The effect of traumatic brain injury on bone healing from a novel exosome centered perspective in a mice model

Abstract

Background In patients with traumatic brain injury (TBI) combined with long bone fracture, the fracture healing is always faster than that of patients with single fracture, which is characterized by more callus growth at the fracture site and even ectopic ossification. Exosomes are nanoscale membrane vesicles secreted by cells, which contain cell-specific proteins, miRNAs, and mRNAs. Methods In this study, we used exosomes as the entry point to explore the mechanism of brain trauma promoting fracture healing. We established a model of tibia fracture with TBI in mice to observe the callus growth and expression of osteogenic factors at the fracture site. Blood samples of model mice were further collected, exosomes in plasma were extracted by ultra-centrifugation method, and then identified and acted on osteoblasts cultured in vitro. The effects of exosomes on osteoblast differentiation at the cell, protein and gene levels were investigated by Western Blot and q-PCR, respectively. Furthermore, miRNA sequencing of exosomes was performed to identify a pattern of miRNAs that were present at increased or decreased levels. Results The results suggested that plasma exosomes after TBI had the ability to promote the proliferation and differentiation of osteoblasts, which might be due to the increased expression of osteoblast-related miRNA in exosomes. They were transmitted to the osteoblasts at the fracture site, so as to achieve the role of promoting osteogenic differentiation. Conclusion The TBI-derived exosomes may have potential applications for promoting fracture healing in future. The Translational Potential of this Article Plasma exosomes early after TBI have the ability to promote osteoblast proliferation and differentiation. The mechanism may be achieved by miRNA in exosomes. Plasma exosomes may be used as breakthrough clinical treatment for delayed or non-union fractures.

The mechanism of bone healing after traumatic brain injury

“…produced a novel and comprehensive murine multi‐trauma model. During TBI induction, a discernible stratification of severity‐based effects on fracture healing was observed [4] . Specifically, different TBI severity gradations were associated with disparate consequences regarding the temporal dynamics of fracture healing.…”

“…TBIs can induce a cascade of far‐reaching consequences that impact various aspects of an individual's existence [2] . In trauma settings, where long bone fractures are frequently encountered, an interesting phenomenon has emerged between concomitant TBIs and accelerated bone healing [3,4] . Over the past few decades, clinical evidence has increasingly highlighted the unexpected synergy between these seemingly disparate injuries.…”

Research Progress of Exosomes in Bone Diseases: Mechanism, Diagnosis and Therapy

“…There are a large number of exosomes in serum/plasma, and increasing studies pointed out that serum/plasma-derived exosomes have a great application prospect in early detection, diagnosis, and later treatment of bone diseases ( Xie et al, 2018 ; Yang et al, 2021 ) ( Supplementary Table S4 ). It is generally recognized that postmenopausal women often miss the best time for treating OP.…”

ERK-estrogen receptor α signaling plays a role in the process of bone marrow mesenchymal stem cell-derived exosomes protecting against ovariectomy-induced bone loss

“…MSC-Exos are also critical in the musculoskeletal system, in which they exert roles in the progression of repair and reconstruction of cartilage and tendon [ 16 , 17 ]. Moreover, several studies have proven that exosomes accelerate fracture healing in animal models [ 18 , 19 ]. In prevalent joint diseases, MSC-Exos can be used to treat osteoarthritis (OA) and osteochondral lesions in animal models [ 20 ].…”