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Targeting Bradykinin Signaling Pathway: PLGA/BK Microspheres as a Therapeutic Strategy for Delaying Intervertebral Disc Degeneration

ABSTRACT: Intervertebral disc degeneration(IVDD) is a common spinal condition with limited effective treatments available. This study aims to investigate the impact of poly(lactic-co-glycolic acid)/Bradykinin (PLGA/BK) microspheres on IVDD and its underlying mechanisms. We collected nucleus pulposus samples from both healthy and degenerated human intervertebral discs and conducted immunohistochemical analyses, revealing reduced BK expression in degenerated tissues. Subsequently, we used BK to treat nucleus pulposus cells and conducted Bulk RNA sequencing (RNA-seq), identifying BK's involvement in cellular senescence, extracellular matrix metabolism, and the PI3K signaling pathway. Further experiments using tert-butyl hydroperoxide (TBHP)-induced cell senescence showed that BK treatment reduced senescence, enhanced extracellular matrix synthesis, and inhibited degradation, along with activation of the PI3K pathway. These effects were mediated through B2R (BK receptor 2) and the downstream PI3K pathway. Following this, we developed sustained-release BK microspheres with an optimized manufacturing process. In vitro co-culture experiments showed no observable toxicity. We established an IVDD model in rat tail vertebrae through fine needle puncture, administering local injections of BK sustained-release microspheres. Using various experimental methods, including X-ray, MRI, histopathology, and immunohistochemistry, we found that these microspheres could slow the progression of IVDD. This study highlights the potential of injectable PLGA/BK microspheres to regulate cellular senescence and extracellular matrix metabolism via the B2R and PI3K pathways, ultimately delaying IVDD.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE277600 | GEO | 2024/09/21

REPOSITORIES: GEO

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Intracellular differential gene expression detected by transcriptome sequencing after lactate treatment of nucleus pulposus cells

Project description:The accumulation of metabolites in the intervertebral disc is regarded as an important inducement of intervertebral disc degeneration (IVDD). Lactate, a metabolite produced by the cellular anaerobic glycolysis process, has been proved to be closely associated with IVDD. However, little was known about the role of lactate in nucleus pulposus cells (NPCs) senescence. This study attempted to investigate the effect and molecular mechanism of lactate on NPCs senescence in vitro and in vivo. A puncture-induced disc degeneration model was established in rats. Metabolomics analysis proved that lactate was significantly increased in the rat degenerated intervertebral disc. Eliminating extra lactate using lactate oxidase (LOx)-overexpressing lentivirus alleviated the progression of IVDD. In vitro experiments showed that high concentration lactate could induce senescence and oxidative stress in NPCs. High-throughput RNA sequencing (RNA-seq) results and bioinformatic analysis exhibited that lactate-stimulated NPCs senescence may be related to the PI3K/Akt signaling pathway. Further study verified that high concentration lactate could induce NPCs senescence and oxidative stress via inhibiting PI3K/Akt signaling and downstream Akt/p21/p27/cyclinD1 and Akt/Nrf2/HO-1 pathway. Utilizing molecular docking, we found that lactate may suppress the Akt phosphoactivation via binding to Lys39 and Leu52 in the PH domain of Akt. In conclusion, this study illuminates that lactate could promote the senescence of NPCs to aggravate IVDD by suppressing the PI3K/Akt signaling pathway and the expression of its downstream genes. These results highlight the involvement of lactate NPCs senescence, which may become a novel potential therapeutic target for the treatment of IVDD.

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2024-03-20 | GSE245147 | GEO

The long noncoding RNA expression profile of human intervertebral disc degeneration identified by microarray analysis

Project description:In addition to the well-known short noncoding RNAs as miRNAs, increasing evidence suggests that long noncoding RNAs (lncRNAs) act as key regulators in a wide aspect of biologic processes. Dysregulated expression of lncRNAs has been demonstrated being implicated in a variety of human diseases. However, there is relative paucity of information regarding the role of lncRNAs in intervertebral disc degeneration (IDD) hitherto. We have addressed the expression profiles of miRNAs in IDD previously. To determine whether lncRNAs is differentially expressed in IDD, we employed a lncRNA-mRNA microarray analysis of human nucleus pulposus (five degenerative as IDD and five normal specimens as control). With abundant probes accounting for 33,045 lncRNAs and 30,215 coding transcripts in our microarray, microarray data profiling indicated that 18995 lncRNAs and 14635 mRNAs were detected in all samples with 2309 lncRNAs and 3017 mRNAs differentially expressed in degenerated samples. Amongst them, 164 lncRNAs (97 up and 67 down) and 265 mRNAs were highly differentially expressed with an absolute fold change greater than ten. The upregulated mRNAs included the extracellular matrix components as COL1A2, LUM, FN1ACAN, DCN and ITFG2. 1100 lncRNAs and 1379 mRNAs were altered in the same direction in at least 4 of the 5 degenerative samples with fold change greater than 2 respectively. Three lncRNAs were chosen for the real-time quantitative PCR (qRT-PCR) analysis. qRT-PCR results showed a high consistency with the microarray data. In this study, to explore the potential involvement of lncRNAs in IDD, we conducted lncRNA and mRNA profiling in 5 human control nucleus pulposus tissue and 5 degenerative nucleus pulposus tissue by microarray.Biological replicates: 5 control, 5 degenerated, independently harvested.

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