Human Aggrecan Keratan Sulfate Undergoes Structural Changes during Adolescent Development

Brown, Gavin M.; Huckerby, Thomas N.; Bayliss, Michael T.; Nieduszynski, Ian A.

doi:10.1074/jbc.273.41.26408

Cited by 59 publications

(56 citation statements)

References 41 publications

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“…An increase of sulfation in blood and urine KS is compatible with that observed in the cartilage and cornea during normal aging (Liles et al 2010;Brown et al 1998). Gal sulfation levels increase during adolescence and early adulthood and then remain fairly constant in human articular cartilage (Brown et al 1998).…”

Section: Discussionsupporting

confidence: 56%

“…Gal sulfation levels increase during adolescence and early adulthood and then remain fairly constant in human articular cartilage (Brown et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…KS is almost always sulfated on C (6) of GlcNAc, while C (6) of Gal is sulfated to a variable extent, depending on the tissue and age (Bhavanandan and Meyer 1968). KS chains of fibromodulin in articular cartilage are highly sulfated compared to that in the cornea (Lauder et al 1997;Nieduszynski et al 1990), and the levels of sulfation in cornea and cartilage increase during normal aging (Liles et al 2010;Brown et al 1998).…”

Section: Introductionmentioning

confidence: 99%

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Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

et al. 2014

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Keratan sulfate (KS) is a storage material in mucopolysaccharidosis IV (MPS IV). However, no detailed analysis has been reported on subclasses of KS: monosulfated KS and di-sulfated KS. We established a novel method to distinguish and quantify mono-and di-sulfated KS using liquid chromatography-tandem mass spectrometry and measured both KS levels in various specimens.Di-sulfated KS was dominant in shark cartilage and rat serum, while mono-sulfated KS was dominant in bovine cornea and human serum. Levels of both mono-and di-sulfated KS varied with age in the blood and urine from control subjects and patients with MPS II and IVA. The mean levels of both forms of KS in the plasma/serum from patients with MPS II, IVA, and IVB were elevated compared with that in age-matched controls. Di-sulfated KS provided more significant difference between MPS IVA and the age-matched controls than mono-sulfated KS. The ratio of di-sulfated KS to total KS in plasma/serum increased with age in control subjects and patients with MPS II but was age independent in MPS IVA patients. Consequently, this ratio can discriminate younger MPS IVA patients from controls. Levels of monoand di-sulfated KS in urine of MPS IVA and IVB patients were all higher than age-matched controls for all ages studied.In conclusion, the level of di-sulfated KS and its ratio to total KS can distinguish control subjects from patients with MPS II, IVA, and IVB, indicating that di-sulfated KS may be a novel biomarker for these disorders. Abbreviations

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Section: Discussionsupporting

confidence: 56%

“…Gal sulfation levels increase during adolescence and early adulthood and then remain fairly constant in human articular cartilage (Brown et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

et al. 2014

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“…However, the structure of keratan sulfate on human aggrecan changes dramatically with age (55). In contrast with aggrecan from young articular cartilage (0 -9 years), aggrecan from adult articular cartilage (18 -85 years) is substantially more sulfated and more highly modified by fucosylation and sialylation.…”

Section: Discussionmentioning

confidence: 88%

“…In contrast with aggrecan from young articular cartilage (0 -9 years), aggrecan from adult articular cartilage (18 -85 years) is substantially more sulfated and more highly modified by fucosylation and sialylation. Maturing cartilage (9 -18 years) has intermediate and increasing levels of sulfation, fucosylation, and sialylation (55). It is interesting to speculate that poten- FIG.…”

Section: Discussionmentioning

confidence: 99%

N-Linked Keratan Sulfate in the Aggrecan Interglobular Domain Potentiates Aggrecanase Activity

Poon

Plaas

Keene

et al. 2005

Journal of Biological Chemistry

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Keratan sulfate is thought to influence the cleavage of aggrecan by metalloenzymes. We have therefore produced a recombinant substrate, substituted with keratan sulfate, suitable for the study of aggrecanolysis in vitro. Recombinant human G1-G2 was produced in primary bovine keratocytes using a vaccinia virus expression system. Following purification and digestion with specific hydrolases, fluorophore-assisted carbohydrate electrophoresis was used to confirm the presence of the monosulfated Gal-GlcNAc6S and GlcNAc6s-Gal disaccharides and the disulfated Gal6S-GlcNAc6S disaccharides of keratan sulfate. Negligible amounts of fucose or sialic acid were detected, and the level of unsulfated disaccharides was minimal. Treatment with keratanases reduced the size of the recombinant G1-G2 by ϳ5 kDa on SDS-PAGE. Treatment with N-glycosidase F also reduced the size of G1-G2 by ϳ5 kDa and substantially reduced G1-G2 immunoreactivity with monoclonal antibody 5-D-4, indicating that keratan sulfate on the recombinant protein is Nlinked. Cleavage of G1-G2 by aggrecanase was markedly reduced when keratan sulfate chains were removed by treatment with keratanase, keratanase II, endo-␤-galactosidase, or N-glycosidase F. These results indicate that modification of oligosaccharides in the aggrecan interglobular domain with keratan sulfate, most likely at asparagine residue 368, potentiates aggrecanase activity in this part of the core protein.Aggrecan is a major structural component of cartilage and together with type II collagen it enables this tissue to bear load and resist compression. Aggrecan has three globular domains, G1 and G2 at the N terminus and G3 at the C terminus. An extended sequence between the G2 and G3 domains is heavily substituted with chondroitin sulfate and keratan sulfate chains, organized into distinct chondroitin sulfate-1, chondroitin sulfate-2, and keratan sulfate-rich regions. An interglobular domain (IGD) 1 of ϳ150 amino acids separates G1 from G2 and is substituted with keratan sulfate chains as well as O-linked and N-linked oligosaccharides.The IGD is highly sensitive to proteinases. Cleavage in the IGD releases the entire chondroitin sulfate and keratan sulfate-rich regions essential for the biomechanical properties of aggrecan and is therefore the most detrimental for cartilage function. In pathology, proteolysis is driven by aggrecanases and, to a lesser extent, by matrix metalloproteinases. Aggrecanase was first identified as a novel activity that cleaved the aggrecan core protein at the E 373 2 374 A bond in the IGD (1-3); the products of this cleavage were found in synovial fluids from patients with osteoarthritis, joint injury, and inflammatory joint disease (4, 5). Subsequently, cartilage enzymes with aggrecanase activity were revealed as members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family (6, 7), and ADAMTS5 has recently been identified as the major aggrecanase in mouse cartilage (8,9).Proteolysis by matrix metalloproteinases at the N 341 2 342 F bond i...

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Proteoglycan and Acidic Polysaccharide Analysis

Lauder

2000

Encyclopedia of Analytical Chemistry

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The isolation and analysis of proteoglycans (PGs) and the acidic polysaccharide glycosaminoglycan (GAG) chains attached to them is an area of increasing importance. PGs are a structurally diverse group of complex macromolecules comprising a core protein, varying in size from 11 to 400 kDa, to which are attached one or more GAG chains of the same or a different type. These chains carry a negative charge derived mainly from sulfate groups and are composed of a repeating disaccharide, a hexosamine and either a hexuronic acid or, in keratan sulfate (KS), galactose.

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Human Aggrecan Keratan Sulfate Undergoes Structural Changes during Adolescent Development

Cited by 59 publications

References 41 publications

Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

N-Linked Keratan Sulfate in the Aggrecan Interglobular Domain Potentiates Aggrecanase Activity

Proteoglycan and Acidic Polysaccharide Analysis

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