Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewStructure, function, aging and turnover of aggrecan in 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
References (103)
- et al.
Complete primary structure of the rat cartilage proteoglycan core protein deduced from cDNA clones
J. Biol. Chem.
(1987) - et al.
Complete coding sequence and deduced primary structure of the human cartilage large aggregating proteoglycan, aggrecan. Human-specific repeats, and additional alternatively spliced forms
J. Biol. Chem.
(1991) - et al.
Complete coding sequence of bovine aggrecan: comparative structural analysis
Arch. Biochem. Biophys.
(1997) - et al.
Complete coding sequence, deduced primary structure, chromosomal localization, and structural analysis of murine aggrecan
Genomics
(1994) - et al.
cDNA cloning of chick cartilage chondroitin sulfate (aggrecan) core protein and identification of a stop codon in the aggrecan gene associated with the chondrodystrophy, nanomelia
J. Biol. Chem.
(1993) - et al.
Sulfation of chondroitin sulfate in human articular cartilage. The effect of age, topographical position, and zone of cartilage on tissue composition
J. Biol. Chem.
(1999) - et al.
Identification of hyaluronan-binding domains of aggrecan
J. Biol. Chem.
(1997) - et al.
N- and O-linked keratan sulfate on the hyaluronan binding region of aggrecan from mature and immature bovine cartilage
J. Biol. Chem.
(1995) - et al.
The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B
J. Biol. Chem.
(1992) - et al.
O-Linked oligosaccharides of human articular cartilage proteoglycan
Biochim. Biophys. Acta
(1982)
Length variation in the keratan sulfate domain of mammalian aggrecan
Matrix Biol.
The glycosaminoglycan attachment regions of human aggrecan
J. Biol. Chem.
A human-specific polymorphism in the coding region of the aggrecan gene. Variable number of tandem repeats produce a range of core protein sizes in the general population
J. Biol. Chem.
Age-related changes in the structure of the proteoglycan subunits from human articular cartilage
J. Biol. Chem.
Aggrecan synthesis and secretion. A paradigm for molecular and cellular coordination of multiglobular protein folding and intracellular trafficking
J. Biol. Chem.
Expression of alternatively spliced epidermal growth factor-like domains in aggrecans of different species. Evidence for a novel module
J. Biol. Chem.
The proteoglycans aggrecan and versican form networks with fibulin-2 through their lectin domain binding
J. Biol. Chem.
Studies on the interaction of newly secreted proteoglycan subunits with hyaluronate in human articular cartilage
Biochim. Biophys. Acta
A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis
Am. J. Hum. Genet.
A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans
Am. J. Hum. Genet.
A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan
Am. J. Hum. Genet.
Undersulfation of proteoglycans synthesized by chondrocytes from a patient with achondrogenesis type 1B homozygous for an L483P substitution in the diastrophic dysplasia sulfate transporter
J. Biol. Chem.
TNF-alpha and IL-1beta promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral disc
J. Biol. Chem.
MMPs are less efficient than ADAMTS5 in cleaving aggrecan core protein
Matrix Biol.
Characterization of human aggrecanase 2 (ADAM-TS5): substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4)
Matrix Biol.
Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4
J. Biol. Chem.
Hyal2—less active, but more versatile?
Matrix Biol.
The many ways to cleave hyaluronan
Biotechnol. Adv.
Link protein can retard the degradation of hyaluronan in proteoglycan aggregates
Osteoarthritis Cartilage
In vivo racemization in mammalian proteins
Methods Enzymol.
On the accumulation of D-aspartate in elastin and other proteins of the ageing aorta
Atherosclerosis
Age-related accumulation of the advanced glycation endproduct pentosidine in human articular cartilage aggrecan: the use of pentosidine levels as a quantitative measure of protein turnover
Matrix Biol.
Effect of collagen turnover on the accumulation of advanced glycation end products
J. Biol. Chem.
Aspartic acid racemization and collagen degradation markers reveal an accumulation of damage in tendon collagen that is enhanced with aging
J. Biol. Chem.
Aggrecan turnover in human intervertebral disc as determined by the racemization of aspartic acid
J. Biol. Chem.
Longevity of elastin in human intervertebral disc as probed by the racemization of aspartic acid
Biochim. Biophys. Acta
Collagen turnover in normal and degenerate human intervertebral discs as determined by the racemization of aspartic acid
J. Biol. Chem.
On the origin of bile pigment in normal man
J. Biol. Chem.
Enhanced level of non-enzymatic glycation and pentosidine crosslinking in spontaneous osteoarthritis progression
Osteoarthritis Cartilage
In vivo racemization in mammalian proteins
Non-enzymatic, post-translational, amino acid modifications in ageing. A brief review
Mech. Ageing Dev.
Senescence and the accumulation of abnormal proteins
Mutat. Res.
Deamidation, isomerization, and racemization at asparaginyl and aspartyl residues in peptides. Succinimide-linked reactions that contribute to protein degradation
J. Biol. Chem.
Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer's disease
J. Biol. Chem.
Isoaspartate formation and neurodegeneration in Alzheimer's disease
Arch. Biochem. Biophys.
Racemization of Asp23 residue affects the aggregation properties of Alzheimer amyloid beta protein analogues
J. Biol. Chem.
The molecular basis of intervertebral disc degeneration
Spine J.
Genetic polymorphisms associated with intervertebral disc degeneration
Spine J.
Link protein N-terminal peptide binds to bone morphogenetic protein (BMP) type II receptor and drives matrix protein expression in rabbit intervertebral disc cells
J. Biol. Chem.
The effects of needle puncture injury on microscale shear strain in the intervertebral disc annulus fibrosus
Spine J.
Cited by (0)
- 1
Equal contribution.