Elucidating the role of bone morphogenetic protein-4 in regulating secondary injury mechanisms following traumatic spinal cord injury

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Hart, Christopher
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Traumatic spinal cord injury (SCI) initiates secondary injury cascades that include, but are not limited to, inflammation, ischemia, reactive astrogliosis and apoptosis. These mechanisms contribute to tissue degeneration and limit neural regeneration and repair after injury. To optimize future therapeutic approaches, it is necessary to identify factors that regulate the early stages of these endogenous responses in order to limit their deleterious effects. In a pre-clinical in vivo model of clip compressive/contusive SCI in rats, we found that the active form of bone morphogenetic protein-4 (BMP4) is transiently and acutely upregulated after injury. BMP4 is a key signaling protein that regulates embryogenesis and neurodevelopment. BMP4 has also been implicated in modulating glial scarring and remyelination in sub-acute and chronic SCI in rodents. However, the role of BMP4 in early injury cascades after SCI is not well understood. This work sought to elucidate the impact of BMP4 upregulation in acute SCI by utilizing two BMP inhibitors, noggin and LDN193189. We also utilized primary in vitro systems to determine the cell-specific effects of BMP4 on spinal cord neural stem/progenitor cells (NPCs), oligodendrocyte precursor cells (OPCs), astrocytes and neurons. Here, for the first time, we demonstrate that BMP4 promotes cleaved caspase-3 expression in cultured neurons and oligodendrocytes and that acute BMP inhibition attenuates apoptosis and lipid peroxidation after SCI. We also show that BMP4 directly inhibits oligodendrocyte differentiation in NPCs and OPCs in vitro, and BMP inhibition is sufficient to promote oligodendrocyte differentiation and preservation in acute SCI. Intriguingly, LDN193189 treatment also increases myelin thickness of remyelinated axons in chronically injured rats. Importantly, BMP4 potentiates the deposition of inhibitory chondroitin sulfate proteoglycans (CSPGs) by reactive astrocytes in vitro, and this can be attenuated with noggin or LDN193189 treatments in SCI rats. Despite these early benefits, our work reveals that acute inhibition of BMP antagonism was not sufficient to improve long-term functional recovery in SCI rats. Overall, our work provides new insights into the role of BMP4 in acute secondary injury mechanisms of SCI and recognizes BMP4 as a potential target for combinatorial approaches to improve endogenous repair processes in the injured spinal cord.
Bone morphogenetic protein-4, Spinal cord injury, Neural stem/progenitor cells, Cell differentiation, Reactive astrogliosis, Oligodendrocytes, Cell death
Hart, C. G., Dyck, S. M., Kataria, H., Alizadeh, A., Nagakannan, P., Thliveris, J. A., ... & Karimi-Abdolrezaee, S. (2019). Acute upregulation of bone morphogenetic protein-4 regulates endogenous cell response and promotes cell death in spinal cord injury. Experimental Neurology, 325, 113163.