Department of Ophthalmology, University of Pittsburgh, 203 Lothrop Street, Pittsburgh, PA 15213, USA
Accepted on June 27, 2000;
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Abstract |
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Key words: keratan sulfate/proteoglycan/cornea/cartilage/minireview
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Six decades of keratan sulfate |
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Keratan sulfate structure |
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Corneal KSI
Corneal KS is the prototype for KSI and is the most extensively characterized. The amount of KS in cornea is more than 10-fold that in cartilage and is 24 orders of magnitude greater than KS found in other tissues (Funderburgh et al., 1987). Linkage of corneal KS to protein involves a complex-type biantennary oligosaccharide N-linked to asparagine in the core protein (illustrated in Figure 1A). Analyses of a highly purified subfraction of porcine corneal KS found the KS chain to extend only the C-6 branch of the linkage oligosaccharide with the C-3 branch terminating with a single lactosamine capped by sialic acid (Oeben et al., 1987
). This model is illustrated in Figure 1A.
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This evidence for biantennary extension of the KSI linkage is also supported by experiments in which endo-ß-galactosidase-treated bovine corneal KS proteoglycans were labeled on the GlcNAc "stub" from which the KS chain had been cleaved and also labeled on sialic acids oxidized by mild periodate (Funderburgh et al., 1991b). Tryptic peptides from the labeled proteins were identified that contained label for both KS and sialic acids, as would be predicted from a single-arm extension of KS as shown in Figure 1A. Additionally, some peptides were labeled only for KS attachment indicating a lack of sialic acid in the linkage and a possible biantennary KS extension at these sites. These studies suggest that both mono- and biantennary extensions of the linkage may occur in KSI and that the location of the site on the core protein may influence the type of extension. Heterogeneity is also seen in modification of the linkage region of ZP3, a zona pellucida protein substituted with N-linked KS. In this protein KS can modify either the C-3, the C-6, or both arms of the biantennary linkage oligosaccharide (Noguchi and Nakano, 1992
).
Oeben et al. (1987) found sulfation of a purified fraction of porcine corneal KS to be distributed in a distinct, non-random pattern. Disaccharides nearest the reducing end were found to be nonsulfated (Figure 1A), and distal to this nonsulfated domain follows a series of disaccharides sulfated only on the GlcNAc moiety. The nonreducing end of the porcine corneal KS chains consists of a domain of variable length (834) of only disulfated disaccharides. This highly sulfated domain is responsible for the heterogeneity in the charge and size characteristic of corneal KS. There is also a suggestion that N-sulfation of GlcN may occur in the highly sulfated domain of corneal KS (Tang et al., 1986
). The nonreducing terminus of each chain is capped with a variety of structures. In bovine corneal KS about 70% of corneal chains terminate with neuraminic acid, the remainder with ßGalNAc or
-Gal (Tai et al., 1997
, 1996).
Non-corneal KSI
Fibromodulin, PRELP, and osteoadherin are proteins in cartilage and bone modified with N-linked KS chains (Antonsson et al., 1991; Bengtsson et al., 1995
; Sommarin et al., 1998
). Several proteins of the ovarian zona pellucida carry carbohydrates considered to be KS (Noguchi and Nakano, 1992
). The cartilage proteoglycan aggrecan also contains 23 N-linked KS chains in addition to 20 or more that are O-linked (Barry et al., 1995
). N-linked KS has also been isolated from the dermis of the pacific mackerel (Ito et al., 1984
). In addition to these well-defined examples of non-corneal KSI, sulfated lactosamine appears to be a common component of cell surface and extracellular glycoproteins. Some of this sulfation involves O-linked Lewis x structures, that differ from KS in that they are sulfated only at the non-reducing terminus and are fucosylated at the terminal GlcNAc (Hemmerich et al., 1995
; Capon et al., 1997
). Structures of other sulfated lactosaminoglycans are yet to be characterized, and it seems likely that some will be found to be KS.
Although the KSI linkage is not tissue specific, other characteristics of KS in non-corneal tissues diverge from the corneal model. KS chains in fibromodulin and osteoadherin are relatively short (89 disaccharides) and are more highly sulfated than KS in cornea (Lauder et al., 1997). KS in fibromodulin lacks the clear domain structure of corneal KS, but like corneal KS it displays reduced Gal sulfation near the reducing terminus. Groups capping the non-reducing terminus of fibromodulin KS are more typical of those on cartilage KS (Figure 1B) than of those on corneal KS (Lauder et al., 1997
). KS structure, therefore, may be dictated primarily by tissue-specific factors, such as glycosyltransferases, rather than the type of linkage to core protein.
KSII
A structure of bovine articular cartilage KS is illustrated in Figure 1B. The chains are shorter than KS of cornea (511 disaccharides) and lack the characteristic domain structure. Cartilage KSII is highly sulfated, consisting almost completely of disulfated monomers interrupted occasionally by single monosulfated lactosamine monomers (Nieduszynski et al., 1990b). Linkage to the protein is via serine or threonine and involves a mucin type "core 2" oligosaccharide. Sialylation of Gal linked to the C-3 of the linkage GalNAc is only partial. The KSII chains are capped by sialic acid at the C-3 or C-6 of the terminal GlcNAc.
-Linked fucose is also present on the C-3 of sulfated GlcNAc throughout the chain but not within four hexose moieties of the nonreducing terminus (Brown et al., 1996
). This feature distinguishes KS molecules from the Lewis x (Lex) antigens which are fucosylated on the GlcNAc penultimate to the nonreducing terminus. These KS-like glycoforms are present at endothelial cell surfaces and serve as selectin ligands (Tangemann et al., 1999
). KS from tracheal cartilage does not exhibit fucosylation of the internal GlcNAc, and carries only (2
3) linked sialic acids at the chain terminus (Nieduszynski et al., 1990b
; Dickenson et al., 1991
). Thus, tissue-specific glycosyltransferase activities and not primary protein sequence appear to major determinants of much of KSII chain structure and capping.
Man-O-linked KS (KSIII)
A third type of linkage between KS and protein has been described in proteoglycans from brain (Krusius et al., 1986). These KS chains are linked to Ser/Thr in the core protein via mannose, i.e., KS-Man-O-Ser. This linkage appears to be present in phosphocan-KS (I. Nieduszynski, personal communication), however, full characterization of the proteins in which the Man-O-Ser KS linkage occurs is pending.
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KS biosynthesis |
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The N-acetylglucosaminyltransferase (GnT) enzyme responsible for KS synthesis has not been identified. A number of GnT enzymes are known, of which two seem potential candidates. A widely distributed enzyme (iGnT) has been shown to participate in synthesis of linear polylactosamine (known as "i" antigens) (Sasaki et al., 1997). RNA transcripts for this enzyme are enriched in brain, a tissue in which KS is actively synthesized. Recently a second GnT enzyme (ß3GnT) active in synthesis of linear polylactosamine has been identified and cloned (Zhou et al., 1999
). At the current time, however, no evidence has been presented linking a specific GnT to KS synthesis.
Sulfation of KS in cornea is carried out by at least two sulfotransferase enzymes (Ruter and Kresse, 1984). Two enzymes have been identified and cloned that add sulfate to KS (Habuchi et al., 1996
; Fukuta et al., 1997
). One of these adds sulfate to GalNAc moieties of chondroitin sulfate and also to Gal in KS. The second enzyme also transfers sulfate to Gal of KS but does not act on chondroitin sulfate. Messenger RNA for the KS-specific sulfotransferase shows enhanced expression in brain and cornea. It would therefore appear likely that this sulfotransferase represents an enzyme involved in KS biosynthesis.
KS is also sulfated on the GlcNAc moieties and presumably a specific enzyme is responsible for this activity. Nakazawa et al. (1998) have demonstrated that GlcNAc-6-sulfotransferase (Gn6ST) activity in keratocyte extracts specifically sulfates nonreducing terminal GlcNAc(ß13)Gal-R. Partially desulfated KS received sulfation only on Gal moieties by these extracts. The cDNAs for two Gn6ST enzymes with specificity for nonreducing terminal GlcNAc have been identified and cloned (Uchimura et al., 1998
; Lee et al., 1999
); however, there remains a question if either of these represent the enzymes involved in KS synthesis. Patients with macular corneal dystrophy, a disease in which KS lacks GlcNAc sulfation throughout the body, had unaltered levels of this enzyme activity in their serum (Hasegawa et al., 1999
). The implication of these findings is that an enzyme of similar specificity with restricted tissue localization may be responsible for KS synthesis.
The specificity of the Gn6ST enzyme suggests that KS GlcNAc sulfation may occur simultaneously with elongation and only on the terminus of the growing chain (Degroote et al., 1997; Uchimura et al., 1998
). The idea of coordinated elongation and sulfation of KS is supported by biosynthetic studies with cell-free corneal extracts that showed a coordinate change in the Vmax of both elongation and sulfation activities with respect to KS chain length (Keller et al., 1989
).
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KS-linked proteins |
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Aggrecan
The major proteoglycan of cartilage is the very large protein aggrecan in which KS is found in two separate domains. The majority of KS is O-linked to aggrecan between the G2 and G3 regions in a domain characterized by a repeated six-amino acid motif (Flannery et al., 1998). The sequence of the motif is highly conserved in different vertebrate species, but the numbers of repeated units varies (Barry et al., 1994
; Flannery et al., 1998
). This variation may account for differences in KS content of aggrecan of different species. In rodents the motif sequence is not conserved, and in these species skeletal KS is greatly reduced or absent. KS is also linked to aggrecan near the N-terminus of the protein in the HA-binding domain in both O- and N-linked forms (Barry et al., 1995
). KS chains in the HA-binding region may have different length and sulfation compared to the chains from the GAG-binding region of the molecule. This suggests that protein conformation in this huge molecule may control access to the glycosyl- or sulfotransferases during passage through the Golgi.
Cell-associated proteoglycan
KS has been recently demonstrated to be associated with a number of epithelial tissues. Keratinocytes, uterine endometrial cells, corneal endothelium, sebaceous gland, salivary gland, and sweat gland epithelia exhibit KS immunoreactivity in adult tissues (Sorrell and Caterson, 1990; Shiozawa et al., 1991
; Fullwood et al., 1996
). KS is also found in a variety of epithelia-derived carcinoma cells (Ito et al., 1996
; Leygue et al., 1998
). The endometrial protein MUC1 has recently been shown to be modified with KS (Aplin et al., 1998
). MUC1 is a common component of the mucin layer associated with the apical surfaces of secretory epithelia. This single molecule might prove to be responsible for the presence of KS in many of the numerous glandular surfaces in which it has been reported. Another cell-surface molecule CD44 contains KS (Takahashi et al., 1996
; Tuhkanen et al., 1997
). This protein occurs as a number of alternately spliced forms, some of which contain heparan sulfate. CD44 and SV2 (discussed below) are the first known integral membrane proteins to be identified with KS. A third type of cell-associated KS was described as the modification of intracellular keratin molecules with KS in keratinocytes (Schafer and Sorrell, 1993
). These examples of cell-associated KS demonstrate that, like chondroitin and heparan sulfates, KS molecules are not restricted to interstitial connective tissues but modify a variety of proteins with considerable variety in localization.
Brain proteoglycans
One of the most active areas of recent KS research concerns proteoglycans of the central nervous system. After cornea and skeletal tissues, brain appears to exhibit the most abundant KS and is one of the tissues most rich in enzymes of KS biosynthesis. The major cartilage proteoglycan aggrecan is present in neural tissues, but aggrecan in the CNS may not contain KS (Domowicz et al., 1995). Several proteoglycans that appear to be unique to nervous tissue have been described, including ABAKAN (Seo and Geisert, 1995
), SV2 (Carlson, 1996
), PG-1000 (Carlson et al., 1996
), claustrin (Burg and Cole, 1994
), and phosphocan-KS (Margolis et al., 1996
). Each appears to be a unique KS-linked protein with highly specific localization, produced by a limited population of cells. Other KS-linked proteins also occur in neural tissue but are yet to be fully characterized (Miller et al., 1997
).
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Control of KS synthesis |
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Cartilage KS appears to exhibit developmental changes similar to those of cornea. The KS content of aggrecan in cartilage undergoes an age-related increase in KS chain length and sulfation (Brown et al., 1998; Lauder et al., 1998
). Rat brain, as well, shows little embryonic KS, developing the majority of KS activity after birth (Meyer-Puttlitz et al., 1995
). On the other hand, much of the KS in the brain exhibits unique, complex, developmentally-regulated patterns (Miller et al., 1997
). This level of fine modulation suggests a specialized developmental function for KS-linked molecules of the CNS.
A second widely observed property of KS biosynthesis is its volatility in wound healing and in vitro. Cell types that secrete KS (neural cells, chondrocytes, and keratocytes) are quiescent in vivo, but when maintained in vitro, chondrocytes and keratocytes, depending on culture conditions, often assume a fibroblastic morphology and lose KS synthesis. In corneal wounds keratocytes are activated to divide, adopt a fibroblastic phenotype similar to cultured corneal fibroblasts, and synthesize little KS. Sub-acute or chronic pathological conditions affecting the cornea also frequently lead to loss of KS in the stroma (Funderburgh et al., 1990; Rodrigues et al., 1992
). In the brain, microglial KS is reduced during inflammation (Jander et al., 2000
) and cerebral KS is reduced as a result of Alzheimers disease (Lindahl et al., 1996
). Reduction of KS in both brain and cornea appears in association with inflammation, suggesting a role for proinflammatory cytokines in the downregulation of KS biosynthesis.
Numerous studies have documented the disappearance of KS in cultured corneal fibroblasts. A detailed analysis of the products synthesized by these cultures demonstrated expression of all three of the KS-linked proteins but found them to be modified with truncated oligolactosamine with little or no sulfation (Funderburgh et al., 1996). These results suggest that downregulation of KS biosynthesis in vitro (and by implication in healing wounds) stems from downregulation of KS-specific glycosyl- and/or sulfotransferases. A study using freshly isolated chicken keratocytes showed a marked reduction in sulfation of KS GlcNAc residues after short-term culture of these cells in serum (Nakazawa et al., 1998
). Specific enzymes required for polymerization and sulfation of KS may, therefore, be key regulators of KS biosynthesis in vitro and possibly in vivo as well.
Recent development of a culture method for keratocytes that maintains biosynthesis of macromolecular, fully sulfated KS for extended periods in vitro provides an important tool for identification of KS-specific biosynthetic enzymes (Beales et al., 1999). KS biosynthesis by keratocytes cultured using this method was downregulated by fetal bovine serum and by transforming growth factor ß (TGFß), but fibroblast growth factor 2 (FGF) acted to maintain KS synthesis in vitro (Long et al., 2000
). This experimental system provides the opportunity to examine the effect of various stimuli (e.g., nutrients, inflammatory cytokines, cell-matrix interactions) on KS assembly.
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Biological functions of KS |
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Cell biology of KS
The role of KS in corneal hydration does not explain the presence of small amounts of KS in so many other tissues. Numerous active biological roles have been documented for hyaluronan, heparan sulfate, and chondroitin sulfate (Iida et al., 1996; Toole, 1997
; Lindahl, 1999
). Recent studies of KS have presented data suggesting that KS also is an active participant in the cellular biology of the tissues in which it is located. Mouse macrophages express a high-affinity cell surface receptor for lumican and for lumican modified with nonsulfated oligolactosamine. These cells do not bind lumican that carries sulfated KS chains, nor will they attach and spread on plastic surfaces coated with lumican-KS. Removal of KS with endo-ß-galactosidase restored attachment and spreading of the cells in vitro (Funderburgh et al., 1997b
). This anti-adhesive character of KS has been observed in other studies. KS-containing molecules constitute a barrier to neurite growth in vitro and appear to direct axon growth patterns during development or regeneration in vivo (Burg and Cole, 1994
; Olsson et al., 1996
). The "barrier" character of KS is also implicated in the findings that KS chains on aggrecan block development of an immune response in vivo and in vitro to the G1 domain of this protein, suppressing development of antigen-induced osteoarthritis (Guerassimov et al., 1999
).
Abundance of the cell-associated KS in the endometrial uterine lining varies markedly during the menstrual cycle, reaching a peak at the time at which embryo implantation occurs (Graham et al., 1994). At this time keratanase-sensitive molecules block access of antibodies to MUC1 ectodomain epitopes, normally accessible at other times in the cycle (DeLoia et al., 1998
). These findings suggest a potential role for KS in the implantation process. KS has also been implicated in motility of corneal endothelial cells, a single layer epithelium that lines the posterior surface of the cornea. These cells normally display a mosaic distribution of KS at their apical surface, but after wounding the KS is reduced or absent on migrating cells. KS returns in abundance to the cell surface when the cells cease migration (Davies et al., 1999
). Anti-adhesive molecules function in complex and sometimes paradoxical roles during cell attachment and motility (Greenwood and Murphy-Ullrich, 1998
). The anti-adhesive properties of KS may well play significant roles in implantation and endothelial cell migration as well as in other biological processes. Correlative studies such as these suggest potential experimental systems in which molecular mechanism of these biological effects can be determined.
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Conclusion |
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Acknowledgments |
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References |
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