Elsevier

Matrix Biology

Volumes 71–72, October 2018, Pages 368-379
Matrix Biology

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

https://doi.org/10.1016/j.matbio.2018.02.025Get rights and content

Highlights

  • 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

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.

Section snippets

Background

The human spinal column contains 23 intervertebral discs, each flanked by sequential pairs of vertebrae forming a basic spinal motion segment. Each segment represents a polyaxial diarthrodial joint, where the intervertebral disc is specifically tasked with permitting motion and transmitting applied biomechanical loads [1].

The intervertebral disc comprises an outer fibrocartilaginous annulus fibrosus (AF), encompassing a hydrophilic nucleus pulposus (NP), bordered superiorly and inferiorly by

Extracellular matrix composition of the disc

The healthy disc ECM contains PGs covalently substituted with glycosaminoglycans (GAG) chains, collagens and other glycoproteins [[16], [17], [18], [19], [20]]. The three disc compartments are composed of unique patterns of these ECM molecules, based on their specific mechanical and cellular function. Importantly, the most abundant PG in the NP is aggrecan [21]. The aggrecan core protein is bound by both chondroitin sulfate (CS) and keratan sulfate (KS) GAG chains, providing aggrecan with its

Regulation of GAG biosynthesis in the disc

The GAGs are divided into four major groups depending on their core disaccharide structures: chondroitin sulfate/dermatan sulfate (CS/DS), heparan sulfate (HS), keratan sulfate (KS), and hyaluronic acid (HA) [33]. Both CS/DS and HS are synthesized in the Golgi apparatus, where protein cores are post-translationally modified at specific serine residues with a common linkage tetrasaccharide: GlcAβ1- 3Galβ1- 3Galβ1- 4Xylβ1-O- Ser. Biosynthesis of the linkage tetrasaccharide starts with transfer of

The consequences of impaired GAG synthesis in the disc

Aging and degeneration of the disc is principally characterized by a loss of ECM molecules resulting in compromised mechanical function [2]. It is well documented that degradation of the ECM is induced by catabolic inflammatory cytokines, including IL1-β and TNF-α, which activate ECM degrading enzymes such as metallopeptidases and disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) [4]. During degeneration, loss of ECM integrity can also be due to decreased ECM anabolism,

Conclusion and future studies

If the loss of expression or dysregulation of GAG biosynthesis enzymes represents an initiating factor in disc degeneration, then they represent possible therapeutic targets. Synthetic PGs have been explored for disc regeneration to restore biomechanical function. Most of these PG biomimetics attempt to replicate the functional properties of aggrecan without being vulnerable to proteolytic degradation. Aggrecan mimetics have already been developed for use in the field of articular cartilage

Conflict of Interest

None to declare.

Competing Interest

None to declare.

Acknowlegements

This work was supported by grants from the National Institutes of Health AR055655 and AR064733. The first author is supported by an NIH training grant, T32 AR052273, funded by Dr. Irving Shapiro.

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