11, 12 The skeleton homeostasis was maintained by continuous bone remodeling, which is accomplished by HSCs lineage osteoclasts-induced bone resorption and bMSCs-derived osteoblasts-mediated bone formation. 5, 6, 7, 8, 9, 10 However, whether there is a direct association between the central nervous system (CNS) and accelerated bone healing followed with TBI remains unclear.īone marrow provides a unique microenvironment for hematopoietic stem cells (HSCs) and bone marrow mesenchymal stem cells (bMSCs). 3, 4 The role of circulating growth factors, alkalotic environment, noncoding RNAs and small extracellular vesicles have been established in TBI-accelerated fracture healing. 1, 2 Generally, patients suffered from TBI shows an accelerate fracture healing rate and callus ossification. These results implicate that the adrenergic signals could serve as potential targets for fracture management.įractures combined with traumatic brain injury (TBI) are commonly observed in industrialized society. Thus, we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow. Moreover, β3- and β2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process. Importantly, flow cytometry confirmed that deletion of β2-AR inhibits M2 polarization of macrophages at 7th day and 14th day and TBI-induced HSCs proliferation was impaired in β3-AR knockout mice. RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells. Knockout of β3- or β2-adrenergic receptor (AR) eliminate TBI-mediated anti-inflammation macrophage expansion and TBI-accelerated fracture healing. TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells (HSCs) and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days, which favor fracture healing. Here, we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing chemical sympathectomy blocks TBI-induced fracture healing. However, the impact of CNS injury on hematopoiesis commitment was overlooked. Accumulating evidence indicates that the central nervous system (CNS) plays a pivotal role in regulating immune system and skeletal homeostasis. Traumatic brain injury (TBI) accelerates fracture healing, but the underlying mechanism remains largely unknown.
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