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Page 60 Al-Sammarraie et al. Neuroimmunol Neuroinflammation 2021;8:53-63 I http://dx.doi.org/10.20517/2347-8659.2020.34

ROLE OF BMP SIGNALING IN INFLAMMATION AFTER SCI
Inflammation is encountered in both the acute and chronic phases of SCI and results in expansion of
the initial lesion, destruction of nearby tissue, neuronal loss, axonal demyelination, and fibrosis or scar
[53]
formation . Shortly after SCI, there is massive infiltration of neutrophils and after 24 hours, infiltration
[9]
of reactive microglia/macrophages increases progressively . Several weeks following SCI, there is an
increase in the infiltration of CD45-positive cells and CD68-positive reactive microglia/macrophages,
which mark the phase of chronic inflammation in SCI and are associated with impairment of locomotive
[11]
function . Recent studies suggest contradictory roles of the inhibition of BMP signaling on inflammatory
responses after SCI. The transplantation of noggin-expressing NSCs in SCI rats results in a marked increase
[16]
in macrophage infiltration . In contrast, the overexpression of BAMBI in a rat model of SCI results
in inhibition of neuroinflammation, which is characterized by reduction in the levels of expression of
[54]
interleukin (IL)-1β, IL-6, IL-10, TGFβ, and mechanistic target of rapamycin .
ROLE OF BMP SIGNALING IN NEURONAL AND GLIAL CELL DEATH AFTER SCI
Both neurons and oligodendrocytes are highly susceptible to cellular damage and death following SCI
resulting in axonal demyelination and neurological deficits [7,55] . In vitro and in vivo studies have shown that
[24]
BMP7 exerts beneficial effects on neuronal and oligodendrocyte cell survival [24,56] . de Rivero Vaccari et al.
studied the protective mechanism of BMP7 on neuronal survival after SCI in vitro and in vivo. BMP7
[24]
promotes neuronal survival after SCI in rats and inhibits glutamate induced neuronal cell death in vitro .
Similarly, Wang et al. tested the effects of BMP7 on the survival of oligodendrocytes in vitro. Results
[56]
showed that BMP7 treatment prevented tumor necrosis factor α-induced oligodendrocyte death. These
results imply that BMP7 protects neurons and oligodendrocytes from cell death in SCI models. On the
[57]
other hand, a recent study conducted by Hart et al. has shown that BMP4 induces apoptosis in both
neurons and oligodendrocytes via the activation of caspase-3 (the final executioner of apoptosis) after SCI,
while its inhibition using BMP signaling inhibitors attenuates the activation of caspase-3. These results
suggest different roles of different BMP ligands on neuronal and glial cell survival post-SCI, which requires
further investigation.

CONCLUSION AND FUTURE PROSPECTIVE
BMP ligands, receptors, and inhibitors are differentially expressed in the intact spinal cord in rodents.
BMP ligands, receptors, and canonical and non-canonical pathways are upregulated after SCI. In general,
augmented BMP signaling results in adverse cellular responses and impairs functional recovery in SCI
animal models. On the other hand, the inhibition of BMP signaling improves neuronal cell survival,
neuronal outgrowth, and functional recovery after SCI. Although BMP dysregulation is reported in SCI,
the cell-type specific role of BMP signaling in SCI remains poorly understood. Several gaps in knowledge
still exist regarding the molecular mechanisms underlying BMP dysregulation, the direct causal link
between individual BMP ligands and receptors and progression of pathogenesis in SCI, the spatial and
temporal effects of BMP signaling in the pathogenesis of acute, subacute, and chronic phases in SCI, and
the mechanisms by which BMP ligands regulate autophagy, inflammation, differentiation, and apoptosis.
Further in vivo studies using conditional knockout rodent models are needed to understand the specific
requirements of different BMP ligands in SCI and neurological recovery, the ligand-receptor pairs that are
involved in the regulation of SCI pathogenesis, and the downstream canonical or non-canonical pathways
that impact neuronal survival after SCI.

DECLARATIONS
Authors’ contributions
Conceptualized the theme and conducted the literature review process: Al-Sammarraie N
Contributed to the preparation and revision of the manuscript, interpretation of subtopics, and preparation