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

Abstract

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.

Keywords: Extracellular matrix; GAG synthesis; Intervertebral disc; Intervertebral disc degeneration; Proteoglycans.

Figure 1

Major proteoglycans in the intervertebral disc. Schematic of the GAG-substituted proteoglycans in the intervertebral disc showing their subcellular localization, core protein structure, and GAG-chains. Abbreviations: heparan sulfate (HS), chondroitin sulfate/dermatan sulfate (CS/DS), keratin sulfate (KS), and hyaluronic acid (HA).

Figure 2

Regulation of enzymes involved in GAG biosynthesis in the intervertebral disc. Schematic of the hexoses and hexotransferases involved in CS/DS and HS GAG chain biosynthesis. The common CS/DS and HS linkage chain is thought to be synthesized in either the pre-golgi or endoplasmic reticulum exit sites. The GAG repeating disaccharide region shown is specific for CS chains and occurs in the Golgi. Transcription factors and environmental cues regulating enzyme expression in the disc are shown for enzymes highlighted in green. Enzymes with regulation not yet known in the disc are shown in black. Abbreviations:

Figure 3

Pathologies associated with dysregulation of GAG synthesis in the intervertebral disc.