 ] and others are involved in the process of fracture healing, miR-223-3p associated with osteoblasts was selected in this study.…”

Exosome Derived From Traumatic Brain Injury Patients Accelerates Fracture Healing via SMAD7 Signaling Regulation

“…Interestingly, patients combined with fracture and TBI have long been observed to have a obvious short healing period than the isolated fracture patients. And prior studies have reported a potential relationship between TBI and rapid fracture healing [3][4]. However, the potential mechanisms underlying this interesting phenomenon remain unknown.…”