Review Article
Department of
Medical Biochemistry and Microbiology, Biomedical Center, Box 575, S-751 23
Uppsala, Sweden.
_________________________________________________________________________________________________
Correspondence: Paraskevi Heldin, Ph.D., Phone: 46 18
4714261; Fax: 46 18 4714975;
E-mail: Paraskevi.Heldin@medkem.uu.se
Key words: Hyaluronan, hyaluronan
synthase, HAS1, cytokine, extracelular matrix
Abbreviations: HAS, hyaluronan synthase; PDGF,
platelet-derived growth factor; TGF-§,
transforming growth factor-§; TNF,
tumor necrosis factor; IL,
interleukin; IFN, interferon
Hyaluronan is an ubiquitous glycosaminoglycan found in almost all tissues of the body in vertebrates and in the extracellular capsule of certain pathogenic bacteria. Hyaluronan is biologically active and affects cell migration and proliferation. The amount of hyaluronan in the extracellular matrix increases during inflammation, wound healing and certain forms of cancer. Hyaluronan is synthesized by a membrane-bound enzyme which uses UDP-sugar nucleotides precursors (UDP-glucuronic acid and UDP-N-acetylglucosamine). Three mammalian hyaluronan synthase genes (HAS1, HAS2 and HAS3) have been identified. The encoded proteins share 56-71% sequence similarities. The synthesis of hyaluronan is carefully regulated in a cell specific manner. Certain growth factors and cytokines lead to an increased activity of existing synthase molecules as well as induce the synthesis of new enzyme molecules.
Hyaluronan was first
isolated by Meyer and Palmer (1934) from the vitreous body of the eye and
therefore named hyaluronic acid (from the Greek word hyalos, which means glass). Its architectural construction of
repeating disaccharide units [D-glucuronic acid (1-b-3) N-acetyl-D-glucosamine(1-b-4)]n was
established twenty years later by Weissmann and Meyer (1954). Hyaluronan is an
unbranched linear polysaccharide with a molecular mass ranging from about 200
kDa in blood to 5000 kDa in synovial fluid. The largest molecules have a chain
length in the average of 10 µm. The chains form in solution kinked coils which
immobilize water within their domains (Laurent and Fraser, 1992; Fraser and
Laurent, 1996) (Figure 1).
Hyaluronan is found virtually in every tissue and body fluid in vertebrates and
in the capsules of certain bacterial pathogens, e.g Gram-positive group A and C streptococci and type A Pasteurella multocida (Carter and Annau,
1953; Laurent and Reed, 1991). Excessive amounts of hyaluronan are found during
the first stage in the generation of extracellular matrix. This stage is
followed by a decrease in the hyaluronan content as cell growth and
differentiation ensues. In normal healthy tissues the amount of hyaluronan is
maintained in equilibrium by a balance between synthesis and degradation.
However, during inflammation, wound healing and certain forms of cancer the
amount of hyaluronan increases and hyaluronan becomes the dominant
glycosaminoglycan in the extracellular matrix. Accumulation of hyaluronan leads
to retention of fluid which most likely contributes to the swelling of tissues
characterizing inflammation (Laurent, 1998; Knudson, 1998). However, during
restoration of damaged tissue hyaluronan-rich matrix has been shown to have
beneficial effects; increased amounts of hyaluronan in the matrix forms a
favorable environment which promotes cell migration and proliferation. For
example, treatment with
Figure 1. Schematic drawing of cell
surface associated hyaluronan chains and hyaluronan chains asociated with
extracelular matrix proteins.
Figure 2. Hyaluronan containing coat surrounding a normal human mesothelial
cell. The coat is visualized by the exclusion of formalin fixed erythrocytes.
The picture was kindly provided by Dr. Hkan Pertoft (Uppsala, Sweden).
hyaluronan gel led to improved healing with less scar formation of damaged tendons and the tympanic membrane of the ear (Balazs and Denlinger, 1989; Laurent et al, 1986). The biological effects of hyaluronan in tumor tissues have not yet been clarified. Hyaluronan may facilitate tumor invasion (Lesley et al, 1997; Knudson, 1998) or may be involved in a host defense response (Teder et al, 1995).
Hyaluronan
stabilizes the architecture of extracellular matrix through its interactions
with specific matrix proteins and receptors, collectively referred to as
hyaladherins (Toole, 1990). Moreover, it is involved in many biological
processes modulating cell behavior during embryogenesis, inflammation and
tumorigenesis (Knudson and Knudson, 1993; Sherman et al, 1994). These effects
may be mediated through hyaluronan containing coats which constitute the
immediate cellular environment (Figure 2).
These coats are three-dimensional gels formed around some cells, and can be
visualized in vitro by their
exclusion of formalin-fixed erythrocytes (Clarris and Fraser, 1968; Knudson et
al, 1993; Heldin and Pertoft, 1993). The most thoroughly studied hyaladherins
are the link protein and aggrecan of cartilage (Hardingham and Muir, 1972)
which have analogues in other tissues such as versican in connective tissues
(Zimmermann and Ruoslahti, 1989), and hyaluronectin in the brain (Delpech et
al, 1989). Hyaladherins are also found in certain body fluids, e.g. tumor necrosis factor
(TNF)-stimulated gene-6 (TSG-6) found in synovial fluids of patients with
arthritis and in sera of patients with different inflammatory or autoimmune
disorders. TSG-6 forms a complex with the plasma protein inter-a-trypsin inhibitor that is also a hyaluronan binding protein (Day and
Parkar, 1998). Cell-associated hyaluronan receptors are not only confined to
connective tissue cells. Hyaluronan binding to cells of non mesodermal origin
was demonstrated by the aggregation of lymphoma cells but not normal
lymphocytes after addition of the polysaccharide (Wasteson et al, 1973). A
putative hyaluronan receptor is the lymphocyte homing receptor gp90Hermes
(CD44). The interaction between CD44 and hyaluronan leads to internalization of
hyaluronan by lung macrophages and chondrocytes, adhesion of lymphocytes to the
endothelium, formation of pericellular matrices around chondrocytes and
increased invasion of certain tumors (Knudson and Knudson, 1993; Sherman et al,
1994). Another hyaluronan receptor is the receptor for hyaluronan-mediated
motility (RHAMM) which affects cell locomotion and proliferation (Hall et al,
1994, 1995; Savani et al, 1995). Furthermore, the liver endothelial cells carry
specific receptors for clearance of hyaluronan from the blood (Smedsrod et al,
1990). The non-immunogenic character of hyaluronan and its ability to bind
specifically to cell surface receptors has led to the use of hyaluronan-based
products in areas such as drug delivery and tissue repair (Balazs and Laurent,
1998).
Hyaluronan
forms a capsule around group A and group C Streptococci. This is a perfect
camouflage which allows these bacteria to be more successful pathogens by
evading host defense (Schmidt et al, 1996; Husmann et al, 1997). Acapsular
mutants of group A Streptococci exhibit considerable losses in virulence
(Wessels et al, 1994).
The
molecular mechanisms that regulate the biosynthetic pathway of hyaluronan are
yet unclear. Hyaluronan biosynthesis in mammalian cells differs from that of
other glycosaminoglycans which are synthesized in the endoplasmic
reticulum/Golgi and then transported to the cell surface. The key enzymes in
hyaluronan biosynthesis are hyaluronan synthases (HAS), a family of enzymes located
in plasma membrane, which have beeen identified both in bacteria and
vertebrates (Sugahara et al, 1979; Prehm, 1984; Philipson and Schwartz, 1984).
During the synthesis process the hyaluronan chains are extruded into the
intercellular space. This unique route of biosynthesis may be facilitated
through interactions between the hydrophobic patches of hyaluronan chains and
plasma membrane phospholipids (Ghosh et al, 1994); continuous extrusion through
the membrane may be necessary because of the large size of hyaluronan chains.
Hyaluronan synthesis requires intracellular sources of UDP-glucuronic acid
(UDP-GlcA) and UDP-N-acetyl-glucosamine (UDP-GlcNAc), which are generated in
the glycolytic pathway (OĞRegan et al, 1994).
A. Growth factor and cytokine regulation of hyaluronan biosynthesis
The tissue hyaluronan
content is increased during inflammation, wound healing, certain malignancies, e.g. mesotheliomas and WilmĞs tumor, and
in other destructive injuries such as reumatoid arthritis. Some pathways on the
molecular mechanisms of regulation of hyaluronan synthesis during cancer cell
metastasis, wound healing and inflammation have recently been deciphered.
Initial studies by us and other laboratories revealed that exogenously added
growth factors, conditioned media, body fluids, as well as tumor promotors,
lead to stimulation of hyaluronan synthesis in cultures of mesenchymal origin, e.g. fibroblasts (Heldin et al, 1989;
Westergren-Thorsson G, 1990; Suzuki et al, 1995), normal human mesothelial
cells (Honda et al, 1991; Heldin et al, 1992; Heldin and Pertoft, 1993), and
hepatic stellate cells (Heldin et al, 1991; Gressner and Haarmann, 1988;
Vrochides et al, 1996). Among these stimulators, platelet-derived growth factor
(PDGF)-BB, transforming growth factor-§ (TGF-§) and the tumor promotor TPA
exhibited the highest activity. PDGF-BB and TGF-§ mediated their stimulatory
activity on hyaluronan synthesis at least in part through protein kinase C
(PKC), since the PKC inhibitor calphostin C inhibited most of the hyaluronan
synthesis induced by the growth factors. Direct activation of PKC by phorbol
esters also stimulated hyaluronan production, and the combination of either
PDGF or TGF-§ and TPA gave an increased effect. The stimulations by PDGF and
TGF-§ were dependent on protein synthesis since cycloheximide inhibited their
effects. In contrast, the effects mediated by TPA were not (Suzuki et al, 1995)
(Figure 3). Thus, these results
indicate that PKC is involved in the transduction of the effects of growth
factors on hyaluronan biosynthesis in foreskin fibroblasts and normal human
mesothelial cells, and that the effects involve direct or indirect activation
of existing HAS molecules, as well as induction of new enzyme molecules or
other factors involved in the transduction of growth factor signaling (Suzuki
et al, 1995). The insulin-growth factor (IGF)-I and epidermal growth factor
(EGF) also enhance the production of hyaluronan in mesothelial cell cultures
derived from pericardium through a receptor tyrosine-kinase-involved
transmembrane signaling process (Honda et al, 1991).
In
inflammed tissues, hyaluronan accumulation is induced following infiltration by
inflammatory cells which secrete growth factors and cytokines, many of which
are capable of stimulating hyaluronan synthesis. In vitro studies on hyaluronan biosynthesis in human fibroblasts
derived from various organs, revealed differential responses to cytokines, e. g. tumor necrosis factor (TNF)-a, interleukin (IL)-1a, interferon (IFN)-g, and leukoregulin (Elias et al, 1988; Butler et al, 1988; Smith et al,
1995; Sampson et al, 1992). For example, treatment of human orbital fibroblasts
(Smith et al, 1995) by leukoregulin, a cytokine released by activated T
lymphocytes, resulted in a 3-fold higher stimulation of hyaluronan synthesis
compared to leukoregulin stimulation of dermal fibroblasts (Mauviel et al,
1991). The leukoregulin-induced accumulation of hyaluronan in orbital
fibroblasts was dependent on ongoing protein synthesis and was not mediated
through the PKC pathway (Smith et al, 1995). However, prostaglandin E2
stimulated hyaluronan synthesis in mesothelial cell cultures obtained from
pericardium through a cAMP signaling pathway (Honda et al, 1993). Further in vitro studies revealed that
combinations of IFN-g and TNF-a augmented the
synthesis of high molecular mass hyaluronan whereas combination of IL-1 and
TNF-a induced
the production of hyaluronan chains of low molecular mass (Sampson et al,
1992). These findings may be important for our understanding of the presence of
abnormally low molecular weight hyaluronan chains (about 50 kDa) in several
inflammatory disorders, such as in reumatoid arthritis where the hyaluronan
found in joints has a low viscosity (Dahl and Husby, 1985). The differencies in
the ability to synthesize hyaluronan may be due both to differences in
intracellular signaling pathways (Figure
3) as well as to variations in the regulation of the expression of the
three HAS isoforms (see below).
Figure 3. Schematic depiction of
mechanisms that regulate hyaluronan synthesis.
Figure 4. Comparison of amino acid
sequencies between vertebrate HAS enzymes (mouse, mHAS1, mHAS2, mHAS3; frog,
DG42) and bacteria enzymes (Streptococcus
pyogenes, spHAS; Streptococcus
equisimilis, seHAS). Conserved residues are boxed.
Although
hyaluronan was isolated about 60 years ago, the genes involved in its
biosynthesis were identified and characterized only recently. Their
identification has been approached by isolating stable acapsular mutants of
Streptoccocci via transposon mutagenesis and subsequent identification of the
DNA flanking the inserted transposon (Dougherty and van de Rijn, 1994;
DeAngelis et al, 1993a,b). These studies led to the identification of group A
Streptococci genetic locus for hyaluronan synthesis termed has (hyaluronic acid synthesis). The has operon is composed of three genes, hasA, hasB, and hasC. The hasA gene codes for a hyaluronan synthase designated spHAS for S. pyogenes HAS (Weigel et al., 1997).
The hasB gene encodes UDP-glucose
dehydrogenase (converts UDP-glucose to UDP-GlcA) and hasC gene exhibits homology to UDP-glucose pyrophosphorylase
(converts glucose 1-phosphate and UTP to UDP-glucose). The mechanisms that
regulate the expression of the has
operon are yet not known. However, the has
operon is adjacent to genes involved in DNA repair (DeAngelis and Weigel,
1995). Operons similar to the has
operon in Streptococcus pyogenes are
also found in other Gram-positive bacteria such as Streptococcus pneumonia; the Cap3B glycosyltransferase enzyme which
produces a cellobiuronic acid is encoded in an operon flanked by UDP-glucose
dehydrogenase and UDP-glucose pyrophosphorylase (Arrecubieta et al, 1996). The
spHAS protein has a molecular weight of 42 kDa (DeAngelis and Weigel, 1994),
possesses 4 transmembrane domains and one inner membrane-associated domain
(Weigel et al, 1997; Tlapak-Simmons et al, 1998) with a large intracellular
loop which contains the catalytic activity of the enzyme. However, its exact
membrane topology has not yet been experimentally derived. The spHAS protein
shows about 10% similarity to the rizobium nodC
gene product (a fungal chitin synthase) (Atkinson and Long, 1992), and 30%
similarity to the Xenopus laevis protein
DG42 which was expressed transiently in frog embryos (Developmentally
expressed during Gastrulation) (Rosa et al, 1988; DeAngelis et al, 1993a).
Recently the hyaluronan synthase from the highly encapsulated strain of group C
Streptococcus equisimilis, seHAS, was
also cloned (Kumari and Weigel, 1997). The two bacterial synthases exhibit
about 70% amino acid sequence similarity and are of similar size (Figure 4). There is, however, a
difference in the rate of hyaluronan synthesis; seHAS polymerizes the growing
hyaluronan chains 2-fold faster. More recently a new hyaluronan synthase from
the bacterial pathogen type A Pasteurella
multocida, PmHAS, was cloned (DeAngelis et al, 1998). PmHAS is twice the
size of other bacterial HAS (972 amino acids versus 417 residues) and shows
higher amino acid similarity to other bacterial glycosyltransferases, such as
galactose transferase, than to the known HAS molecules from streptococci.
Moreover, PmHAS is predicted to have only two transmembrane domains and
possibly both termini are intracellular; this implies that a large part of the
enzyme is located outside of the cell. It is a challenge to elucidate the mechanisms
through which different bacterial HAS polymerize the same product.
The
similarity of spHAS with DG42, whose function at that time was unknown, led to
a series of experiments, e.g
infection of mammalian cells with a DG42 vaccinia virus construct (Meyer and
Kreil, 1996), as well as transfection of recombinant enzyme in yeast cells
(DeAngelis and Achyuthan, 1996; Pummill et al, 1998) showing that the gene
product exhibited hyaluronan synthesizing activity. Thus, DG42 was the first
vertebrate enzyme found which had hyaluronan synthase activity. However, other
studies have shown that DG42 synthesizes chitin even more efficiently (Semino
et al, 1996; Varki, 1996). In 1996, almost simultaneously, several groups
reported the molecular cloning of two mammalian HAS genes designated HAS1 and
HAS2 (Watanabe and Yamaguchi, 1996; Itano and Kimata, 1996; Shyjan et al, 1996;
Spicer et al, 1996). One year later a third HAS gene, HAS3, was identified
(Spicer et al, 1997) which was found to exhibit 57%, 71%, 56% and 28% amino
acid sequence similarities to HAS1, HAS2, DG42, and spHAS, respectively (Figure 4). The similarities between the
same HAS gene from different mammalian species are larger than 95%. An
important question raised is of course how the expression and enzymatic
activity of HAS are regulated.
The
mammalian HAS gene family (Spicer et al, 1997; Spicer and McDonald, 1998) has
most likely arisen by sequencial gene duplication and divergence. Family
members share characteristics such as similarity in flanking genes, location
within the genome and location of exon-intron boundaries (Ruddle et al, 1994;
Brown et al, 1995; Aruga et al, 1996). Mammalian HAS are located in different
chromosomes, HAS1 on human chromosome 19q13.3-q13.4, HAS2 on 8q24.12, and HAS3
on 16q22.1. However, similarities in exon-intron boundaries as well as
similarities in the expression pattern of HAS genes in developing mouse embryos
(Spicer et al, 1997; Spicer and McDonald, 1998) support the notion that
mammalian HAS isoforms belong to an ancient gene family and that the related
genes appeared through sequential gene duplication events.
Surprisingly,
a glycosyltransferase with the ability to synthesize hyaluronan has recently
been described in Chlorella virus PBCV-1 that infects a chlorella-like green
algae (DeAngelis et al, 1997). This is the first report where hyaluronan is
found outside vertebrates and pathogens. It is important to point out here that
the PBCV-1 genome possess genes that encode, in similarity with A Streptococci, UDP-Glc dehydrogenase
and fructose-6-phosphate amidotransferase that is involved in the UDP-GlcNAc
metabolic pathway. Therefore it is likely that the HAS operon in group A Streptococci evolved in context with
other capsule polysacharide operons in procaryotic organisms as well as in some virus genomes.
Further studies are needed in order to understand the evolution of HAS enzymes.
The
expression pattern of mRNAs for the three HAS isoforms in response to growth
factors differs, indicating different functional roles of the synthases
(Sugiyama et al, 1998). Moreover, studies in our laboratory suggest that the
three eukaryotic HAS isoforms are expressed differentially, and possess
different intrinsic properties in their abilities to polymerize hyaluronan and
in their interactions with other proteins (unpublished observations). Recently,
Yamada and his collegues (1998) have reported the structural organization of
the mouse HAS1 gene; a CCAAT box is located in the promoter region of the HAS1
gene upstream of the transcription initiation site, as well as binding sites
for AP-2 (activated in response to cAMP and phorbol ester), MyoD (regulatory
gene for skeletal myogenesis), SPY and Sox-5 genes (expressed during
embryogenesis), and IRF-1, IRF-2, and p53. Further studies by site-directed
mutations in the HAS1 gene and expression in transgenic mice may elucidate the
regulation of HAS1 expression. Yet, nothing is known about the structural
organization of the HAS2 and HAS3 genes.
III. Future prospects
Hyaluronan
has preserved its simple primary structure throughout the evolution in contrast
to the diversification seen in other macromolecules of the extracellular
matrix. In inflammatory conditions, such as lung fibrosis, myocardial
infarctions, as well as in certain invasive tumors, increased levels of
hyaluronan are observed in tissues and exudates. This accumulation of
hyaluronan often leads to organ dysfunction and increased tumor invasion and,
therefore, the excess hyaluronan has to be eliminated. Increased knowledge
about the molecular mechanisms which regulate the activities of hyaluronan
synthases will make it possible to design specific inhibitors for hyaluronan
synthases which may be of clinical value.
Acknowledgement
I
would like to thank prof. Torvard Laurent for constructive criticism of this
review.
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