Dataset Information

Galectin‐3 and RAGE differentially control advanced glycation endproduct‐induced collagen damage in murine intervertebral disc organ culture

ABSTRACT: Abstract

Background

Back and neck pain are leading causes of global disability that are associated with intervertebral disc (IVD) degeneration. Causes of IVD degeneration are multifactorial, and diet, age, and diabetes have all been linked to IVD degeneration. Advanced glycation endproducts (AGEs) accumulate in the IVD as a result of aging, diet, and diabetes, and AGE accumulation in the IVD has been shown to induce oxidative stress and catabolic activity that result in collagen damage. An association between AGE accumulation and IVD degeneration is emerging, yet mechanism behind this association remains unclear. The Receptor for AGEs (RAGE) is thought to induce catabolic responses in the IVD, and the AGE receptor Galectin 3 (Gal3) had a protective effect in other tissue systems but has not been evaluated in the IVD.

Methods

This study used an IVD organ culture model with genetically modified mice to analyze the roles of RAGE and Gal3 in an AGE challenge.

Results

Gal3 was protective against an AGE challenge in the murine IVD ex vivo, limiting collagen damage and biomechanical property changes. Gal3 receptor levels in the AF significantly decreased upon an AGE challenge. RAGE was necessary for AGE‐induced collagen damage in the IVD, and RAGE receptor levels in the AF significantly increased upon AGE challenge.

Discussion

These findings suggest both RAGE and Gal3 are important in the IVD response to AGEs and highlight Gal3 as an important receptor with protective effects on collagen damage. This research improves understanding the mechanisms of AGE‐induced IVD degeneration and suggests Gal3 receptor modulation as a potential target for preventative and therapeutic treatment for IVD degeneration. This study investigates the role of the advanced glycation endproduct (AGE) receptors RAGE and Gal3 in modulating collagen damage using intervertebral disc organ culture models with genetically modified mice. AGE challenge induced collagen damage and altered biomechanical properties in IVD organ cultures ex vivo. Gal3 was protective and RAGE presence was necessary for AGE‐induced collagen damage.

SUBMITTER: Gallate Z

PROVIDER: S-EPMC10285763 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Project description:IntroductionThe goal of this study is to characterize transcriptome changes and gene regulation networks in an organ culture system that mimics early post-traumatic intervertebral disc (IVD) degeneration.MethodsTo mimic a traumatic insult, bovine caudal IVDs underwent one strike loading. The control group was cultured under physiological loading. At 24 hours after one strike or physiological loading, RNA was extracted from nucleus pulposus (NP) and annulus fibrosus (AF) tissue. High throughput next generation RNA sequencing was performed to identify differentially expressed genes (DEGs) between the one strike loading group and the control group. Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes analyses were performed to analyze DEGs and pathways. Protein-protein interaction (PPI) network was analyzed with cytoscape software. DEGs were verified using qRT-PCR. Degenerated human IVD tissue was collected for immunofluorescence staining to verify the expression of DEGs in human disc tissue.ResultsOne strike loading resulted in significant gene expression changes compared with physiological loading. In total 253 DEGs were found in NP tissue and 208 DEGs in AF tissue. Many of the highly dysregulated genes have known functions in disc degeneration and extracellular matrix (ECM) homeostasis. ACTB, ACTG, PFN1, MYL12B in NP tissue and FGF1, SPP1 in AF tissue were verified by qRT-PCR and immunofluorescence imaging. The identified DEGs were involved in focal adhesion, ECM-receptor interaction, PI3K-AKT, and cytokine-cytokine receptor interaction pathways. Three clusters of PPI networks were identified. GO enrichment revealed that these DEGs were mainly involved in inflammatory response, the ECM and growth factor signaling and protein folding biological process.ConclusionOur study revealed different DEGs, pathways, biological process and PPI networks involved in post-traumatic IVD degeneration. These findings will advance the understanding of the pathogenesis of IVD degeneration, and help to identify novel biomarkers for the disease diagnosis.