Bone marrow derived extracellular vesicles activate osteoclast differentiation in traumatic brain injury induced bone loss

Abstract

Traumatic brain injury (TBI) is a major source of worldwide morbidity and mortality. Patients suffering from TBI exhibit a higher susceptibility to bone loss and an increased rate of bone fractures; however, the underlying mechanisms remain poorly defined. Herein, we observed significantly lower bone quality and elevated levels of inflammation in bone and bone marrow niche after controlled cortical impact-induced TBI in in-vivo CD-1 mice. Further, we identified dysregulated NFB signaling, an established mediator of osteoclast differentiation and bone loss, within the bone marrow niche of TBI mice. Ex vivo studies revealed increased osteoclast differentiation in bone marrow-derived cells from TBI mice, as compared to sham injured mice. Finally, we found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy of bone marrow cells and activated NFB signaling genes in bone marrow-derived cells. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NFB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.

Germacrone alleviates neurological deficits following traumatic brain injury by modulating neuroinflammation and oxidative stress

“…Traumatic brain injury (TBI) is one of the common causes of disability and death. Patients with TBI often have cognitive dysregulation, dyskinesia, memory impairment and other neurological problems [ 1 ]. TBI has both a direct mechanical effect (primary injury) and an indirect effect caused by a complex pathological cascade (secondary injury).…”

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

“…41,42 Currently, research on the increased fracture healing and bone callus formation seen in concomitant brain trauma has largely focused on investigating the effect of cytokines and other proteins, while research on the regulation of miRNAs is still lacking. [43][44][45] However, our study found that the expression level of miRNAs-92a-3p was significantly increased in patients with concomitant fractures and brain trauma, as well as in the mouse model. miRNAs-92a-3p can promote the mineralization and maturation of osteoblast precursor cells in vitro, and local injection of agomiR-92a-3p can significantly promote scab formation at the fracture site in mice.…”