findings highlight the important role played by HS proteoglycans, such as perlecan, in cartilage development and skeletal growth. KEY WORDS: heparan sulfate ...
Critical Reviews'^ in Eukaryotic Gene Expression, 15(l):29-48 (2005)
t
Heparan Sulfate Proteoglycans: Key Players in Cartilage Biology
i
Mary C Farach-Carson,'^ Jacqueline T. Hecht,^ & Daniel D. Carson^-* 'Department of Biologica! Sciences, University of Delaware, Newark, DE 19716; ^Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX 77030 *
All concspondence should be addi«ssed to Daniel Car8artment of Biological Sciences, Unwcrshy of Dekware,^ TeL: (302) 831-4296; Fax: (302) 831-2281; E-mail: dcarson@udeLedu _ • "
19716; (
>
ABSTRACT: The extracellular matrix (ECM) plays a fundamental role in skeletal patterning and fonnation of the vertebrate skeleton. This review focuses on the fundamental roles associated with heparan sulfate (HS) proteoglycans in the ECM during cartilage development, which include regulation of gene expression, presentation of growth factors, establishment of morphogen gradients, and modulation of blood homeostasis. The importance of enzymes involved in biosynthesis and assembly of heparan sulfate is also discussed. Finally, the current evidence for functions of individual HS proteoglycans and biosynthedc enzymes based upon human genetic mutation associations with disease and genetic manipulation in transgenic mice is presented. These findings highlight the important role played by HS proteoglycans, such as perlecan, in cartilage development and skeletal growth. KEY WORDS: heparan sulfate proteoglycan, perlecan, cartilage, growth factor, exostoses
I. INTRODUCTION Cartilage is a fundamental tissue of the vertebrate skeleton both from phylogenetic and developmental standpoints. The most primitive vertebrates contain cartilaginous, rather than bony, skeletons while cartilage primordia provide the foundation for the organization and later development of endochondral bone. Unique genes, for example, collagen types II and X, are activated during endochondral bone formation and provide opportunities to identify key transcriptional controls and signal transduction cascades that drive skeletal morphogenesis. It has long been appreciated that extracellular matrix components not only are abundantly expressed in cartilage, but also contribute greatly to the physical properties of this tissue. Notably, hyaluronic acid and chondroitin sulfate proteoglycans are large molecules with extremely large hydration spheres, which provide a great deal of the compressibility properties of cartilage. Recently, more attention has been paid to the heparan sulfate (HS) proteoglycans present in 1045-4403/05/535.00 © 2005 by Begeli House, Inc.
cartilage. While quantitatively minor relative to chondroitin sulfate proteoglycans, the important roles played by HS proteoglycans are demonstrated by the great impact that defects in genes encoding either HS biosynthetic en:^mes or HS proteoglycan core proteins have on cartilage and skeletal development in mice and humans. In the discussion below, we will review the functions associated with HS proteoglycans and the current evidence obtained from genetic approaches regarding the roles these complex glycoconjugates play in cartilage development and homeostasis.
II. CARTILAGE DEVELOPMENT Cartilage formation initiates with mesenchymal condensation at discrete regions in the embryo. A number of transcription factors, growth factors, cell surface, and extracellular matrix components have been identified that are expressed very early in mesenchymal commitment to chondrogenesis, including Sox9, TGF-pi, NCAM, and tenascin
29
(reviewed in Hall and Miyake^ and van der Eerden et al.^). Nonetheless, the precise factors that trigger or set boundaries in cartilaginous structures remain unclear. Expression of the Sox9 transcription factor is critical in early events in cartilage formation.^ In addition, several observations indicate that BMP actions also are critical. BMP-7 is an early marker of cartilage formation and drives expression of the powerfiil BMP antagonist, noggin.** Neutralization of BMP action by overexpression of noggin in cartilage results in embryos tbat are largely devoid of cartilaginous structures.^ Likewise, noggin-nuU embryos develop cartilage hyperplasia and fail to develop joints consistent witb unabated BMP action driving continued cartilage growtb.^ Cartilage development is conveniently studied in two contexts. One is the asynchronous, but ordered, differentiation of cartilage primordia along the spinal column. The process initiates earlier toward tbe head and is progressively delayed toward tbe tail. Thus, a spectrum of the stages of cartilage development can be seen in properly oriented sagittal sections of niidgestation mouse embryos. A second context is the growth plate, where a spectrum of cartilage differentiation from proliferative to mineralizing stages is observable starting from day 16.5 of development.^-'' Tbese features provide tbe opportunity to determine, unequivocally, tbe order in which genes are activated and the sites at wbich gene products are deposited relative to the stage of cartilage development. Excellent reviews are available that consider cartilage and bone development in more detail.^-''
III. HEPARAN SULFATE PROTEOGLYCANS A. HS Biosynthesis and Structure HS is a class of large, linear, highly negatively cbarged polysaccbarides assembled by the sequential transfer of sugars from sugar nucleotides to tbe nonreducing termini of the growing polysaccharide chain. Tbe reader is referred to recent reviews that consider HS proteoglycan assembly in more detail.^-'^ In brief, tbe process is initiated by transfer of xylose through the bydroxyl group of serine of a core protein. The steps in HS
30
assembly are indicated in Figure 1. There is no clear consensus peptide sequence for HS acceptor sites; bowever, these sites usually contain serine-glycine dipeptides flanked by negatively charged amino acids. ^° Following the xylose addition, the sequential transfer of two galactosyl residues and one glucuronic acid residue occurs. The resulting tetrasaccharide is a core structure found in chondroitin sulfate and dermatan sulfate polysaccharides as well as HS. HS-specific polymerization appears to be influenced by otber features of the core protein^^; bowever, proteoglycans, such as syndecan and perlecan, can carry both HS and chondroitin sulfate chains, and the HSxbondroitin sulfate ratio varies in different cell types and in response to various environmental cues.^^"^^ Although it has not been rigorously demonstrated, it is presumed tbat both types of glycosaminoglycans are attached at the same sites. Tbus, tbe protein core does not strictly determine the type of glycosaminoglycan that will be polymerized on tbe core tetrasaccharide. HS polymerization occurs through tbe addition of N-acetylglucosamine and glucuronic acid residues in the Golgi apparatus, resulting in a large linear structure tbat may contain 50 or more disaccbaiide units. Tbe enzymes catalyzing these reactions are members of the EXT family.** Following polymerization, the first modification to occur is N-deacetylation and N-sulfation catalyzed by N-deacetylase/N-suifotransferase (NDST). At least four NDSTs genes have been identified with similar activities.'* Althougb aU N-acetylglucosamine units in the polymer are potential substrates for NDSTs, these en2ymes do not act on all of these units, but rather appear to act only on certain regions of the chains, resulting in blocks of unmodified and modified areas.**'''^ Tbe N-sulfated block regions may be further modified by epimerization of glucuronic acid to iduronic acid. This epimerization has more biological consequences tban might be expected because iduronate residues are conformation ally flexible—an attribute tbat may benefit protein binding. "^^-^^ N-sulfated block regions also are substrates for 3- and 6-O-sulfation of glucosamine units and 2-O-sulfation of iduronic acid units. Again, because of the fact tbat not all potential substrate sites are modified, a variety of sequences result rather than simple repeating structures. As
Criticai Reviews'"* in Eukaryotic Gene Expression
Core protein acceptor plus xylosyl, galactosyl and gtucuronosyltransferases
GlcA-Gal-Gal-Xyl-Ser
EXTI/EXT2, EXTLl-3 polymerases
A-D-A-D-A-n-A-n-A-n-A-n-A-n-A-n-A-n-A-D-A-n-GIcA-Gal-Gal-Xyl-Ser NDSTs A-B'A-H-A-B-A-a-A-D-A-a-A-D-A-B-A-a-A-B-A-D-GtcA-Gal-Oal-Xyl-Ser uronosyl epimerase A-B-T-B-T-B-T-B-A-D-A-D-A-D-A-B-T-•-•-•-A-D-GlcA-Gal-Gal-Xyl-Ser
I O-sulfotransferases ^ 3,6S 3S
3S
3.6S 6S
|
A-B-T-»-T-H-T-»-A-n-A-a-A-n-A-B-T-B-T-H-A-n-GIcA-GaI-Gal-Xyl-Ser 2S 2S 2S 2S 2S :' | FIGURE 1. Heparan sulfate assembly. HS polysaccharide assennbly is initiated by the sequential transfer of xylose (Xyl), two galactosyl (Gal) residues, and glucuronic acid (GIcA) via the actions of corresponding glycosyltransferases to the hydroxyl group of serine (Ser) or threonine of tbe proteoglycan core protein. Subsequently, a polymer of N-acetylglucosamine (D) and glucuronic acid (A) is formed through the actions of the EXT family of glycosyltransferases (EXT1, EXT2, EXTL1 -3). Block regions of this polymer are modified to N-sulfated glucosamine residues through the actions of N-deacetylase/N-sulfotransferases (NDSTs). This serves as a signal for glucuronic acid epimerization to iduronic acid (•) through the action of uronosyl epimerase. These regions now can serve as acceptor sites for iduronosyl-2-O-sulfotransferase and N-sulfoglucosaminy!-3 or 6-O-sulfotransferases. Due to the incompleteness of many of these reactions, regions are generated that have more or less highly modified disaccharides and, thus, have different biological activities. For more details, see text. >
discussed below, various growth factors, growth factor receptors, and extracellular matrix molecules display preferential binding to particular niodifications in HS chains, making the balance of the enzyme activities responsible for these modifications important in determining HS bioactivity. Volume 15 Number 1
B. HS Proteoglycan Core Proteins HS proteoglycan core proteins fall into three families: the membrane spanning syndecan family, containing four mammalian members; the glycosylphosphatidylinositol-linked glypican family. 31
containing at least six members; and the secreted or basement membrane-associated proteoglycans, consisting of perlecan, agrin and collagen XVIII. Perlecan, syndecan and glypican family members occur in both cartilage and cartilage primordia.^'^^^ Representative structures are shown in Figure 2. Both syndecans and glypicans, by virtue of their membrane-anchors, function at the cell surface to bind various extracellular matrix components or growth factors. In addition, syndecans have been shown to interact with cytoskeletal components by virtue of their cytoplasmic tails (re\aewed in Beauvais and Rapraeger^^). Therefore, syndecans can link the extracellular matrix and the cytoskeleton. The lipid-linked glypicans do not have the ability to interact directly with the cytoskeleton; however, they may be able to more readily diffuse, at the cell surface, a feature that may have advantages in growth factor presentation.^^ Perlecan, deposited in the extracellular matrix, may help organize the extracellular matrix by virtue of interactions with other extracellular matrix components with either the HS
chains or protein core of this very large multidomain molecule.^^ In addition, the HS chains bind and sequester growth factors, providing a reservoir of such molecules that can be released at later times.
C. HS Proteoglycan Maturation and Degradation Completed HS proteoglycans traverse and are retained at the cell surface, as occurs for the syndecan and glypican family members. Alternatively, they can be secreted directly to the extracellular matrix, as is the case for perlecan. The ectodomains of cell surface proteoglycans may be released via the action of proteases (syndecans) or phospholipases (glypicans). All HS proteoglycans also maybe endocytosed and degraded intracellularly, a process that results in complete degradation of the protein core as well as polysaccharide chains. Extracellularly, HS proteoglycans are targets of metalloproteases that contribute to break-
Perlecan
^ Syndecan
plasma mennbrane FIGURE 2. Representative structures of cartilage heparan sulfate proteoglycans. The figure shows schematics of the three HS proteoglycan types found in cartilage. Perlecan is a large extracelluar matrix proteoglycan, which can contain up to three glycosaminoglycan chains at its annino terminal domain and one at its carboxy terminal domain. Glypicans are a family of cell surface proteoglycans, generically represented in the figure, anchored to the membrane via a glycophosphotipid covalently attached to the carboxy terminus. Syndecans also are a family of cell surface proteoglycans, generically represented in the figure, anchored to the membrane via a transmembrane domain and a short cytoplasmic tail. The blue regions in the figure represent the protein cores while the red regions represent the glycosaminoglycan chains. The thin black lines next to glypican and syndecan represent the plasma membrane. While not drawn to scale, perlecan is substantially larger than either syndecan or glypican.
32
Critical Reviews'™ in Eukaryotic Gene Expression
down of the extracellular matrix. In addition, there are several secreted enzymes that can act upon HS. These include heparanase, an enzyme that specifically degrades HS chains,^^ sulfatases that remove sulfate residues critical for protein binding^** and a proposed N-deacetylase.^^ Actions of metalloproteases and heparanase on HS would be expected to release HS bound growth factors still in association with HS chains. In contrast, sulfatases and N-deacetylases would be expected to convert HS structures to poor binding sites for growth factors, thereby releasing the growth factor from the HS chain. Therefore, these various degradative enzymes are likely to play important roles in modulating growth factor bioavailability.
IV. HS PROTEOGLYCAN FUNCTIONS A. Growth Factor Binding Probably the most highly recognized function of HS proteoglycans is their role in growth factor binding (for reviews see Esko and Selleck^^ and Princivalle and de Agostini^-). One convenient criterion for ascribing HS-binding activity to a given protein is the ability of that protein to bind to heparin—a polysaccharide highly related to HS. In fact, heparin is more highly sulfated than most forms of HS and contains a spectrum of motifs found in HS. As a result, even proteins that recognize specific HS motifs will interact with heparin resins. Because of the highly negatively charged character of heparin, affinity resins, such as heparin-agarose, also act as cation exchange resins. Therefore, it is important to show some degree of specificity in protein binding to heparin or HS, for example, the inability of other glycosaminoglycans, such as chondroitin sulfate, to support binding of the protein. It also is important to demonstrate that interactions with heparin/HS occur under conditions of physiological pH and salt concentrations. The relative strength of the interaction with heparin/HS can be assessed by determining the salt concentration required to elute the proteinfiromthe resin. Thus, proteins requiring relatively low salt concentrarions for elurion (e.g., < 0.25 M NaCl) are considered to bind weakly while those requiring high salt concentrations for elution (e.g., > 0.75 M
Volume 15 Number 1
NaCl) are considered to bind strongly. Other criteria that may be applied to identify a HSbinding protein include the ability to displace the protein from cell surface or extracellular matrix sites with excess HS or heparin or by incubation with heparitinases. Again, appropriate controls must be used to show specificity. Some investigators have suggested certain peptide motifs as determinants for heparin/HS binding^3,34.^ however, there are many examples of proteins that bind heparin/HS quite well without such motifs or depend on an appropriate three-dimensional conformation to create a binding pocket for the interaction.^^••'^ A list of key heparin-binding grovt^th factors and growth factor antagonists known to be expressed and function in cartilage is presented in Table 1. A more comprehensive and current list of these molecules is available in Kirn-Safran et al.-^^ Most of these growth factors display restricted sites of synthesis and deposition in the grovi^h plate. In some cases, such as the fibroblast growth factor (FGF) family members,^^-^"* HS binding is essential for grov\T:h factor activation of signal transduction by its cognate protein receptor. This may not be the case for all HS binding growth factors. In other cases, HS binding may primarily serve to restrict the diffusion or provide a site of growth factor deposition, sequestration, or storage for later release by the extracellular HS proteoglycan degrading enzymes mentioned above. While not known for all growth factors or other types of HS-binding proteins, HS features required for binding of certain growth factors are known, including those for FGF-1, -2, and -18,^^-^^ and vascular endotheUal growth factor (VEGF).-« The proteins listed in Table 1 all bind to HS consdtuents of HS proteogiycans; however, it should be noted that certain growth factors or growth-factor-binding proteins also can bind to proteoglycan core proteins. One example is FGF-7, which binds to domains III and V of perlecan."*' Another example is the FGF-binding protein, which binds to a region of domain III of perlecan very close to the FGF-7 binding site."*^ The known domain-specific interactions of proteins vinth perlecan are show^n in Table 2. While syndecans interact with a variety of intracellular proteins via their cytoplasmic tails (reviewed in 33
TABLE 1 Examples of HS Binding Proteins in Cartilage HS proteoglycan binding protein
References'^
Growth factors FGFs BMPs TGF-ps CTGF VEGF Indian Hedgehog
Stark et al.'^'; Liu et al.i« Hogan^"!; Hoffman and Gross'« Pelton et al.'''^; Hogan"" Takigawa et al.^'" Zelzer et al.^^; Maes et a l . " deCrombrugghe et al.^"^
Growth factor binding proteins Noggin IGFBP-2 (when complexed with IGF-I or IGFBP-5
Brunet et al.* Van Kleffens et al."' Wang et al.«; Van Kleffens et al."'
Cell surface receptors N-CAM FGF receptors
Hall and Peters et
'
Extracellular matrix components Fibronectin Tenascin-C
Kozaki et aV" Tucker et a\.^^
Arai et al.''^ Citations refer to demonstration of these proteins or their transcripts in cartilage. Citations of the heparin-binding properties of each protein can be obtained by performing a standard literature search and cross-listing the name of the protein with "heparin" or "heparan sulfate."
Beauvais and Rapraeger^^), no interactions of the protein core of tbe extracellular domain with otber proteins have been reported. Sites of growtb factor action require cells expressing corresponding receptors. HS proteoglycan-dependent restriction of growtb factor dif]£usion may be critical to fine-tune the delivery and actions of these growtb factors. One interesting example is the potent BMP antagonist, noggin. Noggin strongly binds HS and retains its full BMP antagonist activity even in tbe HS bound In this case, nog^n's ligands also bind 43.44 Xhus, a complex situation may exist within cartilage in wbich both BMPs and their antagonists are restricted by HS, providing a high degree of control of the actions of these proteins. Other interesting examples are the insuHnlike growthfactor-binding proteins, IGFBP-2 and -5.^^ IGFs have important actions in cartilage, but do not themselves bind HS."^'"*' In this case, the HSbinding IGFBPs may provide a means to reduce the actions of IGFs at sites of HS accumulation. Alternatively, HS-binding IGFBPs may provide 34
a means of converting IGFs to HS-binding growtb factors at these same sites, where tbey can be released either by the HS proteoglycan degrading en2ymes discussed above or IGFBP-degrading proteases."*^ Finally, FGF-binding protein binds strongly to the core protein of perlecan and, thereby, may restrict FGF diffusion and action. In this case, because the interaction occurs in perlecan's protein core, protease activity would be required to liberate FGFs from these sites.
B. Growth Factor Receptor Binding/ Coreceptor Functions HS proteoglycans also bind to certain growtb factor receptors. In the context of cartilage biology, the association with FGF receptors is of particular importance because a variety of skeletal defects are associated with FGF receptor defects.'*'* In addition, the FGF-FGF receptor system is the best studied witb regard to interactions witb HS. HS binding is critical to appropriate FGF receptor
Critical Reviews'™ in Eukaryolic Gene Expression
signaling and involves HS binding to both FGFs and FGF receptors in a ternary complex.-'''-^^ It has been suggested that the interactions watb HS contribute to specificity of the FGF receptor complex.^** Just as different FGFs differentially trigger biologic;il responses through different FGF receptors, it also has been shown tbat distinct HS motifs elicit differential FGF response patterns through FGF receptors lc and 3c.^^ Thus, regional special-
ization of HS structures within cartilage may contribute to fine control of FGF actions. Recently, it has become appreciated that FGF receptors not only can function intracellularly, but also may be downstream mediators of bone morphogenetic protein (BMP) actions. In particular, splice variants of FGF receptor-1, wbich retain botb FGF binding and tyrosine kinase activity, have been found located in cell nuclei, \vbere
TABLE 2 Domain Specific Interactions of Proteins with Periecan Perlecan domain
Interacting molecule
References
Domain 1 (Unique)
PRELP
HBGFs (bFGF, VEGF) TSP-1 (via hs) HIP (via hs) Amyloid polypeptide (via hs) Laminin 1 (via hs)
Bengtsson et ai.'** Various Feitsma et al.'*' Rohde et al.^^° Park and Vercher* Sasaki et ai.^^^
Domain 2 (LDL receptor-like)
LDL, VLDL
Hummel et al.'^
Domain 3 (Laminin I-EGF-Uke repeats)
PDGF-BB (III-2)
FGF7 (to core) FGFBP
Gohring et a i . ' " Ghiseiii et ai.^^ Mongiat et a i . ' "
Domain 4-1 (Ig-iike repeats 2-9)
Nidogen (lg3-coXstal) Heparin/ sulfatide (!g5) Nidogen 1 and II (Ig3) critical for laminin Fibronectin (lg4-5) Fibulin 2 (NOT 1) (Ig2,15) Collagen IV (weak)
Kvansakul et ai.'^ Hopf et a l . * ' ' " Hopf et a l . * ' ' " Hopf et a l . * " " Hopf et a l . * ' ' " Hopf et a l . * ' ' "
Domain 4-2 (Ig-iike repeats 10-15)
Fibronectin (weak) Fibulin 2 (weak)
Hopf et a l . * ' ' " Hopf et a l . * ' ' "
Domain 5/Endorepellin (Laminin l-ghbular homohgy- EGF-like)
Progranuiin
Laminin (via hs) Pi Integrin (via laminin?) Nidogen Heparin Fibulin-2
Gonzalez et a i . ' ^ Mongiat et al.3'^' Bengtsson et ai.'* Friedrich et ai.'*° Brown et ai.'* Brown et ai.'* Brown et ai.'* Brown et al.'*
Type Xill coliagen Endostatin (type XVIIi collagen) Dystroglycan (via iaminin?) CTGF/Hcs24 Histone HI Thrombospondin i
Tu et a l . ' " Miosge et ai.^" Henry et ai.'*-^ Nishida et ai.'*" Henriquez et ai.'*' Vischer et a i . ' "
Unknown
Volume 15 Number 1
ECM1 PRELP
35
they presumably contribute to regulation of transcriptional acrivities.^^ Interesdngly, HS also can be found in the nucleus under certain circumstances although the details of how HS transport to this compartment occurs are unclear.^•*'^'* Nuclear FGF receptors have not been studied in chondrocytes, but should be examined. HS binding VEGF isoforms are expressed in cartilage and appear to be important for proper formation of this tissue.^^'^'' VEGF receptors are not found in cartilage proper, but are abundantly expressed in the perichondrium and at the chondro-osseous junction.^^ Though less well studied than FGF receptors, VEGF receptors bind HS and also may form ternary complexes with VEGF." Thus, VEGF is produced and stored in the pericellular matrix and, presumably, must be released from these sites to activate VEGF receptors in surrounding tissue. It is noteworthy that the strong expression of perlecan observed in cartilage abruptly and markedly diminishes at the chondro-osseous junction.-^ Interestingly, domain V of perlecan is reported to have antiangiogenic activity.^^ This activity may contribute, in part, to maintenance of the avascular nature of cartilage. In addition, destruction of the perlecan core protein at the chondro-osseous junction would be expected to promote angiogenesis not only by releasing sequestered angiogenic factors, such as FGFs and VEGF, but also by destroying antiangiogenic motifs within perlecan. This is consistent with the observations that null mutations in the metalloproteases MMP-9 and M T l MMP severely impact cartilage development and angiogenesis
59,60
C. Models of HS-Dependent Growth Factor Presentation/Signal Activation It is not immediately obvious why binding HS offers an advantage in terms of growth factor delivery, and, indeed, there are many growth factors, hormones, and cytokines along with their receptors that do not use HS in any aspect of their action. One benefit is the ability to concentrate these proteins in an insoluble form whether this is at the cell surface or in the extracellular matrix. While not determined for many HS-binding growth factors, studies with FGF-2 demonstrate 36
that multiple FGF-2 molecules can bind to a single HS chain (heparin was actually used in the study). Furthermore, larger HS chains bind more FGF-2 molecules.""^ In this study, the high molecular form of heparin used had a mean molecular weight of 15,000 and, on average, bound approximately six FGF-2 molecules. Considering that HS at cell surfaces and in the extracellular matrix can be much larger than this, it is almost a certainty that typical HS chains bind more than one protein under most circumstances. In fact, the multivalent nature of HS appears to be critical to bridge FGF and FGF receptors leading to receptor activation.*^ The ability of multiple proteins to interact with a single HS chain also creates the opportunity for heparanase to cleave at sites within these chains not occupied by growth factors and release HS fragments containing bound growth factors that, in turn, can difRise to the cell surface to activate growth factor receptors. Heparanase action and proteolysis of proteoglycan protein cores are very likely to be important modes of growth factor delivery from sites of deposition in the extracellular matrix. In terms of cartilage biology, this type of delivery is expected to be the major operative process for articular cartilage as well as hypertrophic zone cartilage where perlecan dominates. Other regions of cartilage contain cell surface proteoglycans of the syndecan and glypican families either along with perlecan or as the predominant HS proteoglycans. Other models for how these types of cell surface molecules might participate in growth factor delivery have been proposed and are presented w^ell by Nybakken and Perrimon^'' (and references vidthin). These models will be summarized briefly here and are not mutually exclusive. All models involve growth factor binding to HS chains and, as mentioned above, the likelihood of multiple growth factors being bound to a single HS chain must be considered as a means of concentrating the growth factors. One proposed role is promotion of receptor dimerization required for signal transmission. In this matter, the HS chains are large enough not only to bind growth factors and a receptor simultaneously, but also to bridge gaps between separate receptor subunits. A second model proposes that HS chains stabilize complexes between receptors and ligands. In this case, in the absence of HS ligands inefficiently stimulate re-
Critical R£tiiev}s"* in EukaryoHc Gene Expression
ceptors either by diffusing away more quickly or by failing to form dimers required for receptor activation. The presence of HS permits functional multimeric growth factor presentation. A third model proposes that cell surface HS proteoglycans are capable of diffusing within the plasma membrane and, therefore, control the distribution of growth factors from their sites of secretion. While the density of HS at the cell surface is high, growth factor binding to HS is relatively weak. Therefore, growth factors are expected to continuously dissociate firom HS and gradually move along the cell surface away from the site of secretion driven by mass action. A fourth model is derivative of the third and suggests that grovith factors are essentially "passed" from the surface of one cell to another either via release from HS chains from one cell surface and capture by HS chains of the neighboring cell or by actual physical movement of the HS proteoglycan from one cell to another as occurs in some cases.^^ The recipient cell, not the donor cell, would have the corresponding growth factor receptor and, therefore, can now not only respond to the signal, but also do so in an extremely localized fashion because growth factor diffusion is highly limited by its interactions with HS. A fifth model proposes that endocytosis of the HS proteoglycan-growth factor complex provides a means to deliver the complex to a neighboring cell via vesicular transport. Following vesicle movement to the neighboring cell, the vesicle would move through a standard secretory pathway to the cell surface thereby delivering the complex to the receptor. As mentioned below, there is some evidence that HS binding growth factor receptors occur in the nucleus. Thus, it is conceivable that this vesicular transport model provides a means of delivering HS proteoglycan-growth factor complexes to this organelle.
D. Extracellular Matrix and Cell Surface Component Binding HS binding motifs are found on many extracellular matrix proteins, including laminins, collagens, fibriUins, and fibulins.''**^' Fibronectin also has weU-known HS-binding domains, including splice variants found in cartilage.^^ The multivalent
Volume 15 Number 1
nature of HS chains provides the opportunity for individual HS chains to interact with more than one protein. Thus, interactions with HS chains augment protein-protein interactions and help to cross-link, stabilize, and organize the extracellular matrix. i Cell surface components found in cartilage also display HS-binding activities. As discussed above, cell surface FGF receptors bind HS, a property important for growth factor signaling. Another interesting example is neural cell adhesion protein (NCAM).*''' NCAM is a marker and mediator of mesenchymal condensation, which occurs very early in the commitment to chondrogenesis (reviewed in Hall and Miyake^). NCAM has both homotypic and HS-binding properties, but it is not clear if the HS-binding activity of NCAM plays a role in early chondrogenic differentiation. Nonetheless, both HS and the related mast cellderived polysaccharide, heparin, have been reported to promote chondrogenic condensation.™ The large heparan sulfate proteoglycan, perlecan, or a recombinant fragment of perlecan retaining only domain I also triggers condensation and chondrogenic differentiation in multipotential mouse embryonic stem cell lines as well as primary cultures of human chondrocytes.-^'''^ The above studies demonstrated that the glycosaminoglycan constituents were essential by showing that either point mutations that destroyed glycosaminoglycan attachment sites or enzymatic removal of glycosaminoglycans also destroyed chondrogenic activity. Curiously, either destruction of HS or chondroitin sulfate chains was sufficient to destroy activity. Thus, it is possible that the glycosaminoglycans serve a passive role by altering the physical properties of perlecan and perlecan domain I such that the protein core may be presented appropriately to trigger differentiation. Alternatively, the chondroitin sulfate chains also may function directly, perhaps by binding and presenting growth factors as can occur in some highly sulfated chondroitin sulfate species.^^ These observations along with the recent findings of severe cartilage abnormalities found in mice harboring HS biosynthetic enzyme mutations warrant more careful examination of the HS and chondroitin sulfate structures used in chondrogenic assays as well as the HS structures found on cartilage perlecan. Perlecan or its active frag37
ment only appears to be able to trigger tbe initial events of cbondrogenesis, i.e., condensation and expression of collagen type II, glycosaminoglycan accumulation, and aggrecan and perlecan expression; however, in conjunction with BMP-2, perlecan or its active fragment can drive differentiation through to the hypertrophic stage as evidenced by the expression of collagen type XJ^ How these actions of perlecan are mediated is unclear, however, the observation that these activities require the presence of intact glycosaminoglycan chains demonstrates that these polysaccharides are involved. In addition to the interactions of various proteins with perlecan occurring tbrough HS cbains in domains I and V (Table 2), the large perlecan molecule also interacts with a variety of other proteins through core protein domain interactions. Unique domain I contains a SEA domain and is one site of interaction with PRELP.^"* Domain II, which contains four LDL receptor a domains, possesses potential sites for interactions with proteins containing EGF or LDL receptor b domains (http://www.sanger.ac.uk/software/Pfam/), but tbe exact identities of these in tbe context of perlecan have not yet been demonstrated. A recent study"^ revealed interactions of two lowdensity lipoproteins (LDL and VLDL) witb recombinant domain II of chicken perlecan, which the autbors proposed may serve a vesicular transport function. Domain III contains a series of laminin-B and laminin-EGF-like domains, which potentially can interact with similar domains in other extracellular matrix proteins that include laminin in addition to those listed in Table 2. Domain IV consists of a series of tandem Ig module repeats tbat form functional interactions with a variety of other proteins, including the basement membrane proteins nidogen and collagen IV. In the context of interactions with other matrix proteins present in the cartilage pericellular matrix, this domain is of considerable interest, but only limited studies with it have been performed in this tissue. Domain V contains laminin-G and EGF-like repeats that also form stable interactions witb a variety of proteins (Table 2). It has been proposed that this domain may interact vvdth tbe (3^ integrins,'^ but this may be an indirect interaction requiring laminin. EGF-like domains, in a manner similar to Ig domains, pro-
38
vide sites for multiple protein core interactions. In fact, EGF-iike domains are predicted to form interactions with 14 other Pfam domain families. Understanding these interactions in the context of cartilage matrix biology remains an area of high research priority.
E. Anticoagulant Activity and HIP/RPL29 Binding
I
The first and best described example of protein recognition of a particular HS structure is the case of antithrombin-3.^'''' Antithrombin-3 is a serum protein that, in the presence of heparin or HS, binds the procoagulant, thrombin and inhibits tbrombin activity. In the absence of heparin/HS binding, antithrombin's anticoagulant activity is reduced approximately 1000-fold. Most species of heparin (or HS) do not bind to antitl-irombin-3 due to the fact that a specific HS pentasaccharide sequence containing a relatively rarely found 3-Osulfated N-sulfo-glucosaminyl residue is required for binding. Other specific features of the pentasaccbaride are required as well. HS sequences lacking these features bind antithrombin-3 poorly and fiiil to demonstrate anticoagulant activity. Thus, in this example, HS (or heparin) acts as an enCTmatic cofactor. In spite of a great deal of compelling evidence that indicates a requirement for tbe specific 3-O-suifate modification for anticoagulant activity, mice in whicb the gene encoding the 3-Osulfotransferase has been knocked out display normal blood coagulation activities.'^ While it is possible that isozymes for this enzyme exist, antithrombin-3 binding sites appear to be largely absent in these animals, bringing into question the true role this HS modification plays in the blood coagulation cascade. It is not dear if either antitbrombin-3 or antithrombin-3 binding sites occur in cartilage; however, given the avascular nature of cartilage, it is unclear what function either would serve in this tissue. There are other examples in which HS binding has been shown to function similarly in the sense that binding results in alterations of protein conformation required to observe biological activities. Tbese include FGF receptors and FGF-1.''' A related case is HS binding to heparin/HS interacting protein/ribosomal protein L29 (HIP/
Critical Reviews'"* in Eukaryotic Gene Expression
RPL29).s" In tbis case and similar to the FGF-1 observations, HIP/RPL20 demonstrates very little secondary structure in solution in the absence of HS, but assumes an ordered stmcture upon HS binding. The large conformational change observed is paralleled by protease protection studies, indicating that all but a small region at the N-terminus of this protein is involved in HS binding.^" HIP/RPL29 inhibits both heparindependent anticoagulant activity and heparanase activity, suggesting that it can bind to tbe specific sequences recognized by both of these proteins.^^-^^ However, this does not necessarily imply that HIP/RPL29 recognizes specific HS sequences, but ratber may be able to bind promiscuously to many HS sequences. In fact, more recent studies indicate that the latter is tbe case.^^ While FGF-1 is not a major FGF family member in terms of cartilage biology, HIP/RPL29 is highly expressed in hypertropbic cartilage and is abrupdy lost at the chondro-osseous junction.^
F. Impact of HSPG Mutations 1. Core Proteins It has been pointed out tbat virtually every animal model, including the mouse, that lacks a specific HS core protein has a mutant pbenotype, even tbougb other HS core proteins are expressed in the affected cells and even though the pattern of HS sulfation on the chains that are made is virtually the same.^^ This indicates that HS proteoglycan core polypeptides have functional roles that extend beyond their role as carriers of HS chains. Arikawa-Hirasawa et al.^*" created global perlecan-nuU mice by disruption of the Hspg2 gene. Some 40% of the nuU embryos died at embryonic day 10.5 with defects in cephalic development. Some embryos survived to birth and exhibited severe skeletal dysplasia with bowed long bones, a narrow tborax, and craniofacial abnormalities. Hspg2"''" mouse cartilage showed profound disorganization of the columnar stmcture of growtb plate cartilage and defective endochondral ossification. By comparison to similar abnormalities in mice with activating mutations in FGFR3, it was concluded tbat perlecan may be involved in maintenance of this signaUng path-
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way, a function consistent vtdth its role as a coreceptor for FGF. Mice lacking exon 3 of perlecan (Hspg2 gene) were generated as well.^'' This deletion maintains the proper reading frame, but deletes the attachment sites for the three HS chains in domain I. HS chains, if present in domain V, sbould be unaffected by loss of exon 3. These mice are viable and fertile, but have small eyes and sbow degeneration of the lens capsule. Basement membranes and skeletal tissues are grossly normal. There are four known syndecan family members, and all variously have been reported to be expressed in cartilage although the results of these analyses remain fairly inconsistent. Skeletal formation occurs normally in the case of disruption of any of the four syndecan genes in the mouse. In light of the key role of Wnt signaling in limb development,^^ it is of interest that syndecan 1 has been reported to modulate Wnt signaling in tbe mouse.^^ Glypican family members also bave been studied in the mouse. Six family members occur in vertebrates. Although the specific functions of tbe glypicans remain elusive, deletions in the mouse glypican-3 gene (Gpc3) created either by gene trapping or by targeted gene dismption result in severe skeletal malformations. These may be attributed to interactions wdth Bmp4 during limb patterning and development.''^ It sbould be noted that while perlecan is expressed as tbe product of a single gene from w^bich stmctural diversity can be generated by alternative splicing, both syndecan and glypican occur as multiple family members from separate genes. Functional redundancy may tbus explain the failure to detect a major phenotype in skeletal tissues after deletion of a single gene.^* Interestingly, overexpression of syndecan-3 contributes to cbondrocyte proliferation and widespread distribution of Indian hedgehog, suggesting the normal function of this growth factor in cartilage may be limited by HS.^'^ Mutations in two human HS proteoglycans, perlecan and glypican-3, cause tbree recognizable but rare syndromes tbat affect grovvth. Schwartz-Jampel (SJS) (OMIM255800) and Dyssegmental dysplasia, Silverman-Handmaker (DDSH) {OMIM 224410) syndromes are caused by mutations in perlecan and are associated with mild to severe skeletal dysplasias while SimpsonGolabi-Behemel (SGBS) (OMIM312870) syn-
39
drome is caused by mutations in glypican-3, which leads to overgrowth. SJS was first reported in 1962 in two siblings with blepharophimosis.^^ Subsequently, the condition was described in the same siblings, but the expanded phenotype included short stature, myotonic myopathy, epiphyseal and metaphyseal abnormalities, joint contractures, blepharophimosis, unusual pinnae, myopia, and pigeon breast.^"* Numerous case reports have followed describing the phenotypic characteristics of SJS and autosomal recessive inheritance in a majority of cases. A few reports suggest an autosomal dominant form of SJS.*^""^^ SJS demonstrates interfamilial variability, which led to subclassification into types lA and IB and 2. Type lA is identified in childhood and is associated with a mild skeletal dysplasia.^^ Type IB is usually recognized at birth and is associated with a more severe skeletal dysplasia resembling Kniest dysplasia and increased mortality. Type 2 has a more severe skeletal dysplasia phenotype similar to Pyle disease and increased mortality. Type 2 is now recognized to be Stuve-Wiedemann Syndrome (STWS)'^ and is caused by null mutations in the leukemia inhibitory factor receptor gene on chromosome 5pl3.1}'^ Homozygosity maps the SJS locus to chromosome Ip36-p34,^'*' containing the perlecan gene. Mutations in the perlecan gene subsequently were identified^*'^ and the description of different mutations followed.^"^^ Both compound heterozygous and homozygous mutations have been identified and may account for the observed clinical variability.
affected males led to the recognition of an Xlinked recessive etiology.'^^ Families with multiple SGBS males were used to map the genetic locus to Xq26.^^^ Shortly thereafter, the glypican-3 gene was identified in X/autosome translocation cell lines and deletions in the glypican-3 gene were shown to cause SGB3.'^^"""' Single base pair substitutions also have been reported and result in a truncated GPC3 protein.^^^ Recendy, single base pair substitutions were identified in Wilm's tumor samples, suggesting that GPC3 may play a role in
G. HS Biosynthetic Enzymes
In this section, we will discuss information available on the known patterns of expression and the impact of mutations in enzymes involved in HS assembly on cartilage development and fiinction following the pathway of HS assembly described in Figure 1. In this regard, there is little information and no known mutations in enzymes assembling the tetrasaccharide core of region of HS. Nonetheless, it can be reasonably assumed that these gene products are expressed at high levels in cartilage due to the extremely high amount of proteoglycan production occurring in this tissue. EXT gene expression has been studied in some detail during mouse development.'i^ EXTl, EXT2, and EXTLl are all found in skeletal elements undergoing endochondral ossification. EXTLl mRNA is highly expressed during early stages of chondrogenesis DDSH is a very rare lethal chondrodystrophy, while EXTl and EXT2 are present at relatively which was first described in 1978.^'^^ Vertebral seglow levels at the same sites. At later stages of mentation defects are always present, and the verdevelopment (E14.5 and later), EXTl and EXT2 tebral bodies vary in size and are separate ossified are found in developing bone while EXTLl is bodies. Clinical features include narrow chest, rerestricted from this region. EXTLl is uniformly duced joint mobility, deft palate, hydronephrosis, expressed in proliferating, prehypertrophic and and hydrocephalus.^*^^ All affected infants are either hypertrophic chondrocytes. In contrast, EXTl stillborn or live for only a few months. DDSH has and EXT2 are excluded from the hypertrophic an autosomal recessive etiology^** and also is caused zone. Transgenic mice harboring an EXT2 by mutations in perlecan. ^'^' AU types of mutations transgene driven by collagen XI promoter dishave been identified, with most resulting in proplayed high levels of EXT2 overexpression in tein truncation. prehypertrophic chondrocytes as well as develSGBS is characterized by a broad stocky apoping rib and vertebral regions.'^" As expected pearance, distinctive "buUdoglike" faces, enlarged tongue, and broad, short hands and fingers.'^'^^'^*'^ these mice display increased HS synthesis and a modest increase in trabecular bone formation. Prenatal and postnatal overgrowth is present and Taken together with the expression data, these intelligence is normal. The observation of only
40
Critical Reviews"' in Eukaryotic Gene Expression
observations suggest that EXT2 is a limiting factor in bone formation. NuU mutations have been created in some EXT genes in mice. EXTl nulls display many defects, starting at gastrulation, and synthesize very little HS, demonstrating a critical role for this gene in HS assembly. Similar results are reported for EXT2 nulls.'^^ As one approach to circumvent embryonic lethality, Zak et al.'^^ studied exostoses formation and HS assembly in mice heterozygous for either or both genes. A hierarchy for exostoses formation is reported with few (10-15% incidence) found in EXTl*'" or EXT2*'" mice, whereas the frequency considerably increases (approximately 30%) in compound heterozygotes, along with shorter chain lengths in HS synthesized by chondrocytes isolated from these animals. As a result, these authors suggest that maintaining threshold levels of HS are critical in controlling exostoses penetrance. In humans, mutations in EXT genes result in hereditary multiple exostosis (HME), a defect
characterized by multiple cartilage-capped bony prominences called exostoses or osteochondromas.^'^ Exostoses arise by asymmetrical overgrowth of the metaphyseal cortical bone, which lies adjacent to the growth plate.'^'^ The exostoses may evolve in two different directions. Most commonly, as the parent bone lengthens, the exostosis may appear to migrate toward the diaphysis (Figs. 3A and 3B). However, this migration reflects normal juxtaepiphyseal metaphyseal bone growth. Alternatively, the exostosis may remain at the metaphysis and expand to produce a cauliflower shape at the end of the parent bone. Exostoses develop shortly after birth and continue to appear and grow throughout chUdhood and into puberty (Figs. lA and IB). Each exostosis has a growth plate that ftises at puberty, leading to cessation of the exostosis bone growth. Exostoses are most frequently observed at the ends of the long bones, scapulae. Iliac crest, ribs, and, less commonly, on the vertebrae. HME is estimated to affect 1/25-50,000 indiviuals, and 70% of cases
FIGURE 3. Exostoses (arrows) surrounding the large joints of the lower extremities (A) and on the distal end of the radius as well as the ulna (B).
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report a positive family history of HME. ^-' In comparison, isolated exostoses are more common and are reported to affect 1% of the population. ^'^ HME is associated with significant orthopedic morbidity, including leg length discrepancies, bowing deformities, and nerve and blood vessel compression, which often require surgical intervention.^-^ Stature is only minimally reduced and disproportionate short stature is not observed. Malignant degeneration is the most serious complication and occurs in less than 2-4% of individuals with HME.'-^-^^-^ Chondrosarcoma and, rarely, osteosarcomas, are the types of cancer reported most commonly in adulthood; early detection is necessary for the best outcome. HME is an autosomal dominant condition caused by heterozygous germline mutations in EXTl and EXT2 genes, on chromosomes 8q24.1 and llpll-n.^^"*'^^^ To date, more than 49 germline mutations in ElXTl gene and 25 in the EXT2 gene have been described in patients with HME with about 80% predicted to cause heterozygous loss of function (nonsense and frameshift mutations).^*" Missense mutations comprise the remaining 20% and are predicted to produce abnormal protein. Three additional genes— EXTLl, EXTL2, and E^XTI_3—on chromosomes Ip36, lpll-12, and 8pl2-p22, respectively, have homology to EXTl and EXT2, but have not been implicated in causing HME.^^'^-^^''"^^^ Studies of chondrosarcoma samples from HME patients identified multiple mutational events involving the EXTl and/or EXT2 genes and/or loss of heterozygosity also involving theses genes as well as other chromosomal regions.^^^•^•^^ This finding suggested that development of chondrosarcoma in HME follows a multistep model of tumorigenesis described for the development of retinoblastoma.^^-* A similar model was proposed for the development of the exostosis, but multiple mutational events have not been identified in the majority of exostoses samples. ^•'"^ A heterozygous mutation in either the EXTl or EXT2 gene is the most common mechanism associated with HME. Although expression studies have not been performed, Li et al. recently created a mouse null mutant for HS giucuronosyl epimerase.^^^ The mice develop to birth, but display a number of large defects, including renal agenesis, and mas-
42
sive skeletal defects. More studies on the expression of this epimerase in cartilage as well as a careful examination of the nature of the skeletal defects are warranted. Some information is available on the patterns of 0-sulfotransferase gene expression in developing cartilage. Developing chick limb buds show complementary expression of HS-6-O-sulfotransferase-l and -2 mRNA in the anterior proximal and posterior proximal regions, respectively. In contrast, HS-2-Osulfotransferase is distributed uniformly through these tissues.^^* Presumably, the two HS-6-Osulfotransferases recognize different features in their HS substrates and, therefore, generate different HS structural motifs in these regions. This appears to be a reasonable assumption, but has not been shown rigorously. Neither overexpressing nor null mutations have been created for HS-6O-sulfotransferases; however, a gene-trap approach has generated mice null for HS-2-Osulfotransferase.^^''-^-^^ These mice display several large defects, including renal agenesis. In addition. Bullock et al.^-'^ reported increased bone mineralization, ectopic ossification vertebral fusion, and polydactyly, however, more careful studies of cartilage formation in these animals are warranted. Finally, as noted above, mice null for HS-3-O-sulfotransferase have been generated.''^ No overt defects in cartUage or skeleton formation were noted, but the animals display some unexpected phenotypes, including some subtle growth defects that were compared to intrauterine growth retardation; however, direct studies of cartilage were not reported. Given the failure to observe coagulopathies in these animals, the authors suggested that the 3-O-sulfate modification is likely to serve additional purposes. It is possible that these modifications play a role, albeit subde, in cartilage development.
V. SUMMARY AND CONCLUSIONS While the existence of HS in cartilage has been known for many years, only recently have the core proteins carrying these polysaccharides been identified. The core proteins found in this tissue are certain members of the glypican and syndecan families and perlecan. More work needs to be done to determine if these proteoglycan core pro-
Critical Reviews'™ in Eukaryotic Gene Expression
teins have distinct patterns of distribution in developing and adult cartilage, implying different functions. The constituent HS chains serve multiple purposes, notably in the binding of growth factors and growth factor antagonists as well as certain cell surface and extracellular matrix components. Tbe critical roles tbat HS proteoglycans play in vivo is demonstrated by the severe cartilage and skeletal phenotypes associated with mutations in core proteins, particularly perlecan, as well as various HS biosynthetic enzymes (e.g., EXT genes) in both mouse models and humans. Future studies sbould employ cartilage-specific targeting of HS proteoglycan mutations in model systems to avoid potential complications in interpretation of phenotypes due to potential HS proteoglycan-dependent defects in associated, noncartilaginous tissues, which may modulate cartilage formation. In addition, more work needs to be done to determine if expression of HS modifying enzymes as well as HS motifs is regionally controlled within cartilage. Sucb specialization may account for regionally distinct differences in bioavailability and responsiveness to growth factors and impact of mutations in HS proteoglycan assembly on chondrogenesis-
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