Review
Structure, function, aging and turnover of aggrecan in the intervertebral disc

https://doi.org/10.1016/j.bbagen.2014.07.013Get rights and content

Highlights

  • Aggrecan abundance reaches a plateau in the early twenties, then slowly declines.

  • Aggrecan abundance declines due to proteolysis, mainly by MMPs and aggrecanases.

  • Aggrecan loss is an early event in disc degeneration.

  • The low turnover rate of the degraded aggrecan prevents its replacement.

  • Aggrecan restoration or bioimimetic supplementation may retard disc degeneration.

Abstract

Background

Aggrecan is the major non-collagenous component of the intervertebral disc. It is a large proteoglycan possessing numerous glycosaminoglycan chains and the ability to form aggregates in association with hyaluronan. Its abundance and unique molecular features provide the disc with its osmotic properties and ability to withstand compressive loads. Degradation and loss of aggrecan result in impairment of disc function and the onset of degeneration.

Scope of review

This review summarizes current knowledge concerning the structure and function of aggrecan in the normal intervertebral disc and how and why these change in aging and degenerative disc disease. It also outlines how supplementation with aggrecan or a biomimetic may be of therapeutic value in treating the degenerate disc.

Major conclusions

Aggrecan abundance reaches a plateau in the early twenties, declining thereafter due to proteolysis, mainly by matrix metalloproteinases and aggrecanases, though degradation of hyaluronan and non-enzymic glycation may also participate. Aggrecan loss is an early event in disc degeneration, although it is a lengthy process as degradation products may accumulate in the disc for decades. The low turnover rate of the remaining aggrecan is an additional contributing factor, preventing protein renewal. It may be possible to retard the degenerative process by restoring the aggrecan content of the disc, or by supplementing with a bioimimetic possessing similar osmotic properties.

General significance

This review provides a basis for scientists and clinicians to understand and appreciate the central role of aggrecan in the function, degeneration and repair of the intervertebral disc.

Section snippets

Structure of aggrecan

Aggrecan belongs to the family of proteoglycans that are characterized by the presence of glycosaminoglycan (GAG) chains attached covalently to a core protein. In the case of aggrecan there may be over 100 GAG chains bound to its large core protein, making it the most glycosylated of the proteoglycans. The proteoglycans can be subdivided according to the type of GAG chain present and the function of the core protein. In this respect aggrecan can be described as a large chondroitin sulfate

Aggrecan function in the disc

Aggrecan function depends on both its core protein and GAG constituents. The core protein endows aggrecan with the ability to aggregate, giving the molecules a vast size, limiting their diffusion and maintaining their location within the tissue. It is interesting to note that upon secretion by the cells, individual aggrecan molecules do not interact well with HA, and only attain this ability within the ECM [24]. This may allow the molecule time to diffuse away from the HA-rich coat present at

Age-related changes in aggrecan structure

The aggrecan molecules present in the disc do not maintain a constant structure or abundance throughout life. These age-related changes may be due to intracellular events affecting GAG synthesis, as well as extracellular events affecting core protein and HA degradation or modification (Fig. 3).

Racemization and glycation

A reliable method for assessing protein age and turnover is the measurement of the accumulation of the D-isomer of amino acids. Due to stereochemical constraints, amino acids are synthesized in nature as the L-isomers. However, spontaneous, non-enzymatic racemization slowly converts L-form amino acids into a racemic mixture of L- and D-forms. The characteristic racemization rate for each amino acid depends on protein conformation as well as on the temperature, pH and ionic strength of the

Consequence of age-related changes in aggrecan

Age-related changes in aggrecan include altered tissue content, impaired ability to interact with HA and fragmentation, all of which can affect tissue function. A decrease in aggrecan content and interaction and an increase in fragmentation can all be viewed as being detrimental. In contrast, it is not clear whether the change in GAG structure that accompanies growth has detrimental or beneficial consequences.

In the fetal and neonatal human disc, the majority of aggrecan resides in the

Implications for the repair of disc degeneration

At present there is no medical treatment for the repair of the degenerate disc, and ultimately surgical intervention is required for symptomatic relief. This can involve excision of a disc protrusion or, if degeneration is more extensive, removal of the whole disc followed by spinal fusion or insertion of a disc prosthesis. These procedures are not benign and do not restore normal disc function. In the case of fusion, the mechanics of the spine are altered and degeneration of the discs at

Aggrecan biomimetics and disc repair

While restoration of the aggrecan content of the disc may be the ideal means of restoring disc function in early stage degeneration, it may not be effective unless ongoing proteolysis can be prevented. Otherwise the newly synthesized aggrecan will suffer the same fate as its predecessors. To overcome this problem, recent research has focused on the development of biomimetics that replicate the functional properties of aggrecan but are not susceptible to proteolytic degradation. One such

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