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Page 54 Al-Sammarraie et al. Neuroimmunol Neuroinflammation 2021;8:53-63 I http://dx.doi.org/10.20517/2347-8659.2020.34

Figure 1. Molecular components and pathways of BMP signaling. The BMP signaling is initiated by the binding of BMP ligands to BMPR1
and BMPR2. In the canonical pathway, BMP receptors phosphorylate Smad1/5/8, which can bind to Co-Smad4 and are translocated
to the nucleus to regulate the expression of target genes. In the non-canonical pathways, BMP receptors activate non-Smad pathways.
Termination of BMP signaling is achieved by noggin, Smad6, and/or Smad7. BMP: bone morphogenic protein; BMPR: BMP receptor

injury, congenital malformations, degenerative diseases, malignancy, autoimmune diseases, or infections
in the spinal cord [2,5,6] . Traumatic SCI is a devastating neurological condition characterized by both acute
and chronic phases of progressive spinal cord damage that involve neuroinflammation, oligodendrocytes
[7,8]
loss, neuronal loss, demyelination, and reactive astrogliosis with scar formation . The acute phase is
characterized by oligodendrocyte death and demyelination, reactive astrocyte proliferation, axonal swelling,
and acute inflammatory cell infiltration [9,10] . The chronic phase is characterized by chronic infiltration of
inflammatory cells, partial neuronal regrowth and remyelination, and glial scar establishment [10,11] . The
upregulation of detrimental factors and pathways cause progressive pathogenesis leading to the activation
of cysteine proteases (calpains and caspases) for neuronal and glial cell death, and declining neurological
function (motor and sensory) in both acute and chronic traumatic SCI [12,13] . Current research is mostly
focused on traumatic SCI for understanding of its pathogenesis and developing effective new therapeutic
strategies. The main goals in developing new therapies for traumatic SCI are to minimize neural cell loss
and prevent glial scar formation to promote remyelination and functional recovery [8,14] .

Bone morphogenetic proteins (BMPs) are a group of approximately 15 growth regulating polyfunctional
cytokines that belong to the transforming growth factor beta (TGFβ) superfamily and are widely expressed
in both the intact and injured spinal cord [15,16] . Signal activation and transduction include the binding
of BMP cytokines to BMP receptor 1 (BMPR1A, BMPR1B, or ActR-1A) and BMP receptor 2 complex,
followed by phosphorylation and activation of Smad1/5/8 intracellular receptor regulated proteins or
R-Smads [15,17,18] . Smad1/5/8 proteins then bind to the common Smad4 or the Co-Smad4 to form a complex,
which is translocated to the nucleus to regulate transcription of BMP-targeted genes in a context dependent
manner [15,17,18] . Inhibition of signaling is usually achieved via the activation and competitive binding of
Smad6, Smad7, and noggin inhibitory proteins. Smad6 and Smad7 inhibit the interaction between BMP
receptors and R-Smads and/or the interaction between the R-Smads and the common Smad4 [19-21] . Noggin
inhibitory proteins bind with high affinity to BMP ligand proteins and prevent their association with their
[22]
receptors [Figure 1].

Growing evidence from rodent models of SCI [16,23] show that BMP ligands and receptors are expressed
in the intact spinal cord and are drastically upregulated post-injury. This is summarized in Table 1.