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Al-Sammarraie et al. Neuroimmunol Neuroinflammation 2021;8:53-63 I http://dx.doi.org/10.20517/2347-8659.2020.34 Page 55

Table 1. Expression of BMP signaling components before and after SCI in rodent models
BMP signaling SCI
component model Outcomes Ref.
BMP ligands Rats BMP7 mRNA was mildly expressed in glial cells in intact spinal cord but markedly expressed in [27]
glial cells and motoneurons post-SCI
Rats BMP2/4 mRNA was mildly expressed in intact spinal cord but markedly expressed in [23]
oligodendrocytes, astrocytes, and microglia surrounding the damaged site post-SCI
Mice BMP2, 4, and 7 levels were increased in neurons, microglia, oligodendrocytes, and NSCs post- [37]
SCI, which enhanced astrocyte proliferation. BMP4 promoted differentiation of astrocytes and
inhibited differentiation of neurons and oligodendrocytes
Rats BMP2 and 4 levels were increased post-SCI and promoted differentiation of the engrafted OPCs [40]
cells into astrocytes
Mice BMP7 expression was increased after SCI and further augmented after agmatine treatment, [30]
leading to reduced collagen scar formation and improved BBB score post-SCI
Rats BMP4 expression was increased in astrocytes cultured from injured thoracic spinal cord [36]
Rats BMP2/4 expression was increased after SCI and associated with low BBB scores [29]
Rats BMP7 was expressed in glial cells of the intact spinal cord and increased in glial cells and [27]
motoneurons after SCI
Mice BMP2 was slightly expressed in intact spinal cord and markedly increased post-SCI [38]
Mice BMP4 level was increased in neurons of gray and white matter and ependyma cells near the [28]
damaged site post-SCI
Rats BMP4 was overexpressed after acute SCI [57]
Rats BMP2, 3, 4, 5, 7, 9, 12, and 13 were expressed in intact spinal cord [16]
BMP receptors Rats BMPR1A and BMPR2 expression levels were increased in neurons post-SCI [23]
BMP antagonists Rats Noggin was minimally expressed in intact spinal cord [16]
Canonical pathway Mice p-Smad1, 5, and 8 were activated in neurons, oligodendrocytes, OPCs, astrocytes, and NSCs post- [37]
SCI
BMP: bone morphogenic protein; SCI: spinal cord injury; OPCs: oligodendrocyte precursor cells; NSCs: neural stem cells; BBB: Basso,
Beattie, and Bresnahan; BMPR: BMP receptor

Table 2. Effects of BMP treatment on neuronal and non-neuronal cells in SCI in in vitro models
BMP signaling Treatment Outcomes Ref.
component
BMP ligands BMP7 BMP7 inhibited tumor necrosis factor α-mediated oligodendrocyte death [56]
BMP7 BMP7 inhibited glutamate induced neuronal cell death [24]
BMP4 In vitro culture of NSCs in the presence of BMP4 resulted in amelioration of oligodendrocyte [25]
differentiation and increase in astrocyte differentiation. Smad1 and 5 were activated in
response to BMP4 treatment of NSCs
BMP7 Noggin expressing OPCs treated with BMP7 showed less astrocytic differentiation [16]
BMP antagonists Noggin Noggin treatment reduced astrocyte numbers. Inhibition of BMP4 using noggin attenuated [37]
differentiation of NSCs into astrocytes
Noggin Noggin treatment of OPCs partially reduced astrocytic differentiation [40]
Noggin Noggin treatment reduced differentiation of OPCs into astrocytes in astrocyte conditioning [36]
media. p-Smad1, 5, and 8 levels were increased in OPCs in astrocyte conditioning media
compared to control. OPCs cultured in astrocyte conditioning media predominantly
differentiated into astrocytes
Noggin and Treatment attenuated BMP4 induced activation of caspase-3 for cell death in neurons and [57]
LDN193189 oligodendrocytes post-SCI
Noggin Noggin treatment reduced astrocytic differentiation and increased the differentiation of NSCs [25]
into oligodendrocytes
BMP: bone morphogenic protein; SCI: spinal cord injury; OPCs: oligodendrocyte precursor cells; NSCs: neural stem cells

Furthermore, in vitro studies [24,25] extensively elucidated the protective and deregulatory role of BMP
components in a variety of cellular events on both neuronal and non-neuronal cells, which are summarized
in Table 2. Most of these studies focused mainly on the level of expression of BMP signaling proteins and
the resultant cellular damage, describing only limited knowledge on molecular regulation and downstream
targets. This article will focus mainly on the role of different BMP ligands and receptors on neuronal and
glial cell differentiation, neuroinflammation, cell death, and autophagy in the in vivo and in vitro models