TY - JOUR
T1 - Bone Marrow Derived Extracellular Vesicles Activate Osteoclast Differentiation in Traumatic Brain Injury Induced Bone Loss
AU - Singleton, Quante
AU - Vaibhav, Kumar
AU - Braun, Molly
AU - Patel, Chandani
AU - Khayrullin, Andrew
AU - Mendhe, Bharati
AU - Lee, Byung R.
AU - Kolhe, Ravindra
AU - Kaiser, Helen
AU - Awad, Mohamed E.
AU - Fariyike, Tunde
AU - Elsayed, Ranya
AU - Elsalanty, Mohammed Elsayed
AU - Isales, Carlos M.
AU - Liu, Yutao
AU - Hamrick, Mark W.
AU - Dhandapani, Krishnan M.
AU - Fulzele, Sadanand
N1 - Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/1
Y1 - 2021/1
N2 - 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-κB 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. We also found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy and activated NF-κB signaling genes in bone marrow-derived cells. Additionally, we showed that miRNA-1224 up-regulated in bone marrow-derived EVs cargo of TBI. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NF-κB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.
AB - 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-κB 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. We also found bone marrow derived extracellular vesicles (EVs) from TBI mice enhanced the colony forming ability and osteoclast differentiation efficacy and activated NF-κB signaling genes in bone marrow-derived cells. Additionally, we showed that miRNA-1224 up-regulated in bone marrow-derived EVs cargo of TBI. Taken together, we provide evidence that TBI-induced inflammatory stress on bone and the bone marrow niche may activate NF-κB leading to accelerated bone loss. Targeted inhibition of these signaling pathways may reverse TBI-induced bone loss and reduce fracture rates.
KW - Animals
KW - Biomarkers/metabolism
KW - Bone Marrow/metabolism
KW - Bone Resorption/etiology
KW - Brain Injuries, Traumatic/complications
KW - Cell Differentiation
KW - Cytokines/metabolism
KW - Extracellular Vesicles/metabolism
KW - Femur/diagnostic imaging
KW - Gene Expression Regulation
KW - Inflammation/genetics
KW - Male
KW - Mice
KW - MicroRNAs/genetics
KW - NF-kappa B/metabolism
KW - Osteoclasts/cytology
KW - Osteogenesis
KW - Signal Transduction
KW - X-Ray Microtomography
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U2 - 10.3390/cells8010063
DO - 10.3390/cells8010063
M3 - Article
C2 - 30658394
SN - 1615-6846
VL - 8
JO - Fuel Cells
JF - Fuel Cells
IS - 1
M1 - 63
ER -