ReviewGlycosaminoglycan synthesis in the nucleus pulposus: Dysregulation and the pathogenesis of disc degeneration
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.
References (83)
- et al.
Is the spinal motion segment a diarthrodial polyaxial joint: what a nice nucleus like you doing in a joint like this?
Bone
(2012) - et al.
Extracellular osmolarity regulates matrix homeostasis in the intervertebral disc and articular cartilage: evolving role of TonEBP
Matrix Biol.
(2014) - et al.
RNA sequencing reveals a role of TonEBP in regulation of pro-inflammatory genes in response to hyperosmolarity in healthy nucleus pulposus cells: a homeostatic response?
J. Biol. Chem.
(2016) Biochemistry of the intervertebral disc
Int. Rev. Connect. Tissue Res.
(1979)- et al.
Extracellular matrix in development of the intervertebral disc
Matrix Biol.
(2001) - et al.
TGFβ regulates Galectin-3 expression through canonical Smad3 signaling pathway in nucleus pulposus cells: implications in intervertebral disc degeneration
Matrix Biol.
(2016) - et al.
Early changes in morphology, bone mineral density and matrix composition of vertebrae lead to disc degeneration in aged collagen IX −/− mice
Matrix Biol.
(2016) - et al.
Structure, function, aging and turnover of aggrecan in the intervertebral disc
Biochim. Biophys. Acta Gen. Subj.
(2014) Chapter - 1 glycosaminoglycan (GAG) biosynthesis and GAG-binding proteins
Mol. Biol. Transl. Sci. Glycosaminoglycans Dev. Heal. Dis.
(2010)- et al.
The characterization of versican and its message in human articular cartilage and intervertebral disc
J. Orthop. Res.
(2002)