Silencing of the MEKK2/MEKK3 Pathway Protects against Spinal Cord Injury via the Hedgehog Pathway and the JNK Pathway

Abstract

Spinal cord injury (SCI) is a devastating medical condition, often accompanied by motor and sensory dysfunction. The Hedgehog (Hh) pathway has a protective role in pathological injury after SCI. However, the specific mechanism remains unclear. The present study aimed to confirm the effects of the mitogen-activated protein kinase kinase-2 (MEKK2)/MEKK3/JNK/Hh pathway on SCI. SCI rat models were established and then inoculated with plasmids overexpressing MEKK2/MEKK3 or with small interfering RNA (siRNA) against MEKK2/MEKK3. The expression of MEKK2 and -3 was detected in dorsal root ganglia (DRG) cells. The motor function of hindlimbs, the expression of the c-Jun N-terminal kinase (JNK)- and Hh-pathway-related genes, and the level of neurofilament-200 (NF-200) and glial fibrillary acidic protein (GFAP) were measured. MEKK2 and -3 were expressed at a high level in DRG cells. The silencing of MEKK2/MEKK3 in rats caused an increase in the expression of glioma-associated oncogene homolog-1 (Gli-1), Nestin, smoothened (Smo), and Sonic Hedgehog (Shh). The Basso, Beattie, and Bresnahan (BBB) rating and the level of NF-200 protein also increased. However, the expression of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1β (MIP-1β), MIP-3α, p-JNK/JNK, and p-c-Jun/c-Jun and the level of GFAP were reduced. Downregulation of MEKK2/MEKK3 ameliorated the symptoms of SCI by promoting neural progenitor cell differentiation via activating the Hh pathway and disrupting the JNK pathway. The findings in this study reveal a potential biomarker for SCI treatment. Keywords: spinal cord injury, Hedgehog signaling pathway, MEKK2/MEKK3, JNK signaling pathway, neural progenitor cell differentiation