Osteopontin Promotes Angiogenesis in the Spinal Cord and Exerts a Protective Role Against Motor Function Impairment and Neuropathic Pain After Spinal Cord Injury.

STUDY DESIGN: Basic science study using a hemisection spinal cord injury (SCI) model. OBJECTIVE: We sought to assess the effect of blocking osteopontin (OPN) upregulation on motor function recovery and pain behavior after SCI and to further investigate the possible downstream target of OPN in the injured spinal cord. SUMMARY OF BACKGROUND DATA: OPN is a noncollagenous extracellular matrix protein widely expressed across different tissues. Its expression substantially increases following SCI. A previous study suggested that this protein might contribute to locomotor function recovery after SCI. However, its neuroprotective potential was not fully explored, nor were the underlying mechanisms. MATERIALS AND METHODS: We constructed a SCI mouse model and analyzed the expression of OPN at different time points and the particular cell distribution in the injured spinal cord. Then, we blocked OPN upregulation with lentivirus-delivering siRNA targeting OPN specifically and examined its effect on motor function impairment and neuropathic pain after SCI. The underlying mechanisms were explored in the OPN-knockdown mice model and cultured vascular endothelial cells. RESULTS: The proteome study revealed that OPN was the most dramatically increased protein following SCI. OPN in the spinal cord was significantly increased three weeks after SCI. Suppressing OPN upregulation through siRNA exacerbated motor function impairment and neuropathic pain. In addition, SCI resulted in an increase in vascular endothelial growth factor (VEGF), AKT phosphorylation, and angiogenesis within the spinal cord, all of which were curbed by OPN reduction. Similarly, OPN knockdown suppressed VEGF expression, AKT phosphorylation, cell migration, invasion, and angiogenesis in cultured vascular endothelial cells. CONCLUSION: OPN demonstrates a protective influence against motor function impairment and neuropathic pain following SCI. This phenomenon may result from the proangiogenetic effect of OPN, possibly due to activation of the VEGF and/or AKT pathways.

Upregulation of Spinal miR-155-5p Contributes to Mechanical Hyperalgesia by Promoting Inflammatory Activation of Microglia in Bone Cancer Pain Rats.

Bone cancer pain (BCP) seriously deteriorates the life quality of patients, but its underlying mechanism is still unclear. Spinal microRNAs might contribute to the development of BCP and the role of microglial activation is controversial. In this study, we established a BCP model by injecting Walker 256 breast carcinoma cells into the tibial intramedullary cavity of rats and significant hyperalgesia was observed in the BCP rats. The lumbar spinal cords were harvested to perform RNA sequencing (RNA-seq), and 31 differentially expressed miRNAs (26 upregulated and 5 downregulated) were identified in the BCP rats. Among them, miR-155-5p was significantly upregulated in the BCP rats. Spinal microglial activation was observed during BCP development. miR-155-5p could be expressed in spinal microglia and was significantly upregulated in microglia treated with lipopolysaccharide (LPS) in vitro. Serum/glucocorticoid regulated kinase family member 3 (Sgk3) was predicted to be the possible downstream target of miR-155-5p and this was confirmed using a dual-luciferase reporter assay in vitro. The inhibition of miR-155-5p restored Sgk3-expression-attenuated microglial activation and alleviated hyperalgesia in the BCP rats. In conclusion, spinal miR-155-5p/Sgk3/microglial activation might play an important role in BCP pathogenesis.

Ropivacaine represses the proliferation, invasion, and migration of glioblastoma via modulating the microRNA-21-5p/KAT8 regulatory NSL complex subunit 2 axis.

Ropivacaine (Rop) is available to suppress the growth of glioblastoma (GBM), while its mechanism has not been completely elaborated. In this study, we explore the latent mechanism of Rop repressing GBM's growth via mediating the microRNA (miR)-21-5p/KAT8 regulatory NSL complex subunit 2 (KANSL2) axis. MiR-21-5p was declined in GBM, while KANSL2 was elevated. Clinical association studies manifested miR-21-5p was distinctly linked to the tumor size and grade of GBM. Rop constrained GBM cell proliferation, invasion, and migration but boosted apoptosis. Elevated miR-21-5p strengthened Rop's action, while augmented KANSL2 weakened Rop's role. Furthermore, the impact of silencing miR-21-5p on GBM was turned around via declining KANSL2 in Rop-treated GBM cells. KANSL2 was the target gene of miR-21-5p. In short, Rop exerted an anti-tumor impact on GBM via mediating the miR-21-5p/KANSL2 axis, which offered novel viewpoints for the later adoption of Rop as GBM drugs.