Circulating MiRNA-21-enriched extracellular vesicles promote bone remodeling in traumatic brain injury patients

Bone fracture: faster healing after traumatic brain injuryExtracellular vesicles enriched with a particular microRNA released following traumatic brain injury (TBI) help fractures heal faster and could inform treatments for skeletal disorders. Patients with TBI and associated fractures experience shorter fracture recovery times than patients with fractures only, but precisely why is unclear. Ze Lin at Huazhong University of Science and Technology, Wuhan, China, and co-workers examined molecules released during recovery in samples taken from patients with TBI and fractures, those with fractures only, and mouse models with femur fractures. They found that exosomes (extracellular vesicles that transport metabolites including microRNA) released following TBI are enriched with miRNA-21-5 p, which enhances differentiation of bone-forming cells and bone repair. No miRNA-21-5 p enrichment occurred in patients with fractures only. Knocking out exosomal miRNA-21-5 p impaired bone repair in mice, while injecting exosomes from TBI patients boosted bone formation. Fracture combined with traumatic brain injury (TBI) is one of the most common and serious types of compound trauma in the clinic and is characterized by dysfunction of cellular communication in injured organs. Our prior studies found that TBI was capable of enhancing fracture healing in a paracrine manner. Exosomes (Exos), as small extracellular vesicles, are important paracrine vehicles for noncell therapy. However, whether circulating Exos derived from TBI patients (TBI-Exos) regulate the prohealing effects of fractures remains unclear. Thus, the present study aimed to explore the biological effects of TBI-Exos on fracture healing and reveal the potential molecular mechanism. TBI-Exos were isolated by ultracentrifugation, and the enriched miR-21-5 p was identified by qRT-PCR analysis. The beneficial effects of TBI-Exos on osteoblastic differentiation and bone remodeling were determined by a series of in vitro assays. Bioinformatics analyses were conducted to identify the potential downstream mechanisms of the regulatory effect of TBI-Exos on osteoblasts. Furthermore, the role of the potential signaling pathway of TBI-Exos in mediating the osteoblastic activity of osteoblasts was assessed. Subsequently, a murine fracture model was established, and the effect of TBI-Exos on bone modeling was demonstrated in vivo. TBI-Exos can be internalized by osteoblasts, and in vitro, suppression of SMAD7 promoted osteogenic differentiation, whereas knockdown of miR-21-5 p in TBI-Exos strongly inhibited this bone-beneficial effect. Similarly, our results confirmed that preinjection of TBI-Exos led to enhanced bone formation, whereas knockdown of exosomal miR-21-5 p substantially impaired this bone-beneficial effect in vivo.