Deciphering Disc Degeneration: Untangling the Roles of Age and Inflammation

About This Grant

Low back pain is the world’s leading cause of disability and the degeneration of the intervertebral disc is implicated as a primary driver of pain. A hallmark of disc degeneration is loss of proteoglycans (PG), which reduces disc hydration and osmotic pressure, diminishing the ability of the disc to resist compressive loads during physical activity. This results in instability, abnormal loading conditions in adjacent joints and tissues, disc herniation and possibly low back pain. Thus, the disruption of PG homeostasis is both a key metric of disc degeneration and an opportunity for therapeutic intervention. While PG catabolism induced by inflammation and aging has been extensively studied in disc degeneration, much less is known about PG anabolism. Our global objective is to identify factors that diminish PG anabolism and lead to disc degeneration. Glucose metabolism is a key regulator of PG biosynthesis. Nucleotide sugars are essential for PG biosynthesis and are synthesized through two minor branches of glycolysis, the uronic acid pathway and the hexosamine biosynthetic pathway. ATP serves as an energy source and a building block in PG biosynthesis and is predominantly generated in disc cells by glycolysis. However, the relationship between glycolysis and disc degeneration is unclear. We hypothesize that (1) Aging decreases glycolytic enzyme activities and PG biosynthesis, while Inflammatory conditions increase glycolysis but decrease PG biosynthesis by limiting activities along the uronic acid and hexosamine pathways; (2) An age-related decrease in gluocse uptake is mediated by inflammation; (3) Disc degeneration can occur due to age and inflammation-related effects on PG biosynthesis. The hypotheses will be tested by the following specific aims. Since the imbalance of anabolism and catabolism is implicated in disc degeneration, in Aim 1, we will systematically quantify how age and inflammation impact anabolic (i.e., glucose and PG metabolism) and catabolic activities of human disc cells in vitro. Then, in Aim 2, we will investigate the in vivo correlation between glycolysis, inflammation, and disc degeneration by performing FDG PET on discs in spinal fusion patients and measuring the inflammation in discarded disc tissues. In Aim 3, we will refine our virtual human disc to include inflammation. We will then use the model to probe age and inflammation in silico and to train a lightweight AI model for image-based disc disease prediction that can integrate into the electronic health record. Combining our expertise in in vitro, in vivo, and computational analysis of disc disease will identify new therapeutic targets for disc degeneration and validate imaging and computational tools for diagnosing disc inflammation and degeneration.