The transcriptome and secreted factors of the intervertebral discs in STZ-HFD Type 2 diabetic male mice reveal extensive inflammation.

Abstract

The chronic inflammation observed during type 2 diabetes (T2D) is associated with spinal pathologies, including intervertebral disc (IVD) degeneration and chronic spine pain. Despite the presence of confounding factors, such as obesity, studies have shown that after adjusting for age, body mass index, and genetics (e.g. twins), patients with T2D suffer from disproportionately more IVD degeneration and/or back pain. We hypothesize that chronic T2D fosters a proinflammatory microenvironment within the IVD that promotes degeneration and disrupts IVD 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). Compared to their genetic controls-C57BL/6 wild-type mice for STZ-HFD and heterozygous littermates for db/db-STZ-HFD IVDs exhibited more severe degeneration and elevated chemokine expression profiles. RNA-seq further revealed extensive transcriptional dysregulation in STZ-HFD IVDs that was not observed in the db/db model. The STZ-HFD IVDs also expressed enzymes that enhanced production of glycolytic AGE precursors, impaired non-AGE DAMP pathways, and reduced suppressors of RAGE turnover. These results suggest that, under controlled genetic and environmental conditions, the STZ-HFD model more accurately reflect the multifactorial inflammatory milieu characteristic of T2D-induced IVD degeneration.