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Secreted chemokines and transcriptomic analyses reveal diverse inflammatory and degenerative processes in the intervertebral disc of the STZ-HFD mouse model of Type 2 diabetes

ABSTRACT: The chronic inflammation resultant from type 2 diabetes (T2D) is also associated with spinal pathologies, including intervertebral disc (IVD) degeneration and chronic neck and back pain. Although confounding factors, such as increased weight gain in obesity, studies have shown that even after adjusting age, body mass index, and genetics (e.g. twins), patients with T2D suffer from disproportionately more IVD degeneration and back pain. We hypothesize that chronic T2D fosters a proinflammatory microenvironment within the IVD that promotes degeneration and disrupts disc homeostasis. To test this hypothesis, we evaluated two commonly used mouse models of T2D – the leptin-receptor deficient mouse (db/db) and the chronic high-fat diet in mice with impaired beta-cell function (STZ-HFD). STZ-HFD IVDs were more degenerated and showed differential expression of chemokines from the db/db models. Moreover, the RNAseq analysis revealed vast transcriptional dysregulation of many pathways in the STZ-HFD but not in the db/db tissues. Taken together, the STZ-HFD may better recapitulates the complexities of the chronic inflammatory processes in the IVD during T2D

ORGANISM(S): Mus musculus

PROVIDER: GSE288503 | GEO | 2025/03/25

REPOSITORIES: GEO

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Project description:Although the degenerating disc is considered to be the key source of pain in patients with low back pain, the relationship between disc cells, nerves, and pain production is poorly understood. Neurotrophins are signaling molecules involved in the survival, differentiation, migration, and neurite outgrowth of central and peripheral neurons. Neurotrophins are now known to be expressed in non-neuronal tissues, including the intervertebral disc. We hypothesize that the inflammatory cytokine interleukin-1 (IL-1beta), which is produced by disc cells during degeneration, is a key element in the cascade of events involving neurotrophins. To test this, we used an in vitro experimental design which challenged 3D-cultured human annulus cells with IL-1beta and utilized microarray analysis to evaluate neurotrophin- and nerve-related gene expression profiles in treated vs. control cells. Analysis of nerve growth factor levels in conditioned media was also performed. Findings presented here support the hypothesis that proinflammatory cytokines (which are produced by disc cells during degeneration) are involved with a significant increase in the expression of neurotrophins and other nerve-related genes. Findings expand previous data on expression of neurotrophins in the degenerating disc, and provide the first documentation of expression of neurotrophin 3 and neuropilin 2. These results have direct translational relevance because they address the primary clinical issue with disc degeneration (low back pain) and open the possibility of novel analgesic therapies based on development of specific small-molecular antagonists to neurotrophins. Human disc tissue samples were obtained from surgical disc procedures performed on patients with herniated discs and degenerative disc disease. Cultured annulus cells were grown in a 3D collagen construct with or without 10 2 pM IL-1 for a total of 14 days. Following homogenization in TRIzol reagent, total RNA was isolated and analyzed via mircoarray.

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Secreted chemokines and transcriptomic analyses reveal diverse inflammatory and degenerative processes in the intervertebral disc of the STZ-HFD mouse model of Type 2 diabetes

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