TNF‐α induces up‐regulation of MicroRNA‐27a via the P38 signalling pathway, which inhibits intervertebral disc degeneration by targeting FSTL1

Abstract

The mechanism of intervertebral disc degeneration is still unclear, and there are no effective therapeutic strategies for treating this condition. miRNAs are naturally occurring macromolecules in the human body and have many biological functions. Therefore, we hope to elucidate whether miRNAs are associated with intervertebral disc degeneration and the underlying mechanisms involved. In our study, differentially expressed miRNAs were predicted by the GEO database and then confirmed by qPCR and in situ hybridization. Apoptosis of nucleus pulposus cells was detected by flow cytometry and Bcl2, Bax and caspase 3. Deposition of extracellular matrix was assessed by Alcian blue staining, and the expression of COX2 and MMP13 was detected by immunofluorescence, Western blot and qPCR. Moreover, qPCR was used to detect the expression of miR27a and its precursors. The results showed that miR27a was rarely expressed in healthy intervertebral discs but showed increased expression in degenerated intervertebral discs. Ectopic miR27a expression inhibited apoptosis, suppressed the inflammatory response and attenuated the catabolism of the extracellular matrix by targeting FSTL1. Furthermore, it seems that the expression of miR27a was up‐regulated by TNF‐α via the P38 signalling pathway. So we conclude that TNF‐α and FSTL1 engage in a positive feedback loop to promote intervertebral disc degeneration. At the same time, miR27a is up‐regulated by TNF‐α via the P38 signalling pathway, which ameliorates inflammation, apoptosis and matrix degradation by targeting FSTL1. Thus, this negative feedback mechanism might contribute to the maintenance of a low degeneration load and would be beneficial to maintain a persistent chronic disc degeneration.

Mesenchymal Stem Cells May Alleviate the Intervertebral Disc Degeneration by Reducing the Oxidative Stress in Nucleus Pulposus Cells

“…The most enriched biological process was Response to oxidative stress, cellular component was Cytoplasm, and molecular function was Identical protein binding. More importantly, we also investigated the potential signaling pathways involved in the repair process of NPCs cocultured with MSCs, and some of these signaling pathways have been proved to play important roles in the pathophysiology of IDD [38][39][40][41][42]. TNF signaling pathway and IL-17 signaling pathway both were inflammation-related pathways, which indicated that MSCs might reduce the oxidative stress, and then improve the inflammatory status of degenerative NPCs [38,39].…”

“…More importantly, we also investigated the potential signaling pathways involved in the repair process of NPCs cocultured with MSCs, and some of these signaling pathways have been proved to play important roles in the pathophysiology of IDD [38][39][40][41][42]. TNF signaling pathway and IL-17 signaling pathway both were inflammation-related pathways, which indicated that MSCs might reduce the oxidative stress, and then improve the inflammatory status of degenerative NPCs [38,39]. MAPK signaling pathway was another vital biolog-ical pathway in the development of IDD [40][41][42] 7 Stem Cells International degenerative NPCs cocultured with MSCs.…”

Novel insights into the interaction between N6‐methyladenosine methylation and noncoding RNAs in musculoskeletal disorders

“… 85 In IDD, the differentially expressed ncRNAs are involved in regulating cell apoptosis and proliferation, ECM degeneration and inflammation. miR‐338‐3p, 86 miR‐27a 87 and miR‐133a‐5p 88 are upregulated in IDD tissues, and target SIRT6, FSTL1 and FBXO6, respectively, participating in regulating NP cell apoptosis, proliferation and ECM synthesis. The downregulated miR‐181a, 89 miR‐623 90 and miR‐874‐3p 91 are related to inflammatory response and ECM degradation.…”

Crosstalk Among circRNA/lncRNA, miRNA, and mRNA in Osteoarthritis

“…By studying three common human cancers ( Zhang et al, 2021b ), namely, colon cancer, esophagus cancer, and kidney cancer, many miRNAs were confirmed to be connected with the three kinds of cancer. In addition, many studies have proven that miRNA is related to the pathological processes of intervertebral disc degeneration ( Shi et al, 2021b ), muscle atrophy ( Zhang et al, 2021a ), and cardiovascular diseases ( Liu et al, 2021a ).…”