Intervertebral disc degeneration (IVDD) is a predominant contributor to low back pain, characterized by nucleus pulposus cell (NPC) senescence, extracellular matrix (ECM) metabolic dysfunction, and chronic inflammation. Excessive mitochondrial fission contributes to IVDD, yet the underlying regulatory mechanisms remain unclear. Herein, we identified ETS proto-oncogene 1 (ETS1) as a critical regulator of mitochondrial fission in human NPCs. ETS1 was upregulated in severe human IVDD and correlated with disc degeneration severity and NPC senescence. Mechanistically, inflammatory cytokines induced ETS1 upregulation, which directly bound to the dynamin 1-like (DNM1L, encoding DRP1) promoter and activated its transcription. Increased DRP1 triggered excessive mitochondrial fission, leading to reactive oxygen species accumulation, NPC senescence, and ECM catabolism. Inhibition of ETS1 via AAV5-mediated RNA interference or targeting DRP1 with CRISPR/dCas9-KRAB system or Mdivi-1 alleviated mitochondrial dysfunction, cellular senescence, ECM degradation, and attenuated IVDD progression. Collectively, our findings revealed the ETS1/DRP1 axis as a novel pathogenic mechanism and a potential therapeutic target in IVDD.
Pengfei Li, Yichen Que, Shuhao Zhang et al.· Cellular Signalling· 0 citations
Among adolescents worldwide, osteosarcoma (OS) is one of the most frequently occurring cancers. DSCAM-AS1, a recognized lncRNA, has been noted for its abnormal expression in the development of certain cancers, but its role in OS is still unclear. Quantification of DSCAM-AS1, miR-211-5p, and PDCD6 expression was carried out via qRT-PCR or western blotting in human osteosarcoma cell lines (HOS, MG63, U2OS, SaOS-2) and a normal osteoblastic cell line (hFOB 1.19) using quantitative real-time polymerase chain reaction (qRT-PCR) for RNA detection and western blotting for protein detection, respectively. Cellular proliferation, apoptosis, migration, and invasion in OS cell models were comprehensively evaluated through a combination of experimental approaches, including EdU incorporation assay, CFSE labeling coupled with flow cytometric analysis, as well as transwell invasion and migration assays. To shed light on the molecular mechanisms of interactions among pertinent RNA molecules, researchers conducted luciferase reporter assays, RNA pull-down experiments, and RIP assays. Expression of DSCAM-AS1, miR-211-5p, and PDCD6 was analyzed based on the GEO database, and their correlations were evaluated. The levels of DSCAM-AS1and PDCD6 were predominantly overexpressed, while miR-211-5p was apparently lowly expressed in OS cells. Functional loss-of-function experiments demonstrated that silencing (knockdown) of DSCAM-AS1 expression substantially diminished OS cell proliferation, migration, and invasion, while simultaneously promoting cellular apoptosis in vitro. Mechanistically. DSCAM-AS1 acted as an upstream factor for miR-211-5p and could increase the expression of miR-211-5p-targeted PDCD6. DSCAM-AS1 facilitated the advancement of OS by increasing PDCD6 levels through miR-211-5p sponging. This observation could shed light on a novel therapeutic target option for OS.
Qi Wang, Yunzheng Zhao, Long-Bao Shi et al.· Drug development research (P...· 0 citations
