Glycosaminoglycan synthesis in the nucleus pulposus: Dysregulation and the pathogenesis of disc degeneration

Few human tissues have functions as closely linked to the composition of their extracellular matrices as the intervertebral disc. In fact, the hallmark of intervertebral disc degeneration, commonly accompanying low back and neck pain, is the progressive loss of extracellular matrix molecules - specifically the GAG-substituted proteoglycans. While this loss is often associated with increased extracellular catabolism via metalloproteinases and pro-inflammatory cytokines, there is strong evidence that disc degeneration is related to dysregulation of the enzymes involved in GAG biosynthesis. In this review, we discuss those environmental factors, unique to the disc, that control expression and function of XT-1, GlcAT-I, and ChSy/ChPF in the healthy and degenerative state. Additionally, we address the pathophysiology of aberrant GAG biosynthesis and highlight therapeutic strategies designed to augment the loss of extracellular matrix molecules that afflict the degenerative state. •Biomechanical function of the intervertebral disc is directly linked to the integrity of its extracellular matrix•Environmental factors unique to the intervertebral disc control expression of enzymes involved in GAG biosynthesis•Dysregulation of GAG biosynthesis contributes to intervertebral disc degeneration through loss of proteoglycan function