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Hyaluronan and synovial joint: Function, distribution and healing


Abstract and Figures

Synovial fluid is a viscous solution found in the cavities of synovial joints. The principal role of synovial fluid is to reduce friction between the articular cartilages of synovial joints during movement. The presence of high molar mass hyaluronan (HA) in this fluid gives it the required viscosity for its function as lubricant solution. Inflammation oxidation stress enhances normal degradation of hyaluronan causing several diseases related to joints. This review describes hyaluronan properties and distribution, applications and its function in synovial joints, with short review for using thiol compounds as antioxidants preventing HA degradations under inflammation conditions.
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Hyaluronan and synovial joint:
function, distribution and healing
Tamer Mahmoud TAMER 1,2
1 Polymer Materials Research Department, Advanced Technologies and New Materials Research Institute (ATNMRI), City of Scientific Research and Technological
Applications (SRTA-Cit y), New Borg El-Arab City, Alexandria, Egypt
2 Laboratory of Bio organic Chemistry of Drugs, Institute of Exp erimental Pharmacology & Toxicology, Slovak Academy of Sciences, Bratislava, Slovak Republic
ITX060313R03 Received: 18 July 2013 Revis ed: 25 August 2013 Accepted: 10 September 2013
Synovial fluid is a viscous solution found in the cavities of synovial joints. The principal role of synovial fluid is to reduce friction
between the articular cartilages of synovial joints during movement. The presence of high molar mass hyaluronan (HA) in this fluid
gives it the required viscosity for its function as lubricant solution. Inflammation oxidation stress enhances normal degradation of
hyaluronan causing several diseases related to joints.
This review describes hyaluronan properties and distribution, applications and its function in synovial joints, with short review for
using thiol compounds as antioxidants preventing HA degradations under inflammation conditions.
KEY WORDS: synovial joint fluid; hyaluronan; antioxidant; thiol compound
Correspondence address:
Dr. Tamer Mahmoud Tamer
Polymer Materials Research Department, Advanced Technologies and
New Materials Research Institute (ATNMRI), City of Scientific Research
and Technological Applications (SRTA- City)
New Borg El-Arab City 21934, Alexandria, Egypt.
Cartilage functions also as a shock absorber. This
property is derived from its high water entrapping capac-
ity as well as from the structure and intermolecular inter-
actions among polymeric components that constitute the
The human skeleton consists of both fused and individual
bones supported and supplemented by liga ments, tendons,
and skeletal muscles. Articular ligaments and tendons are
the main parts holding together the joint(s). In respect of
movement, there are freely moveable, partially moveable,
and immovable joints. Synovial joints (Figure 1), the
freely moveable ones, allow for a large range of motion
and encompass wrists, knees, ankles, shoulders, and hips
(Kogan, 2010).
Structure of synovial joints
In a healthy synovial joint, heads of the bones are encased
in a smooth (hyaline) cartilage layer. These tough slippery
layers – e.g. those covering the bone ends in the knee joint
belong to mechanically highly stressed tissues in the
human body. At walking, runn ing, or sprinting the strokes
frequency attain approximately 0.5, 2.5 or up to 10 Hz.
Interdiscip Toxicol. 2013; Vol. 6 (3) : 111 –125 .
doi: 10.2478/ intox-2013- 0019
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Joint cavity with
synovial uid
Ligament forming
joint capsule
Figure 1. Normal, healthy synovial joint (adapted from Kogan,
Tamer Mahmoud Tamer
Hyaluronan and synovial joint
ISSN: 1337-6853 (print version) | 1337-9569 (electronic version)
cartilage tissue (Servaty et al., 2000). Figure 2 sketches
a section of the cartilage – a chondrocy te cell that per-
manently restructures/rebuilds its extracellular matrix.
Three classes of proteins exist in articular cartilage: col-
lagens (mostly type II collagen); proteoglycans (primarily
aggrecan); and other noncollagenous proteins (including
link protein, fibronectin, COMP – cartilage oligomeric
matrix protein) and the smaller proteoglycans (biglycan,
decorin, and fibromodulin). The interaction between
highly negatively charged cartilage proteoglycans and
type II collagen fibrils is responsible for the compressive
and tensile strength of the tissue, which resists applied
load in vivo.
Synov ium/syn ovial mem brane
Each synov ia l joint is surrounded by a fibrou s, highly vas-
cular capsule/envelope called synovium, whose internal
surface layer is lined with a synovial membrane. Inside
this membrane, type B synoviocytes (fibroblast-like cell
lines) are localized/embedded. Their primary function is
to continuously extrude high-molar-mass hyaluronans
(HAs) into synovial fluid.
Synovial fl ui d
The synovial fluid (SF) of natural joints normally func-
tions as a biological lubricant as well as a biochemical
pool through which nutrients and regulatory cytokines
traverse. SF contains molecules that provide low-friction
and low-wear properties to articulating cartilage surfaces.
Molecules postulated to play a key role in lubrication
alone or in combination, are proteoglycan 4 (PRG4)
(Swann et al., 1985) present in SF at a concentration of
0.05–0.35 mg/ml (Schmid et al., 2001), hyaluronan (HA)
(Ogston & Stanier, 1953) at 1–4 mg/ml (Mazzucco et al.,
2004), and surface-active phospholipids (SAPL) (Schwarz
& Hills, 1998) at 0.1 mg/ml (Mazzucco et al., 2004).
Synoviocytes secrete PRG4 (Jay et al., 2000; Schumacher
et al., 1999) and are the major source of SAPL (Dobbie
et al., 1995; Hills & Crawford, 2003; Schwarz & Hills,
1996), as well as HA (Haubeck et al., 1995; Momberger et
al., 2005) in SF. Other cells also secrete PRG4, including
chondrocytes in the superficial layer of articular cartilage
(Sch mid et al., 2001b; Schumacher et al., 1994) and, to a
much lesser extent, cells in the meniscus (Schumacher et
al., 2005).
As a biochemical depot, SF is an ultra filtrate of blood
plasma that is concentrated by virtue of its filtration
through the synovial membrane. The synovium is a thin
lining (~50 µm in humans) comprised of tissue macro-
phage A cells, fibroblast-like B cells (Athanasou & Quinn,
1991; Revell, 1989; Wilkinson et al., 1992), and fenes-
trated capillaries (Knight & Levick, 1984). It is backed
Decorin Type IX collagen
Type II collagen
Link protein
Figure 2. Articular cartilage main components and structure (adapted from Chen et al., 2006).
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by a thicker layer (~100 µm) of loose connective tissue
called the subsynovium (SUB) that includes an extensive
system of lymphatics for clearance of transported mol-
ecules. The cells in the synovium form a discontinuous
layer separated by intercellular gaps of several microns
in width (Knight & Levick, 1984; McDonald & Levick,
1988). The extracellular matrix in these gaps contains
collagen types I, III, and V (Ashhurst et al., 1991; Rittig et
al., 1992), hyaluronan (Worrall et al., 1991), chondroitin
sulphate (Price et al., 1996; Worrall et al., 1994), biglycan
and decorin proteoglycans (Coleman et al., 1998), and
fibronectin (Poli et al., 2004). The synovial matrix pro-
vides the permeable pathway through which exchange of
molecules occurs (Levick, 1994), but also offers sufficient
outflow resistance (Coleman et al., 1998; Scott et al.,
1998) to retain large solutes of SF within the joint cavity.
Together, the appropriate ref lection of secreted lubricants
by the synovial membrane and the appropriate lubricant
secretion by cells are necessary for development of a
mechanically functional SF (Blewis et al., 2007).
In the joint, HA plays an important role in the protec-
tion of articular cartilage and the transport of nutrients
to cartilage. In patients with rheumatoid arthritis (RA),
(Figure 3) it has been reported that HA acts as an anti
inflammatory substance by inhibiting the adherence of
immune complexe s to neutrophils th rough t he Fc receptor
(Brandt, 1970), or by protecting the synovial tissues from
the attachment of inflammatory mediators (Miyazaki et
al., 1983, Mendichi & Soltes, 2002).
Reactive oxygen species (ROS) (O
, H
OH) are
generated in abundance by synovial neutrophils from RA
patients, as compared with synovial neutrophils of osteo-
arthritis (OA) patients and periphera l neutroph ils of both
RA and OA patients (Niwa et al., 1983).
McCord (1973) demonstrated that HA wa s susceptible
to degradation by ROS in vitro, and that this could be
protected by superoxide dismutase (SOD) and/or catalase,
which suggests the possibility that there is pathologic
oxidative damage to synovial fluid components in RA
patients. Dahl et al. (19 85) r epor ted that t here are re duce d
HA concentrations in synovial fluids from RA patients.
It has also been reported that ROS scavengers inhibit the
degradation of HA by ROS (Soltes, 2010; Blake et al., 1981;
Betts & Cleland, 1982; Soltes et al., 2004).
These findings appear to support the hypothesis that
ROS are responsible for the accelerated degradation of HA
in the rheumatoid joint. In the study of Juranek and Soltes
(2012) the oxygen radical scavenging activ ities of synovial
fluids from both RA and OA patients were assessed, and
the antioxidant activities of these synovial fluids were
analyzed by separately examining HA, -glucuronic acid,
and N-acetyl--glucosamine.
In 1934, Karl Meyer and his colleague John Palmer iso-
lated a previously unknown chemical substance from the
vitreous body of cows’ eyes. They found that the substance
Cartilage Loss
Inamed Synovium
Synovial Fluid
Joint Capsule
Swollen Joint Capsule
Bone Loss
Bone Loss/Erosion
Figure 3. Normal, (healthy) and rheumatoid arthritis synovial joint.
contained two sugar molecules, one of which was uronic
acid. For convenience, therefore, they proposed the name
“hyaluronic acid”. The popular name is derived from
“hyalos”, which is the Greek word for glass + uronic acid
(Meyer & Palmer, 1934). At the time, they did not know
that the substance which they had discovered would
prove to be one of the most interesting and useful natural
macromolecules. HA was first used com mercially in 1942
Tamer Mahmoud Tamer
Hyaluronan and synovial joint
ISSN: 1337-6853 (print version) | 1337-9569 (electronic version)
when Endre Bala zs applied for a patent to use it as a substi-
tute for egg white in bakery products (Necas et al., 2008).
The t erm “ hya luronan” w as i ntro duce d in 198 6 to con-
form to the international nomenclature of polysaccharides
and is attributed to Endre Balazs (Balazs et al., 1986) who
coined it to encompass the different forms the molecule
can take, e.g, the acid form, hyaluronic acid, and the salts,
such as sodium hyaluronate, which forms at physiological
pH (Laurent, 1989). HA was subsequently isolated from
many other sources and the physicochemi cal structure
properties and biological role of this polysaccharide were
stud ied in numerous laborato ries (Kreil, 1995). This work
has been summarized in a Ciba Foundation Symposium
(Laurent, 1989) and a recent review (Laurent & Fraser,
1992; Chabrecek et al., 1990; Orvisky et al., 1992).
Hyaluronan (Figure 4) is a unique biopolymer com-
posed of repeating disaccharide units formed by N-acetyl-
-glucosamine and -glucuronic acid. Both sugars are
spatially related to glucose which in the β-configuration
allows all of its bulky groups (the hydroxyls, the carbox-
ylate moiety, and the anomeric carbon on the adjacent
sugar) to be in sterically favorable equatorial posi tions
while all of the small hydrogen atoms occupy the less
sterically favorable axial positions. Thus, the structure of
the disaccharide is energetically very stable. HA is also
unique in its size, reaching up to several million Daltons
and is synthesized at the plasma membrane rather than in
the Golgi, where sulfated glycosaminoglycans are added
to protein cores (Itano & K imata, 2002; Weigel et al., 1997;
Kogan et al., 2007a).
In a physiological solution, the backbone of a HA mol-
ecule is stiffened by a combina tion of the chemical struc-
ture of the disaccha ride, internal hydrogen bonds, and
interactions with the solvent. The axial hydrogen atoms
form a non-polar, relatively hydrophobic face while the
eq uato ria l sid e chai ns f orm a more polar, hy d roph ilic fa ce,
thereby creating a twisting ribbon structure. Solutions of
hyaluronan manifest very unusual rheological properties
and are exceedingly lubricious and very hydrophilic. In
solution, the hyaluronan polymer chain takes on the
form of an expanded, random coil. These chains entangle
with each other at very low concentrations, which may
contribute to the unusual rheological proper ties. At
higher concentrations, solutions have an extremely high
but shear-dependent viscosity. A 1% solution is like jelly,
but when it is put under pressure it moves easily and
can be administered through a small-bore needle. It has
therefore been called a “pseudo-plastic” material. The
extraordi nary rheological properties of hyaluronan solu-
tions make them ideal as lubricants. There is evidence
that hyaluronan separates most tissue surfaces that slide
along each other. The extremely lubricious properties
of hyaluronan have been shown to reduce postoperative
adhesion forma tion following abdominal and orthopedic
surgery. As mentioned, the polymer in solution assumes
a stiffened helical configuration, which can be at tributed
to hydrogen bonding between the hydroxyl groups along
the chain. As a result, a coil structure is formed that traps
approximately 100 0 times its weight in w ater (Chabre cek et
al., 1990; Cowman & Matsuoka, 20 05; Schiller et al., 2011)
Properties of hyaluronan
Hyaluronan networks
T he p hy si co -c hem ic a l p rop er t ies of hy al ur on an we re s t ud-
ied in deta il from 1950 onwards (Comper & Lau rent, 1978).
The molecules behave in solution as highly hydrated
randomly kinked coils, which start to entangle at concen-
trations of less than 1 mg/mL. The entanglement point
can be seen both by sedimentation analysis (Laurent et
al., 1960) and viscosity (Morris et al., 1980). More recently
Scott and his group have given evidence that the chains
when entangling also interact with each other and form
stretches of double helices so that the network becomes
mechanically more firm (Scott et al., 1991).
Rheological properties
Solutions of hyaluronan are viscoelastic and the viscosity
is markedly shearing dependent (Morris et al., 1980; Gibbs
et al., 1968). Above the entanglement point the viscosity
increases rapidly and exponentially with concentration
) (Morris et al., 1980) and a solution of 10 g/l may
have a viscosity at low shear of ~10
times the viscosity of
the solvent. At high shear the viscosity may drop as much
as ~10
times (Gibbs et al., 1968). The elasticity of the
system increases with increasing molecular weight and
concentration of hyaluronan as expected for a molecular
network. The rheological properties of hyaluronan have
been connected with lubrication of joints and tissues
and hyaluronan is commonly found in the body between
surfaces that move along each other, for example cartilage
surfaces and muscle bundles (Bothner & Wik, 1987).
Water homeostasis
A fixed polysaccharide network offers a high resistance
to bulk f low of solvent (Comper & Laurent, 1978). This
was demonstrated by Day (1950) who showed that hyal-
uronidase treatment removes a strong hindrance to water
flow through a fascia. Thus HA and other polysaccharides
prevent excessive fluid fluxes through tissue compart-
ments. Furt hermore, the osmotic pressure of a hyaluronan
solution is non-ideal and increases exponentially with the
concentration. In spite of the high molecular weight of
the polymer the osmotic pressure of a 10 g/l hyaluronan
solution is of the same order as an l0 g/l albumin solu-
tion. The exponential relationship makes hyaluronan
and other polysaccharides excellent osmotic buffering
substances – moderate changes in concentration lead
Figure 4. Structural formula of hyaluronan – the acid form.
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to marked changes in osmotic pressure. Flow resistance
together with osmotic buffering makes hyaluronan an
ideal regulator of the water homeostasis in the body.
Network interac tions with other macromolecules
The hyaluronan network retards the diffusion of other
molecules (Comper & Laurent, 1978; Simkovic et al.,
2000). It can be shown that it is the steric hindrance which
restricts the movements and not the viscosity of the solu-
tion. The larger the molecule the more it will be hindered.
In vivo hyaluronan will therefore act as a diffusion barrier
and regulate the transport of other substances through
the intercellular spaces. Furthermore, the network will
exclude a certain volume of solvent for other molecules;
the larger the molecule the less space will be available
to it (Comper & Laurent, 1978). A solution of 10 g/l of
hyaluronan will exclude about half of t he solvent to serum
albumin. Hyaluronan and other polysaccharides therefore
take part in the partition of plasma proteins between the
vascular and extravascular spaces. The excluded volume
phenome non w il l al so a ffe ct t he so lubi lit y of ot her m acro -
molecules in the interstitium, change chemical equilibria
and stabilize the structure of, for example, collagen fibers.
Medical applications of hyaluronic ac id
The viscoelastic matrix of HA can act as a strong bio-
compatible support material and is therefore commonly
used as growth scaffold in surgery, wound healing and
embryology. In addition, administration of purified high
molecular weight HA into orthopaedic joints can restore
the desirable rheological properties and alleviate some of
the symptoms of osteoar thritis (Bala zs & Denlinger, 1993;
Balazs & Denlinger, 1989; Kogan et al., 2007). The success
of the medical applications of HA has led to the produc-
tion of several successful commercial products, which
have been extensively reviewed previously.
Table 1 summarizes both the medical applications and
the commonly used commercial preparations containing
HA used within this field. HA has also been extensively
studied in ophthalmic, nasal and parenteral drug delivery.
In addition, more novel applications including pulmonary,
implantation and gene delivery have also been suggested.
Generally, HA is thought to act as either a mucoadhesive
and retain the drug at its site of action/absorption or to
modif y the in vivo relea se/abs orpti on ra te of the th erap eu-
tic agent. A summary of the drug delivery applications of
HA is shown in Table 2.
Table 1. Summary of the medical applications of hyaluronic acid (Brown & Jones, 2005).
Disease state Applications Commercial products Publications
Osteoarthritis Lubrication and mechanical
support for the joints
Hyalgan® (Fidia, Italy)
Artz® (Seikagaku, Japan)
Healon®, Opegan® and Opelead®
Hochburg, 200 0; Altman, 2000; Dougados, 2000; Guidolin et al.,
2001; Maheu et al., 2002; Barrett & Siviero, 2002; Miltner et al.,
2002;Tascioglu and Oner, 2003; Uthman et al., 2003; Kelly et al.,
2003; Hamburger et al., 2003; Kir wan, 2001; Ghosh & Guidolin,
2002; Mabuchi et al., 1999; Balazs, 2003;
Frase r et al., 1993; Zhu & Granick, 2003.
Surgery and
wound healing
Implantation of artificial
intraocular lens,
viscoelastic gel
Bionect®, Connettivina®
and Jossalind®
Ghosh & Jassal, 2002; Risbert, 1997; Inoue & Katakami, 1993;
Miyazaki et al., 1996; Stiebel-Kalish et al., 1998; Tani et al., 2002;
Vazqu ez et al., 2003; Soldati et al., 1999; Ortonne, 1996; Cantor et
al., 1998; Turino & Cantor, 2003.
Embryo implantation Culture media for the use of
in vitro fertilization EmbryoGlue® (Vitrolife, USA)
Simon et al., 2003; Gardner et al., 1999; Vanos et al., 1991; Kem-
mann, 1998; Suchanek et al., 1994; Joly et al., 1992; Gardner, 2003;
Lane et al., 2003; Figueiredo et al., 2002, Miyano et al., 1994; Kano
et al., 1998; Abeydeera, 2002; Jaakma et al., 1997; Furnus et al.,
199 8;J an g et al., 2003.
Tab le 2 . Summary of the drug deliver y applications of hyaluronic acid.
Route Justification Therapeutic agents Publications
Increased ocular residence of drug,
which can lead to increased
Pilocarpine, tropicamide, timolol, gen-
timycin, tobramycin,
arecaidine polyester, (S) aceclidine
Jarvinen et al., 1995; Sasaki et al., 1996; Gurny et al., 1987; Camber
et al., 1987; Camber & Edman, 1989;
Saettone et al., 1994; Saettone et al., 1991; Bucolo et al., 19 98;
Bucolo & Mangiafico, 1999; Herrero -Vanrell et al., 2000; Moreira
et al., 1991; Bernatchez et al., 199 3;
Gandolfi et al., 1992; Langer et al., 1997.
Nasal Bioadhesion resulting in increased
Xylometazoline, vasopressin,
gentamycin Morimoto et al., 1991; Lim et al., 2002.
Pulmonary Absorption enhancer
and dissolution rate modification Insulin Morimoto et al., 2001; Surendrakumar et al., 2003.
Parenteral Drug carrier and facilitator of liposo-
mal entrapment
Taxol, superoxide dismutase,
human recombinant insulin-like
growth factor, doxorubicin
Drobnik, 1991; Sakurai et al., 1997; Luo and Prestwich, 1999; Luo
et al., 2000; Prisell et al., 1992; Yerushalmi et al., 1994; Yerushalmi
& Margalit, 1998; Peer & Margalit, 2000;
Eliaz & Szoka, 2001; Peer et al., 2003.
Implant Dissolution rate modification Insulin Surini et al., 2003; Takayama et al., 1990.
Gene Dissolution rate modification
and protection Plasmid DNA/monoclonal antibodies Yun et al., 2004; Kim et al., 2003.
Tamer Mahmoud Tamer
Hyaluronan and synovial joint
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Cosmetic uses of hyaluronic acid
HA has been extensively utilized in cosmetic products
because of its viscoelastic properties and excellent bio-
compatibility. Application of HA containing cosmetic
products to the skin is reported to moisturize and restore
elasticity, thereby achieving an antiwrinkle effect, albeit
so far no rigorous scientific proof exists to substantiate
this claim. HA-based cosmetic formulations or sun-
screens may also be capable of protecting the skin against
ultraviolet irradiation due to the free radical scavenging
properties of HA (Manuskiatti & Maibach, 1996).
HA, either in a stabilized form or in combination with
other polymers, is used as a component of commercial
dermal fillers (e.g. Hylaform®, Restylane® and Dermalive®)
in cosmetic surgery. It is reported that injection of such
products into the dermis, can reduce facial lines and
wrinkles in the long term with fewer side-effects and
better tolerability compared with the use of collagen
(Duranti et al., 1998; Bergeret-Galley et al., 2001; Leyden
et al., 2003). The main side-effect may be an allergic reac-
tion, possibly due to impurities present in HA (Schartz,
1997; Glogau, 2000).
Biological function of hyaluronan
Naturally, hyaluronan has essential roles in body func-
tions according to organ type in which it is distributed
(Laurent et al., 1996).
Space fi ller
The specific functions of hyaluronan in joints are still
essentially unknown. The simplest explanation for its
presence would be that a flow of hyaluronan through the
joint is needed to keep the joint cavity open and thereby
allow extended movements of the joint. Hyaluronan is
constantly secreted into the joint and removed by the
synovium. The total amount of hyaluronan in the joint
cavity is determined by these two processes. The half-life
of the polysaccharide at steady-state is in the order of
0.5–1 day in rabbit and sheep (Brown et al., 1991; Fraser
et al., 1993). T he volu me of the cavit y is dete rmi ned by th e
pressure conditions (hydrostatic and osmotic) in the cav-
ity and its surroundings. Hyaluronan could, by its osmotic
contributions and its formation of f low barriers in the
limiting layers, be a regulator of the pressure and f low rate
(McDonald & Leviek, 1995). It is interesting that in fetal
development the formation of joint cavities is parallel with
a local increase in hyaluronan (Edwards et al., 1994).
Hyaluronan has been regarded as an ideal lubricant in
the joints due to its shear-dependent viscosity (Ogston &
Stanier, 1953) but its role in lubrication has been refuted
by others (Radin et al., 1970). However, there are now
reasons to believe that the function of hyaluronan is to
form a film between the cartilage surfaces. The load on
the joints may press out water and low-molecular solutes
from the hyaluronan layer into the cartilage matrix. As a
result, the concentration of hyaluronan increases and a
gel structure of micrometric thickness is formed which
protects the cartilage surfaces from frictional damage
(Hlavacek, 1993). This mechanism to form a protective
layer is much less effective in arthritis when the synovial
hyaluronan has both a lower concentration and a lower
molecular weight than normal. Another change in the
arthritic joint is the protein composition of the synovial
fluid. Fraser et al. (1972) showed more than 40 years ago
that addition of various serum proteins to hyaluronan
substantially increased the viscosity and this has received
a renewed interest in view of recently discovered hyalad-
herins (see above). TSG-6 and inter-α-trypsin inhibitor
and other acute phase reactants such as haptoglobin are
concentrated to arthritic synovial fluid (Hutadilok et al.,
1988). It is not known to what extent these are affecting
the rheology and lubricating properties.
Scavenger functions
Hyaluronan has also been assigned scavenger functions
in the joints. It has been known since the 1940s that
hyaluronan is degraded by various oxidizing systems
and ionizing irradiation and we know today that the
common denominator is a chain cleavage induced by free
radicals, essentially hydroxy radicals (Myint et al., 1987).
Through this reaction hyaluronan acts as a very efficient
scavenger of free radicals. W hether this has any biological
importance in protecting the joint against free radicals is
unknown. The rapid turnover of hyaluronan in the joints
has led to the suggestion that it also acts as a scavenger
for cellular debris (Laurent et al., 1995). Cellular material
could be caught in the hyaluronan network and removed
at the same rate as the polysaccharide (Stankovska et al.,
2007; Rapta, et al., 2009).
Regulation of cellular activities
As discussed above, more recently proposed functions
of hyaluronan are based on its specific interactions with
hyaladherins. One interesting aspect is the fact that hyal-
uronan influences angiogenesis but the effect is different
depending on its concentration and molecular weight
(Satta r et al., 1992). High molecular weight and high
concentrations of the polymer inhibit the formation of
capillaries, while oligosaccharides can induce angiogen-
esis. There are also reports of hyaluronan receptors on
vascular endothelial cells by which hyaluronan could act
on the cells (Edwards et al., 1995). The avascula rity of the
joint cavity could be a result of hyaluronan inhibition of
Another interaction of some interest in the joint
is the binding of hyaluronan to cell surface proteins.
Lymphocytes and other cells may find their way to joints
through this interaction. Injection of high doses of hyal-
uronan intra-articularly could attract cells expressing
these proteins. Cells can also change their expression of
hyaluronan-binding proteins in states of disease, whereby
hyaluronan may inf luence immunological reactions and
cellular traffic in the path of physiological processes
in cells (Edwards et al., 1995). The observation often
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reported that intra-articular injections of hyaluronan
alleviate pain in joint disease (Adams, 1993) may indicate
a direct or indirect interaction with pain receptors.
Hyaluronan and synovial  uid
In normal/healthy joint, the synovial flu id, which consists
of an ultrafiltrate of blood plasma and glycoproteins con-
tains HA macromolecules of molar mass ranging between
6–10 mega Daltons (Praest et al., 19 97). SF serves al so as a
lubricating and shock absorbing boundary layer between
moving parts of synovial joints. SF reduces friction and
wear and tear of the synovial joint playing thus a vital role
in the lubrication and protection of the joint tissues from
damage during motion (Oates et al., 2002).
As SF of healthy humans exhibits no activity of
hyaluronidase, it has been inferred that oxygen-derived
free radicals are involved in a self-perpetuating process
of HA catabolism within the joint (Grootveld et al.,
1991; Stankovska et al., 2006; Rychly et al., 2006). This
radical-mediated process is considered to account for ca.
twelve-hour half-life of native HA macromolecules in SF.
Acceleration of degradation of high-molecular-weight
HA occurring under inflammation and/or oxidative
stres s is accompanied by impairment and loss of its v isco-
elastic properties (Parsons et al., 2002; Soltes et al., 2005;
Stankovska et al., 2005; Lath et al., 2005; Hrabarova et al.,
2007; Valachova & Soltes, 2010; Valachova et al., 2013a).
Low-molecular weight HA was found to exert different
biological activities compared to the native high-molecu-
lar-weight biopolymer. HA chains of 25–50 disaccharide
units are inflammatory, immune-stimulatory, and highly
angiogenic. HA fragments of this size appear to func-
tion as endogenous danger signals, reflecting tissues
under stress (Noble, 2002; West et al., 1985; Soltes et al.,
2007; Stern et al., 2007; Soltes & Kogan, 2009). Figure5
describes the fragmentation mechanism of HA under free
radical stress.
a. Initiation phase: the intact hyaluronan macromol-
ecule entering the reaction with the HO
formed via the Fenton-like reaction:
+ H
+ HO
+ OH
has its origin due to the oxidative action of
the Weissberger system (see Figure 6)
b. Formation of an alkyl radical (C-centered hyal-
uronan macroradical) initiated by the HO
c. Propagation phase: formation of a peroxy-type
C-macroradical of hyaluronan in a process of
oxygenation after entrapping a molecule of O
d. Formation of a hyaluronan-derived hydroper-
oxide via the reaction with another hyaluronan
e. Formation of highly unstable alkoxy-type
C-macroradical of hyaluronan on undergoing
a redox reaction with a transition metal ion in a
reduced state.
f. Termination phase: quick formation of alkoxy-
type C-fragments and the fragments with a termi-
nal C=O group due to the glycosidic bond scission
of hyaluronan. Alkoxy-type C fragments may
continue the propagation phase of the free-radical
hyaluronan degradation reaction. Both fragments
are represented by reduced molar masses (Kogan,
2011; Rychly et al., 2006; Hrabarova et al., 2012;
Surovcikova et al., 2012; Valachova et al., 2013b;
Banasova et al., 2012).
Several thiol compounds have attracted much atten-
tion from pharmacologists because of their reactivity
toward endobiotics such as hydroxyl radical-derived spe-
cies. Thiols play an important role a s biological reductants
(antioxidants) preserving the redox status of cells and
protecting tissues against damage caused by the elevated
reactive oxygen/nitrogen species (ROS/RNS) levels, by
which oxidative stress might be indicated.
Soltes and his coworkers examined the effect of sev-
eral thiol compounds on inhibition of the degradation
kinetics of a high-molecular-weight HA in vitro. High
molecular weight hyaluronan samples were exposed
to free-radical chain degradation reactions induced by
ascorbate in the presence of Cu(II) ions, the so called
Figure 5. Schematic degradation of HA under free radical stress
(Hrabarova et al., 2012).
Tamer Mahmoud Tamer
Hyaluronan and synovial joint
ISSN: 1337-6853 (print version) | 1337-9569 (electronic version)
Weissberger’s oxidative system. The concentrations of
both reactants [ascorbate, Cu(II)] were comparable to
those that may occur during an early stage of the acute
phase of joint inflammation (see Figure 6) (Banasova et
al., 2011; Valachova et al., 2011; Soltes et al., 2006a; Soltes
et al., 2006b; Stankovska et al., 2004; Soltes et al., 2006c;
Soltes et al., 2007; Valachova et al., 2008; 2009; 2010; 2011;
2013; Hrabarova et al., 2009, 2011; Rapta et al., 2009; 2010;
Surovcikova-Machova et al., 2012; Banasova et al., 2011;
Drafi et al., 2010; Fisher & Naughton, 2005).
Figure 7 illustrates the dynamic viscosity of hyaluro-
nan solution in the presence and absence of bucillamine,
-penicillamine and -cysteine as inhibitors for free radi-
cal degradation of HA. The study showed that buci llamine
to be both a preventive and chain-breaking antioxidant.
On the other hand, -penicillamine and -cysteine dose
dependently act as scavenger of
OH radicals within the
first 60 min. Then, however, the inhibition activity is lost
and degradat ion of hyaluronan t akes place (Valachova et al.,
2011; Valachova et al., 2009; 2010; Hrabarova et al., 2009).
-Glutathione (GSH; -γ-glutamyl--cysteinyl-glycine;
a ubiquitous endogenous thiol, maintains the intracel-
lular reduction-oxidation (redox) balance and regulates
signaling pathways during oxidative stress/conditions.
GSH is mainly cytosolic in the concentration range of
ca. 1–10 mM; however, in the plasma as well as in SF, the
range is only 1–3 µM (Haddad & Harb, 2005). This unique
thiol plays a crucial role in antioxidant defense, nutrient
metabolism, and in regulation of pathways essential for
the whole body homeostasis. Depletion of GSH results in
an increased vulnerability of the cells to oxidative stress
(Hultberg & Hultberg, 2006).
It was found that -glutathione exhibited the most
significant protective and chain-breaking antioxidative
effect against hyaluronan degradation. Thiol antioxida-
tive activity, in general, can be influenced by many factors
such as various molecule geometry, type of functional
groups, radical attack accessibility, redox potential, thiol
concentration and pK
, pH, ionic strength of solution, as
well as different ability to interact with transition metals
(Hrabarova et al., 2012).
Figure 8 shows the dynamic viscosity versus time
profiles of HA solution stressed to degradation with
Weissberger’s oxidative system. As evident, addition of
different concentrations of GSH resulted in a marked pro-
tection of the HA macromolecules against degradation.
The greater the GSH concentration used, the longer was
the observed stationary interval in the sample viscosity
values. At the lowest GSH concentration used, i.e. 1.0 µM
(Figure 8), the time-dependent course of the HA degrada-
tion was more rapid than that of the reference experiment
with the zero thiol concentration. Thus, one could classify
GSH traces as functioning as a pro-oxidant.
The effectiveness of antioxidant activity of 1,4-dithio-
erythritol expressed as the radical scavenging capacity was
studied by a rotational viscometry method (Hrabarova et
al., 2010). 1,4-dithioerythritol, widely accepted and used
as an effective antioxidant in the field of enzyme and
protein oxidation, is a new potential antioxidant standard
exhibiting very good solubility in a variety of solvents.
Figure 9 describes the effect of 1,4-dithioerythritol on
Cu (I)
Cu (I)
+ Cu(II) + O2
+ Cu(II) + H2 O2
+ H+
Dynamic viscosity [mPa·s]
Time [min]
Time [min]
Time [min]
100 50
Figure 6. Scheme. Generation of H2O2 by Weissberger’s system
from ascorbate and Cu(II) ions under aerobic conditions (Vala-
chova et al., 2011)
Figure 7. E ect of A) L-penicillamine, B) L-cysteine and C) bucillamine with di erent concentrations (50, 100 µM) on HA degradation induced
by the oxidative system containing 1.0 µM CuCl2 + 100 µM ascorbic acid (Valachova et al., 2011).
Also available online on PubMed Central
Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125
Copyright © 2013 SETOX & Institute of E xperimental Pharmacol ogy and Toxicology, SASc.
degradation of HA solution under free radical stress
(Hrabarova et al., 2010).
N-Acetyl--cysteine (NAC), another significant pre-
cursor of the GSH biosynthesis, has broadly been used as
effective antioxidant in a form of nutritional supplement
(Soloveva et al., 2007; Thibodeau et al., 2001). At low con-
centrations, it is a powerful protec tor of α
against the enzyme inactivation by HOCl. NAC reacts
with HO
radicals and slowly with H
; however, no
reaction of this endobiotic with superoxide anion radical
was detected (Aruoma et al., 1989).
Investigation of the antioxidative effect of N-Acet yl-
-cysteine. Unlike -glutathione, N-acetyl--cysteine was
fo u nd to ha ve pr ef er en ti al t en de nc y t o r ed uc e C u( II ) i on s to
Cu(I), forming N-acetyl--cysteinyl radical that may sub-
sequently reac t with molecular O
to gi ve O
(Sol oveva et
al., 2007; Thibodeau et al., 2001). Contrary to -cysteine,
NAC (25 and 50 µM), when added at the beginning of the
reaction, ex hibited a clear antioxidat ive effect withi n ca. 60
and 80 min, respectively (Figure 10A). Subsequently, NAC
exerted a modest pro-oxidative effect, more profound
at 25-µM than at 100-µM concentration (Figure 10A).
Dynamic viscosity [mPa·s]
Time [min]
Time [min]
0 60 120 180 240 300
Dynamic viscosity [mPa·s]
Time [min]
Figure 8. Comparison of the e ect of L-glutathione on HA deg-
radation induced by the system containing 1.0 µM CuCl2 plus
100 µM L-ascorbic acid. Concentration of L-glutathione in µM:
1–1.0; 2–10; 3, 4, 5–50, 100, and 200. Concentration of reference
experiment: 0–nil thiol concentration (Hrabarova et al., 2009;
Valachova et al., 2010a).
Figure 9. E ect of 1,4-dithioerythritol (1) on HA degradation
induced by Weissberger’s oxidative system (0) (Hrabarova et al.,
Figure 10. Evaluation of antioxidative e ects of N-acetyl-L-cysteine against high-molar-mass hyaluronan degradation in vitro induced by
Weissberger´s oxidative system. Reference sample (black): 1 µM Cu(II) ions plus 100 µM ascorbic acid; nil thiol concentration. N-Acetyl-L-
cysteine addition at the onset of the reaction (A) and after 1 h (B) (25, 50,100 µM). (Hrabarova et al., 2012).
Tamer Mahmoud Tamer
Hyaluronan and synovial joint
ISSN: 1337-6853 (print version) | 1337-9569 (electronic version)
Application of NAC 1 h after the onset of the reaction
(Figure 10B) revealed its partial inhibitory effect against
formation of the peroxy-type radicals, independently
from the concentration applied (Hrabarova et al., 2012).
An endogenous amine, cysteamine (CAM) is a cystine-
depleting compound with antioxidative and anti-inflam-
matory properties; it is used for treatment of cystinosis – a
metabolic disorder caused by deficiency of the lysosomal
cystine carrier. CAM is widely distributed in organisms
and considered to be a key regulator of essential metabolic
pathways (Kessler et al., 2008).
Investigation of the antioxidative effect of cysteamine.
Cysteamine (100 µM), when added before the onset of the
reaction, exhibited an antioxidative effect very similar to
that of GSH (Figure 8A and Figure 11A). Moreover, the
same may be concluded when applied 1 h after the onset
of the reaction (Figure 11B) at the two concentrations (50
and 100 µM), suggesting that CAM may be an excellent
scavenger of peroxy radicals generated during the peroxi-
dative degradation of HA (Hrabarova et al., 2012).
The author would like to thank the Institute of
Experimental Pharmacology & Toxicology for having
invited him and oriented him in the field of medical
research. He would also like to thank Slovak Academic
Information Agency (SAIA) for funding him during his
work in the Institute.
Adams ME. (1993). Viseosupplementation: A treatment for osteoarthritis. J
Rheumatol 20: Suppl. 39: 1–24.
Altman RD. (2000). Intra-articular sodium hyaluronate in osteoarthritis of the
knee. Semin Arthritis Rheum 30: 11–18.
Aruoma OI, Halliwell B, Hoey BM, Butler J. (1989). The antioxidant action of
N-acetyl cysteine: its reaction with hydro gen peroxide, hydroxyl radical, su -
peroxide, and hypochlorous acid. Fre e Radic Bio l Med 6: 593.
Ashhurst DE, Bland YS, Levick JR. (1991). An immunohistochemical study of
the collagens of rabbit s ynovial interstitium. J Rheumatol 18 : 1669–1672.
Athanasou NA, Quinn J. (1991). Immunocytochemical analysis of human sy-
novial lining cells: phenotypic relation to other marrow derived cells. Ann
Rheum Dis 50: 311–315.
Balazs EA, Denlinger JL. (1989). Clinical uses of hyaluronan. Ciba Found Symp
143: 265–280.
Balazs EA, Laurent TC, Jeanloz RW. (1986). Nomencla ture of hyaluronic acid.
Biochemical Journal 235: 903.
Balazs EA. (2003). Analgesic e ect of elastoviscous hyaluronan solutions and
the treatment of arthritic pain. Cells Tissues Org ans 174: 49–62.
Balazs EA, Denlinger JL. (1993). Viscosupplementation: a new concept in the
treatment of osteoarthritis. J Rheumato l 20: 3–9.
Banasova M, Valachova K, Juranek I, Soltes L. (2012). E ect of thiol com-
pounds on oxidative degradation of high molar hyaluronan in vitro. Inter-
discip Toxicol 5(Suppl. 1): 25–26.
Banasova M, Valachova K, Juranek I, Soltes L. (2013b). Aloevera and methyl-
sulfonylmethane as dietary supplements: Their potential bene ts for ar-
thritic patients with diabetic complications. Journal of Information Intelli-
gence and Knowledge 5: 51–68.
Banasova M, Valachova K, Rychly J, Priesolova E, Nagy M, Juranek I, Soltes L.
(2011). Scavenging and chain breaking activity of bucillamine on free-rad-
ical mediated degradation of high molar mass hyaluronan. ChemZi 7: 205–
Baňasová M, Valachová K, Hrabárová E, Priesolová E, Nagy M, Juránek I,
Šoltés L. (2011). Early stage of the acute phase of joint in ammation. In vitro
testing of bucillamine and its oxidized metabolite SA981 in the function of
antioxidants. 16th Interdisciplinary Czech-Slovak Toxicological Conference
in Prague. Interdiscip Toxicol 4(2): 22.
Barrett J P, Siviero P. (2002). Retrospective study of outcomes in Hyalgan(R)-
treated patients with osteoar thritis of the knee. Clin Drug Invest 22: 87–97.
Bergeret-Galley C, Latouche X, Illouz Y G.(2001). The value of a new  ller ma-
terial in corrective and cosmetic surgery: DermaLive and DermaDeep. Aes-
thetic Plast Surg 25: 249–255.
Dynamic viscosity [mPa·s]
Time [min]
Time [min]
Figure 11. Evaluation of antioxidative e ects of cysteamine against high-molar-mass hyaluronan degradation in vitro induced by
Weissberger´s oxidative system. Reference sample (black): 1 mM CuII ions plus 100 µM ascorbic acid; nil thiol concentration. Cysteamine
addition at the onset of the reaction (a) and after 1 h (b) (25, 50,100 µM). (Hrabarova et al., 2012).
Abeydeera LR. (2002). In vitro production of embryos in swine. Theriogenol-
ogy 57: 257–273.
Also available online on PubMed Central
Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125
Copyright © 2013 SETOX & Institute of E xperimental Pharmacol ogy and Toxicology, SASc.
Bernatchez SF, Tabatabay C, Gurny R. (1993). Sodium hyaluronate 0.25-per-
cent used as a vehicle increases the bioavailability of topically adminis-
tered gentamicin. Graefes Arch Clin Exp Ophthalmol 231: 157–161.
Betts WH, Cleland LG. (1982): E ect of metal chelators and antiin ammatory
drugs on the degradation of hyaluronic acid. Arthritis Rheum 25: 1469–1476.
Blake DR, Hall ND, Treby DA. (1981). Protection against superoxide and hy-
drogen peroxide in synovial uid from rheumatoid patients. Clin Sci 61:
Blewis ME, Nugent-Derfus GE, Schmidt TA, Schumacher BL, Sah RL. (2007). A
model of synovial  uid lubricant composition in normal and injured. Euro-
pean cells and materials 13: 26–39.
Bothner H, Wik O. (1987). Rheology of hyaluronate. Acta Otolaryngol Suppl
442: 25–30.
Brandt K. (1970). Modi cation of chemotaxis by synovial uid hyaluronate.
Arthritis Rheum 13: 308 309.
Brown MB, Jones SA. (2005). Hyaluronic acid: a unique topical vehicle for
the localized delivery of drugs to the skin. J Eur Acad Dermatol Venere ol 19:
Brown TJ, Laurent UBG, Fraser JRE. (1991). Turnover of hyaluronan in synovial
joints: elimination of labelled hyaluronan from the knee joints of the rab-
bit. Exp Physiol 76: 125–34.
Bucolo C, Mangia co P. (1999). Pharmacological pro le of a new topical pilo-
carpine formulation. J Ocul Pharmacol Ther 15: 567–573.
Bucolo C, Spadaro A, Mangia co S. (1998). Pharmacological evaluation of a
new timolol/pilocarpine formulation. Ophthalmic Res 30: 101–10 6.
Camber O, Edman P, Gurny R. (1987). In uence of sodium hyaluronate on the
meiotic e ect of pilocarpine in rabbits. Cu rr Eye Res 6: 779–784.
Camber O, Edman P. (1989). Sodium hyaluronate as an ophthalmic vehicle –
some factors governing its e ect on the ocular absorption of pilocarpine.
Curr Eye R es 8: 563–567.
Cantor JO, Cerreta JM, Armand G, Turino GM. (1998). Aerosolized hyaluronic
acid decreases alveolar injury induced by human neutrophil elastase. Proc
Soc Exp Biol Med 217: 471– 475.
Chabrecek P, Soltes L, Kallay Z, Fugedi A. (1990). Isolation and characteriza-
tion of high molecular weight (3H) hyaluronic acid. J Label Compd Radio-
pharm 28: 1121–1125.
Chabrecek P, Soltes L, Kallay Z, Novak I. (1990). Gel permeation chromato-
graphic characterization of sodium hyaluronate and its reactions prepared
by ultrasonic degradation. Chromatographia 30: 201–204.
Chen FH, Rousche KT, Tuan RS. (2006). Technology Insight: adult stem cells
in cartilage regeneration and tissue engineering. Nat Clin Pract Rheumatol
2(7): 373–82.
Coleman P, Kavanagh E, Mason RM, Levick JR, Ashhurst DE. (1998). The pro-
teoglycans and glycosaminoglycan chains of rabbit synovium. Histochem
J 30: 519–524.
Comper WD, Laurent TC. (1978). Physiological function of connective tissue
polysaccharidcs. Physiol Rev 58: 255–315.
Cowman MK, Matsuoka S. (2005). Experimental ap proaches to hyaluronan
structure. Carbohydrate Re search 340: 791–809.
Dahl LB, Dahl IM, Engstrom-Laurent A, Granath K. (1985). Concentration and
mo le cu la r we ig ht o f s od iu m hy al ur ona te in s yn ov ia l  ui d from patients with
rheumatoid arthritis and other arthropathies. Ann Rheum Dis 44: 817–822.
Dobbie JW, Hind C, Meijers P, Bodart C, Tasiaux N, Perret J, Anderson JD.
(1995). Lamellar body secretion: ultrastructural analysis of an unexplored
function of synoviocytes. Br J Rheumatol 34: 13–23.
Dougados M. (2000). Sodium hyaluronate therapy in osteoarthritis: argu-
ments for a potential bene cial structural e ect. Semin Arthritis Rheum 30:
Drá F, Valachová K, Hrabárová E, Juránek I, Bauerová K, Šoltés L. (2010).
Study of methotrexate and β-alanyl-L-histidine in comparison with L-glu-
tathione on high-molar-mass hyaluronan degradation induced by ascor-
bate plus Cu (II) ions via rotational viscometry. 60th Pharmacological Days
inHradec Králové. Acta Medica 53(3): 170.
Drobnik J. (1991). Hyaluronan in drug delivery. Adv Drug Dev Rev 7: 295–308.
Duranti F, Salti G, Bovani B, Calandra M, Rosati ML. (1998). Injectable hyal-
uronic acid gel for soft tissue augmentation – a clinical and histological
study. Dermatol Surg 24: 1317–1325.
Edwards JCW, Wilkinson LS, Jones HM. (1994). The formation of human syno-
vial cavities: a possible role for hyaluronan and CD44 in altered interzone
cohesion. J Anat 185 : 355–67.
Edwards JCW (1995). Consensus statement. Second international meeting
on synovium. Cell biology, physiology and pathology. Ann Rheum Dis 54:
Eliaz RE, Szoka FC. (2001). Liposome-encapsulated doxorubicin targeted to
CD44: a strategy to kill CD44-overexpressing tumor cells. Cancer Res 61:
Figueiredo F, Jones GM, Thouas GA, Trounson AO. (2002). The e ect of extra-
cellular matrix molecules on mouse preimplantation embryo development
in vitro. Reprod Fertil Dev 14: 443– 451.
Fisher AE, Naughton ODP. (2005). Therapeutic chelators for the twenty  rst
century: new treatments for iron and copper mediated in ammatory and
neurological disorders. Curr D rug Delive ry 2: 261–268.
Fraser JRE, Foo WK, Maritz JS. (1972). Viscous interactions of hyaluronic acid
with some proteins and neutral saccharides. Ann Rheum Dis 31: 513–20.
Fraser JRE, Kimpton WG, Pierscionek BK, Cahill RNP. (1993). The kinetics of
hyaluronan in normal and acutely in amed synovial joints – observations
with experimental ar thritis in sheep. Semin Arthritis Rheum 22: 9–17.
Furnus CC, de Matos DG, Mar tinez AG. (1998). E ect of hyaluronic acid on devel-
opment of in vitro produced bovine embryos. Theriogenology 49: 1489–99.
Gandol SA, Massari A, Orsoni JG. (1992). Low-molecular-weight sodium hy-
aluronate in the treatment of bacterial corneal ulcers. Graefes Arch Clin Exp
Ophthalmol 230: 20–23.
Gardner DK, Lane M, Stevens J, Schoolcraft WB. (2003). Changing the start
temperature and cooling rate in a slow-freezing protocol increases human
blastocyst viability. Fertil Steril 79: 407–410.
Gardner DK, Rodriegez-Martinez H, Lane M. (1999). Fetal development after
transfer is increase d by replacing protein with the glycosaminoglyc an hyal-
uronan for mouse emb ryo culture and transfer. Hum Reprod 14: 2575–2580.
Ghosh P, Guidolin D. (2002). Potential mechanism of action of intraarticular
hyaluronan therapy in osteoarthritis: are the e ects molecular weight de-
pendent? Semin Arthritis Rheum 32: 10–37.
Ghosh S, Jassal M. (2002). Use of polysaccharide  bres for modem wound
dressings. Indian J Fibre Textile Res 27: 434–450.
Gibbs DA, Merrill EW, Smith KA, Balazs EA. (1968). Rheology of hyaluronic
acid. Biopolymers 6: 777–91.
Glogau RG. (2000). The risk of progression to invasive disease. J Am Acad Der-
matol 42: S23–S24.
Grootveld M, Henderson EB, Farrell A, Blake DR , Parkes HG, Haycock P. (1991).
Oxidative damage to hyaluronate and glucose in synovial  uid during ex-
ercise of the in amed rheumatoid joint. Detection of abnormal low-mo-
lecular-mass metabolites by proton-N.M.R. spectroscopy. Biochem J 273:
Guidolin DD, Ronchetti IP, Lini E. (2001). Morphological analysis of articular
cartilage biopsies from a randomized. clinical study comparing the e ects
of 500–730 kDa sodium hyaluronate Hyalgan(R) and methylprednisolone
acetate on primary osteoarthritis of the knee. Osteoarthritis Car tilage 9:
Gurny R, Ibrahim H, Aebi A. (1987). Design and evaluation of controlled re-
lease systems for the eye. J Control Release 6: 367–373.
Haddad JJ, Harb HL . (2005). L-gamma-Glutamyl-L-cysteinyl-glycine (glutathi-
one; GSH) and GSH-related enzymes in the regulation of pro- and anti-in-
ammatory cytokines: a signaling transcriptional scenario for redox(y) im-
munologic sensor(s). Mol Immunol 42: 987–1014.
Hamburger MI, Lakhanpal S, Mooar PA, Oster D. (2003). Intra-articular hyal-
uronans: a review of product-speci c safety pro les. Semin Arthritis Rheum
32: 296–309.
Haubeck HD, Kock R, Fischer DC, van de Leur E, Ho meister K, Greiling H.
(1995). Transforming growth factor ß1, a major stimulator of hyaluronan
synthesis in human synovial lining cells. Arthritis Rheum 38: 669–677.
Herrero-Vanrell R, Fernandez-Carballido A, Frutos G, Cadorniga R. (2000). En-
hancement of the mydriatic response to tropicamide by bioadhesive poly-
mers. J Ocul Pharmacol Ther 16: 419–428.
Hills BA, Crawford RW. (2003) Normal and prosthetic synovial joints are lu-
bricated by surface-active phospholipid: a hypothesis. J Arthroplasty 18 :
Hlavacek M. (1993). The role of synovial uid  ltration by cartilage in lubrica-
tion of sy novial joints. J Bi omech 26(10): 1145– 50.
Hochberg MC. (2000). Role of intra-articular hyaluronic acid preparations in
medical management of osteoarthritis of the knee. Semin Arthritis Rheum
30: 2–10.
Tamer Mahmoud Tamer
Hyaluronan and synovial joint
ISSN: 1337-6853 (print version) | 1337-9569 (electronic version)
Hrabarova E, Valachova K, Rapta P, Soltes L. (2010). An alternative standard
for trolox-equivalent antioxidant-capacity estimation based on thiol an-
tioxidants. Comparative 2,2’-azinobis[3-ethylbenzothiazoline-6-sulfonic
acid] decolorization and rotational viscometry study regarding hyaluronan
degradation. Chemistry & Biodiversit y 7(9): 2191–220 0.
Hrab arova E, Val achova K , Rychly J, Rapta P, Sasink ova V, Malikov a M, Solte s L.
(2009). High-molar-mass hyaluronan degradation by Weissberger’s system:
Pro- and anti-oxidative e ects o f some th iol comp ounds. Polymer Degrada-
tion and Stability 94: 1867–1875.
Hrabarova E, Valachova K , Juranek I, Soltes L. (2012). Free-radical degrada-
tion of high-m olar-mass hyaluronan ind uced by ascorbat e plus cupric ions:
evaluation of antioxidative e ect of cysteine-derived compounds. Chemis-
try & Biodiversit y 9: 309–317.
Hrabarova E, Gemeiner P, Soltes L. (2007). Peroxynitrite: In vivo and in vitro
synthesis and oxidant degradative action on biological systems regarding
biomolecular injury and in ammatory processes. Chem Pap 61: 417–437.
Hrabárová E, Valachová K , Juránek I, Šoltés L. (2011). Free-radical degradation
of high-molar-mass hyaluronan induced by ascorbate plus cupric ions. Anti-
oxidative properties of the Piešťany-spa curative waters from healing peloid
and maturation pool. In: “ Kinetics, Catalysis and Mechanism o f Chemical Re-
actions” G. E. Zaikov (eds), Nova Science Publishers, New York, pp. 29–36.
Hrabárová E, Valachová K, Rychlý J, Rapta P, Sasinková V, Gemeiner P, Šoltés
L. (2009). High-molar-mass hyaluronan degradation by the Weissberger´s
system: pro- and antioxidative e ects of some t hiol compounds. Po lym De-
grad Stab 94: 1867–1875.
Hultberg M, Hultberg B. (2006). The e ect of di erent antioxidants on glu-
tathione turnover in human cell lines and their interaction with hydrogen
peroxide. Chem Biol Interact 163(3) : 192–19 8.
Hutadilok N. Ghosh P, Brooks PM. (1988). Binding of haptoglobin. inter-α-
trypsin inhibitor, and l proteinase inhibitor to synovial  uid hyaluronate
and the in uence of these proteins on its degradation byoxygen derived
free radicals. Ann Rheum Dis 47: 377–85.
Inoue M, Katakami C. (1993). The e ect of hyaluronic-acid on corneal epithe-
lial-cell proliferation. Invest Ophthalmol Vis Sci 34: 2313–2315.
Itano N, Kimata K . (2002). Mammalian hyaluronan synthases. IUBMB Life 54:
Jaakma U, Zhang B R, Larsson B. (1997). E ects of sperm treatments on the in
vitro development of bovine oocytes in semide ned and de ned media.
Theriogenology 48: 711–720.
Jang G, Lee BC, Kang SK, Hwang WS. (2003). E ect of glycosaminoglycans on
the preimplantation development of embryos derived from in vitro fertil-
ization and somatic cell nuclear transfer. Reprod Fertil Dev 15: 179–185.
Jarvinen K , Jarvinen T, Ur tti A. (1995). Ocular a bsorption fo llowing topic al de-
livery. Adv Drug Dev Rev 16 : 3–19.
Jay GD, Britt DE, Cha DJ. (2000). Lubricin is a product of megakaryocyte stim-
ulating factor gene expression by human synovial  broblasts. J Rheumatol
27: 594–600.
Joly T, Nibart M, Thibier M. (1992). Hyaluronic-acid as a substitute for proteins
in the deep-freezing of embryos from mice and sheep – an in vitro investi-
gation. Theriogenology 37: 473–480.
Juranek I, Soltes L. 2012). Reactive oxygen species in joint physiology: Possible
mechanism of maintaining hypoxia to protect chondrocytes from oxygen ex-
cess via synovial  uid hyaluronan peroxidation. In: “Kinetics, Catalysis and
Mechanism of Chemical Reactions: From Pure to Applied Science. Volume
2 – Tomorrow and Perspectives” R.M. Islamova, S.V. Kolesov, G.E. Zaikov
(eds), Nova Science Publishers, New York pp. 1–10
Kano K, Miyano T, Kato S. (1998). E ects of glycosaminoglycans on the devel-
opment of in vitro matured and fertilized porcine oocy tes to the blastocyst
stage in vitro. Biol Reprod 58: 1226–1232.
Kelly MA, Goldberg VM, Healy WL. (2003). Osteoarthritis and beyond: a con-
sensus on the past, present, and future of hyaluronans in orthopedics. Or-
thopedics 26: 1064–1079.
Kemmann E. (1998). Creutzfeldt-Jakob disease (CJD) and assisted reproduc-
tive technology (ART) – quanti cation of risks as part of informed consent.
Hum Reprod 13: 1777.
Kessler A, Biasibetti M, da Silva Melo DA, Wajner M, Dutra-Filho CS, de Souza
Wyse AT, Wannmacher CMD. (2008). Antioxidant e ect of cysteamine in
brain cortex of young rats. Neurochem Res 33: 737–44.
Kim A, Checkla DM, Dehazya P, Chen WL. (2003). Characterization of DNA-
hyaluronan matrix for sustained gene transfer. J Control Release 90: 81–95.
Kirwan J. (2001). Is there a place for intra-articular hyaluronate in osteoarthri-
tis of the knee? Knee 8: 93–101.
Knight AD, Levick JR. (1984). Morphometr y of the ultrastructure of the blood -
joint barrier in the rabbit knee. Q J E xp Physiol 69: 271–288.
Kogan G. (2010). Hyaluronan – A High Molar mass messenger reporting on the
status of synovial joints: part 1. Physiological status In: New Steps in Chemical
and Biochemical Physics. ISBN: 97 8-1-61668-923 -0. pp. 121–133.
Kogan G, Soltes L, Stern R, Mendichi R. (2007a). Hyaluronic acid: A biopoly-
mer with versatile physico-chemical and biological properties. Chapter 31
in: Handbook of Polymer Research: Monomers, Oligomers, Polymers and
Composites. Pethrick R. A, Ballada A, Zaikov G. E. (eds.), Nova Science Pub-
lishers, New York, pp. 393–439.
Kogan G, Soltes L, Stern R, Gemeiner P. (2007). Hyaluronic acid: A natural bio -
polymer with a broad range of biomedical and industrial applications. Bio-
technol Lett 29: 17–25.
Kreil G. (1995). Hyaluronidases-A group of neglected enzymes. Protein Sci-
ences 4: 1666–1669.
Lane M, Maybach JM, Hooper K. (2003). Cryo-survival and development of
bovine blastocysts are enhanced by culture with recombinant albumin
and hyaluronan. Mol Reprod Dev 64: 70–78.
Langer K, Mut schler E, Lambrecht G. (1997). Methylmethacrylate sulfopropy l-
methacrylate copolymer nanoparticles for drug delivery – Part III. Evalua-
tion as drug delivery system for ophthalmic applications. Int J Pharm 158 :
Lath D, Csomorova K, Kollarikova G, Stankovska M, Soltes L. (2005). Molar
mass-intrinsic viscosity relationship of high-molar-mass yaluronans: In-
volvement of shear rate. Chem Pap 59: 291–293.
Laurent TC, Laurent UBG, Fraser JRE. (1996). The structure and function of hy-
aluronan: An over view. Immunology and Cell Biology 74: A1–A7.
Laurent TC. (1989). The biology of hyaluronan. In: Ciba Foundation Sympo-
sium. John Wiley and Sons, New York. 143 : 1–298.
Laurent TC, Fraser JRE . (1992). Hyaluronan. FASE B J 6: 2397–2404.
Laurent TC. Laurent UBG, Fraser JRE. (1995). Functions of hyaluronan. Ann
Rheum Dis 54: 429–32.
Laurent TC, Ryan M, Pictruszkiewicz A. (1960). Fractionation of hyaluronic
acid. The polydispersity of hyaluronic acid from the vitreous body. Biochim
Biophys Acta 42: 476–85.
Levick JR. (1994). An analysis of the interaction between interstitial plasma
protein, interstitial  ow, and fenestral  ltration and its application to
synovium. Microvasc Res 47: 90–125.
Leyden J, Narins RS, Brandt F. (2003). A randomized, double-blind, multi-
center comparison of the e cacy and tolerability of Restylane versus Zy-
plast for the correction of nasolabial folds. Dermatol Surg 29: 588–595.
Lim ST, Forbes B, Berry DJ, Martin GP, Brown MB. (2002). In vivo evaluation of
novel hyaluronan/chitosan microparticulate delivery systems for the nasal
delivery of gentamicin in rabbits. Int J Pharm 231: 73–82.
Luo Y, Prestwich GD. (1999). Synthesis and selective cytotoxicity of a hyal-
uronic acid-antitumor bioconjugate. Bioconjug Chem 10: 755–763.
Luo Y, Ziebell MR, Prestwich GD. (2000). A hyaluronic acid-taxol antitumor
bioconjug ate targeted to cancer cells. Biomacromolecules 1: 208–218.
Maheu E, Ayral X, Dougados M. (2002). A hyaluronan preparation (500–
730 kDa) in the treatment of osteoarthritis: a review of clinical trials with
Hyalgan(R). Int J Clin Pract 56: 804–813.
Manuskiatti W, Maibach HI. (1996). Hyaluronic acid and skin: wound healing
and aging. Int J Dermatol 35: 539–544.
Mazzucco D, Scott R, Spector M. (2004). Composition of joint  uid in patients
undergoing total knee replacement and revision arthroplasty: correlation
with  ow properties. Biomaterials 25: 4433–4445.
McCord JM. (1974). Free radicals and in ammation: protection of synovial
uid by superoxide dismutase. Science 185: 529–531.
McDonald JN, Levick JR. (1988). Morphology of surface synoviocytes in situ
at normal and raised joint pressure, studied by scanning electron micros-
copy. Ann Rheum Dis 47: 232–240.
McDonald JN, Leviek JR. (1995). E ect of intra-articular hyaluronan on pres-
sure- ow relation across synovium in anaesthetized rabbits. J Physiol
485(Pt.1): 179 93 .
Mendichi R, Soltes L. (2002). Hyaluronan molecular weight and polydisper-
sity in some commercial intra-articular injectable preparations and in sy-
novial  uid In amm Res 51: 115 –116 .
Meyer K, Palmer JW. (1934). The polysaccharide of the vitreous humor. Jour-
nal of Biology and Chemistr y 107: 629–634.
Also available online on PubMed Central
Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125
Copyright © 2013 SETOX & Institute of E xperimental Pharmacol ogy and Toxicology, SASc.
Miltner O, Schneider U, Siebert CH. (2002). E cacy of intraarticular hyal-
uronic acid in patients with osteoarthritis–a prospective clinical trial. Os-
teoarthri tis Cartilage 10: 680–686.
Miyano T, Hirooka RE, Kano K. (1994). E ects of hyaluronic-acid on the de-
velopment of 1-cell and 2-cell porcine embryos to the blastocyst stage in-
vitro. Theriogenology 41: 1299–1305.
Miyazaki M, Sato S, Yamaguchi T. (1983). Analgesic and antiin ammatory ac-
tion of hyaluronic sodium, Japan Pharmacological Conference. Tokyo, April
4, 1983.
Miyazaki T, Miyauchi S, Nakamura T. (1996). The e ect of sodium hyaluronate
on the growth of rabbit cornea epithelial cells in vitro. J Ocul Pharmacol
Ther 12: 409 –415.
Momberger TS, Levick JR, Mason RM. (2005). Hyaluronan secretion by syn-
oviocytes is mechanosensitive. Matrix Biol 24: 510 –519.
Moreira CA, Armstrong DK, Jelli e RW. (1991). Sodium hyaluronate as a car-
rier for intravitreal gentamicin – an experimental study. Acta Ophthalmol
(Copenh) 69: 45–49.
Moreira CA, Moreira AT, Armstrong DK. (1991). In vitro and in vivo studies with
sodium hyaluronate as a carrier for intraocular gentamicin. Acta Ophthal-
mol (Copenh) 69: 50–56.
Morimoto K, Metsugi K, Katsumata H. (2001). E ects of lowviscosity sodium
hyaluronate preparation on the pulmonary absorption of rh-insulin in rats.
Drug Dev Ind Pharm 27: 365–371.
Morimoto K, Yamaguchi H, Iwakura Y. (1991). E ects of viscous hyaluronate-
sodium solutions on the nasal absorption of vasopressin and an analog.
Pharmacol Res 8: 471– 474.
Morris ER, Rees DA, Welsh EJ. (1980). Conformation and dynamic interactions
in hyaluronate solutions. J Mol Biol 138: 383–400.
Myint P. (1987). The reactivity of various free radicals with hyaluronic acid
steady-state an d pulse radioly sis studies. Biochim Biophys-Aeta 925: 194–202 .
Necas J, Bartosikova L, Brauner P, Kolar J. (2008). Hyaluronic acid (hyaluro-
nan): a review. Veterinarni Medicina 53(8): 397–411.
Niwa Y, Sakane T, Shingu M, Yokoyama MM. (1983). E ect of stimulated neu-
trophils from the synovial  uid of patients with rheumatoid arthritis on
lymphocytes: a possible role of increased oxygen radicals generated by
the neutrophils. J Clin Immunol 3: 228–240.
Noble PW. (2002). Hyaluronan and its catabolic products in tissue injury and
repair. Matrix Biol 21: 25–29.
Oates KMN, Krause WE, Colby RH. (2002). Using rheology to probe the mech-
anism of joint lubrication: polyelectrolyte/protein interactions in synovial
uid. Mat Res Soc Syrnp Proc 711: 53–58.
Ogston AG, Stanier J E. (1953). The physiological func tion of hyaluronic acid in
synovial  uid viscous, elastic and lubricant properties. J Physiol 19 9: 244–
Ortonne JP. (1996). A controlled study of the activit y of hyaluronic acid in the
treatment of venous leg ulcers. J D ermatol Treatment 7: 75–81.
Orvisky E, Soltes L, Chabrecek P, Novak I, Kery V, Stancikova M, Vins I. (1992).
The determination of hyaluronan molecular weight distribution by means
of high perfeormance size exclusion chromatography. J Liq Chromatogr 15:
Parsons BJ, Al-Assaf S, Navaratnam S, Phillips GO. (2002). Comparison of the
reactivity of di erent oxidative species (ROS) towards hyaluronan, in: Kennedy
JF, Phillips GO, Williams PA, Hascall VC (Eds.), Hyaluronan: Chemical, Bio-
chemical and Biological Aspects, Woodhead, Publishing Ltd, Cambridge,
MA, pp. 141–150.
Peer D, Florentin A, Margalit R. (2003). Hyaluronan is a key component in
cryoprotection and formulation of targeted unilamellar liposomes. Bio-
chim Biophys Acta-Biomembranes 1612: 76–82.
Peer D, Margalit R. (2000). Physicochemical evaluation of a stability-driven
approach to drug entrapment in regular and in surface-modi ed lipo-
somes. Arch Biochem Biophys 383: 185–190.
Poli A, Mason RM, Levick JR. (2004). E ects of A rg- Gly-Asp s equence peptide
and hyperosmolarit y on the permeability of interstitial matrix and fenes-
trated endothelium in joints. Microcirculation 11: 463–476.
Praest BM, Greiling H, Kock R. (1997). E ects of oxygen-derived free radicals
on the molecular weight and the polydispersity of hyaluronan solutions.
Carbohydr Res 303 :153 –157 .
Price FM, Levick JR, Mason RM. (1996). Glycosaminoglycan concentration in
synovium and other tissues of rabbit knee in relation to synovial hydraulic
resistance. J Physiol (Lond) 495: 803–820.
Prisell PT, Camber O, Hiselius J, Norstedt G. (1992). Evaluation of hyaluronan
as a vehicle for peptide growth factors. Int J Pharm 85: 51–56.
Radin EL, Swann DA, Weisser PA. (1970). Separation of a hyaluronate-frec lu-
bricating fraction from synovial  uid. Nature 228: 377–8.
Rapta P, Valachova K, Gemeiner P, Soltes L. (2009). High-molar-mass hyaluro-
nan behavior during testing its radical scavenging capacit y in organic and
aqueous media: E ects of the presence of Manganese (II) ions. Chem Bio-
divers 6: 162–169 .
Rapta P, Valachová K, Gemeiner P, Šoltés L. (2009). High-molar-mass hyaluro-
nan behavior during tes ting its antioxidant properties i n organic and aque-
ous media: e ects o f the prese nce of Mn(II) ions. Chem Biodivers 6: 162–169.
Rapta P, Valachová K, Zalibera M, Šnirc V, Šoltés L. (2010). Hyaluronan degrada-
tio n by rea cti ve o xy gen spe cie s: s cav eng ing egg ect of t he h exa py rid oin dol e st o-
badine and two of its derivatives. In Monomers, Oligomers, Polymers, Com-
posites, and Nanocomposites, Ed: R. A. Pethrick P. Petkov, A. Zlatarov G. E.
Zaikov, S. K. Rakovsky, Nova Science Publishers, N.Y, Chapter 7, pp. 113–126.
Rees MD, Kennett EC, Whitelock JM, Davies MJ. (2008). Oxidative damage
to extracellular matrix and its role in human pathologies. Free Radical Biol.
Med 44: 1973–2001.
Revell PA. (1989). Synovial lining cells. Rheumatol Int 9: 49–51.
Risberg B. (1997). Adhesions: preventive strategies. Eur J Su rg 163: 32–39.
Rittig M, Tittor F, Lutjen-Drecoll E, Mollenhauer J, Rauterberg J. (1992). Immu-
nohistochemical study of extracellular material in the aged human syno-
vial membrane. Mech Ageing Dev 64: 219–234.
Rych ly J, Solt es L, Stan kovska M , Janigov a I, Csom orova K , Sasinkov a V, Kogan
G, Gemeiner P. (2006). Unexplored capabilities of chemiluminescence and
thermoanalytical methods in characterization of intact and degraded hyal-
uronans. Polym Degrad Stab 91(12): 3174 –3184.
Saettone MF, Giannaccini B, Chetoni P, et al. (1991). Evaluation of highmolec-
ular-weight and low-molecular-weight fractions of sodium hyaluronate
and an ionic complex as adjuvants for topical ophthalmic vehicles contain-
ing pilocarpine. Int J Pharm 72: 131–139.
Saettone MF, Monti D, Torracca MT, Chetoni P. (1994). Mucoadhesive oph-
thalmic vehicles – evaluation polymeric low-viscosity formulations. J Ocul
Pharmacol 10 : 83–92.
Sakurai K, Miyazaki K, Kodera Y. (1997). Anti-in ammat ory ac tivit y of su perox-
ide dismutase conjugated w ith sodium hyaluronate. Glycoconj J 14: 72 3–728.
Sasaki H, Yamamura K, Nishida K . (1996). Delivery of drugs to the eye by topi-
cal application. Prog Retinal Eye Res 15: 583–620.
Sattar A, Kumar S, West DC. (1992). Does hyaluronan have a role in endothe-
lial cell proliferation ofthe synovium. Semin. Arthritis Rheum 22: 37–43.
Schartz R A. (1997). The actinic ker atoses. A perspective and up date. Dermatol
Surg 23: 1009–1019.
Schiller J, Volpi N, Hrabarova E, Soltes L. (2011). Hyaluronic acid: a natural bio-
polymer In: Handbook of Biopolymers and Their ApplicationsS. Kalia and
L. Averous (eds), Wiley & Scrivener Publishing, USA pp. 3–34.
Schmid T, Lindley K, Su J, Soloveychik V, Block J, Kuettner K, Schumacher B.
(2001a). Super cial zone protein (SZP) is an abundant glycoprotein in hu-
man synovial 
uid and serum. Trans Orthop Res Soc 26: 82.
Schmid T, Soloveychik V, Kuettner K, Schumacher B. (2001b). Super cial zone
protein (SZP) from human cartilage has lubrication activity. Trans O r thop
Res Soc 26: 178.
Schumacher BL, Block JA, Schmid TM, Aydelotte MB, Kuettner KE. (1994). A
novel proteoglycan synthesized and secreted by chondrocytes of the su-
per cial zone of articular car tilage. Arch Biochem Biophys 311: 144–152.
Schumacher BL, Hughes CE, Kuettner KE, Caterson B, Aydelotte MB. (1999).
Immunodetection and partial c DNA sequence of the proteoglycan, super-
cial zone protein, synthesized by cells lining synovial joints. J Orthop Res
17: 110–120.
Schumacher BL, Schmidt TA, Voegtline MS, Chen AC, Sah RL. (2005). Proteo-
glycan 4 (PRG4) synthesis and immunolocalization in bovine meniscus. J
Orthop Res 23: 562–568.
Schwarz IM, Hills BA. (1996). Synovial surfactant: lamellar bodies in type B
synoviocytes and proteolipid in synovial  uid and the articular lining. Br J
Rheumatol 35: 821–827.
Schwarz IM, Hills BA. (1998). Surface-active phospholipids as the lubricating
component of lubricin. Br J Rheumatol 37: 21–26.
Scott DL, Shipley M, Dawson A, Edwards S, Symmons DP, Woolf AD. (1998).
The clinical management of rheumatoid arthritis and osteoarthritis: strate-
gies for improving clinical e ectiveness. Br J Rheumatol 37: 546–554.
Tamer Mahmoud Tamer
Hyaluronan and synovial joint
ISSN: 1337-6853 (print version) | 1337-9569 (electronic version)
Scott JE, Cummings C, Brass A, Chen Y. (1991). Secondary and tertiary struc-
tures of hyaluronan in aqueous solution, investigated by rotary shadowing-
electron microscopy and computer simulation. Biochem J 274: 600–705.
Servaty R, Schiller J, Binder H, Arnold K. (2000). Hydration of polymeric com-
ponents of the cartilage – An infrared spectroscopic study on hyaluronic
acid and chondroitin sulfate. Int J Biol Macromol 28: 123 –129.
Simkovi c I, Hricovin i M, Soltes L , Mendichi R , Cosentino C . (2000). Preparatio n
of water soluble/insoluble derivatives of Hyaluronic acid by cross linking
with epichlorohydrin in aqueous NaOH/NH
OH solution. Carbohydr Polym
41: 9–14.
Simon A, Safran A, Revel A. (2003). Hyaluronic acid can successfully replace
albumin as the sole macromolecule in a human embryo transfer medium.
Fertil Steril 79: 1434–1438.
Soldati D, Rahm F, Pasche P. (1999). Mucosal wound healing after nasal sur-
gery. A controlled clinical trial on the e cacy of hyaluronic acid containing
cream. Drugs Exp Clin Res 25: 253–261.
Soloveva ME, Solovev V V, Faskhutdinova AA, Kudryavtsev AA, Akatov VS.
(2007). Prooxidant and cytotoxic action of N-acetylcysteine and glutathi-
one in combinations with vitamin B12b. Cell Tissue Biol 1: 40–49.
Soltes L, Kogan G. (2009). Impact of transition metals in the free-radical degra-
dation of hyaluronan biopolymer In: “Kinetics & Thermodynamics for Chem-
istry & Biochemistry: Vol. 2” E . M. Pearce, G. E. Zaikov, G. Kirshenbaum (eds),
Nova Science Publishers, New York (181–199).
Soltes L, Mendichi R, Kogan G, Mach M. (2004). Associating Hyaluronan De-
rivatives: A Novel Horizon in Viscosupplementation of Osteoarthritic
Joints. Chem Biodivers 1: 468–472.
Soltes L, Brezova V, Stankovska M, Kogan G, Gemeiner P. (2006a). Degrada-
tion of high-molecular-weight hyaluronan by hydrogen peroxide in the
presence of cupric ions. Carbohydr Res 341: 639– 644.
Soltes L, Mendichi R, Kogan G, Schiller J, Stankovska M, Arnhold J. (2006b)
Degradative action of reactive oxygen species on hyaluronan. Biomacro-
molecules 7: 659–668.
Soltes L, Stankovska M, Brezova V, Schiller J, Arnhold J, Kogan G, Gemeiner P.
(2006c). Hyaluronan degradation by copper (II) chloride and ascorbate: ro-
tational viscometric, EPR spin-trapping, and MALDI-TOF mass spectromet-
ric investigations Carbohydr Res 341: 2826–2834.
Soltes L, Stankovska M, Kogan G, Germeiner P, Stern R. (2005). Contribution
of oxidative reductive reations to high molecular weight hyaluronan ca-
tabolism. Chem Biodivers 2: 1242–1245.
Soltes L, Valachova K, Mendichi R, Kogan G, Arnhold J, Gemeiner P. (2007).
Solution properties of high-molar-mass hyaluronans: the biopolymer deg-
radation by ascorbate. Carbohydr Res 342: 1071–1077.
Soltes L. (2010). Hyaluronan – AHigh-Molar-Mass Messenger Reporting on the
Status of Synovial Joints: Part II. Pathophysiological Status In:New Steps in
Chemical and Bio chemical Physics. Pure and Applie d Science E. M. Pearce,
G. Kirshenbaum, G. E. Zaikov (eds), Nova Science Publishers, New York pp.
Stankovska M, Arnhold J, Rychly J, Spalteholz H, Gemeiner P, Soltes L. (2007).
In vitro scre ening of t he acti on of non -stero idal ant i-in ammatory drugs on
hypochlorous acid-induced hyaluronan degradation. Polym Degrad Stabil
92: 644 –652.
St a n ko v sk a M , S o lt e s L, V ik a r t ov s ka A , Me n d ic h i r , La t h D , Mo l n ar o va M , G e m e i-
ner P. (2004). Study of hyaluronan degradation by means of rotational Vis-
cometry: Contribution of the material of viscometer. Chem Pap 58: 348–352.
Stankovska M, Hrabarova E, Valachova K, Molnarova M, Gemeiner P, Soltes L.
(2006). The degradative action of peroxynitrite on high-molecular-weight
hyaluronan . Neuroendocrinol Lett 27(Suppl. 2): 31–34.
Stankovska M, Soltes L, Vikartovska A, Gemeiner P, Kogan G, Bakos D. (2005).
Degradation of high-molecular-weight hyaluronan: a rotational viscome-
try study. Biologia 60(Suppl. 17 ): 149 –152 .
Stern R, Kogan G, J edrzejas M. J, Soltes L. (2007). The many ways to cleave hy-
aluronan. Biotechnol Adv 25: 537–557.
Stiebel-Kalish H, Gaton DD, Weinberger D. (1998). A comparison of the e ect
of hyaluronic acid versus gentamicin on corneal epithelial healing. Eye 12:
Suchanek E, Simunic V, Juretic D, Grizelj V. (1994). Follicular- uid contents of
hyaluronic-acid, follicle-stimulating-hormone and steroids relative to the
success of in-vitro fertilization of human oocytes. Fer til Steril 62: 347–352.
Surendrakumar K, Martyn GP, Hodgers ECM. (2003). Sustained release of in-
sulin from sodium hyaluronate based dry powder formulations after pul-
monary delivery to beagle dogs. J Control Release 91: 385–394.
Surini S, Akiyama H, Morishita M. (2003). Polyion complex of chitosan and so-
dium hyaluronate as an implant device for insulin delivery. STP Pharm Sci
13: 265–268.
Su ro vci ko va L, Val ac ho va K, Ba na so va M, Sni rc V, P ri es ol ov a E , Na g y M , Ju ra ne k
I, Soltes L. (2012). Free-radical degradation of high-molar-mass hyaluronan
induced by ascorbate plus cupric ions: Testing of stobadine and its two
derivatives in function as antioxidants. General Physiol Biophys 31: 57–64.
Swann DA, Silver FH, Slayter HS, Sta ord W, Shore E. (1985). The molecular
structure and lubricating activity of lubricin isolated from bovine and hu-
man synovial  uids. Biochem J 225: 195–201.
Takayama K, Hirata M, Machida Y. (1990). E ect of interpolymer complex-for-
mation on bioadhesive property and drug release phenomenon of com-
pressed tablet consisting of chitosan and sodium hyaluronate. Chem Phar-
maceut Bull 38: 1993–1997.
Tani E, Katakami C, Negi A (2002). E ects of various eye drops on corneal
wound healing after super cial keratectomy in rabbits. Jpn J Ophthalmol
46: 488–495.
Tascioglu F, Oner C. (2003). E cacy of intra-articular sodium hyaluronate in
the treatment of knee osteoarthritis. Clin Rheumatol 22: 112– 117.
Thibo deau PA, Kocs is-Bedar d S, Courtea u J, Niyonsen ga T, Paquette B. (2001).
Thiols can either enhance or suppress DNA damage induction by catecho-
lestrogens. Free Rad ic Biol Med 30: 62–73.
Turino GM, Cantor JO. (2003). Hyaluronan in respirator y injury and repair. Am
J Respir Crit Care Med 167: 1169–1175.
Uthman I, Raynauld JP, Haraoui B. (2003). Intra-articular therapy in osteoar-
thritis. Postgrad Med J 79: 4 49–453.
Valachova K, Vargova A, Rapta P, Hrabarova E, Dra
F, Bauerova K, Juranek
I, Soltes L. (2011). Aurothiomalate as preventive and chain-breaking anti-
oxidant in radical degradation of high-molar-mass hyaluronan. Chemistry
& Biodiversity 8: 1274–1283.
Valachova K, Banasova M, Machova L, Juranek I, Bezek S, Soltes L. (2013b).
Antioxidant activity of various hexahydropyridoindoles. Journal of Informa-
tion Intelligence and Knowledge 5: 15–32.
Valachova K, Hrabarova E, Priesolova E, Nagy M, Banasova M, Juranek I, Soltes
L. (2011). Free-radical degradation of high-molecular-weight hyaluronan in-
duced by ascorbate plus cupric ions. Testing of bucillamine and its SA981-
metabolite as antioxidants. J Pharma & Biomedical Analysis 56: 664–670.
Valachová K, Hrabárová E, Drá F, Junek I, Bauerová K, Priesolo E, Nagy
M, Šoltés L. (2010a). Ascorbate and Cu(II) induced oxidative degradation of
high-molar-mass hyaluronan. Pro- and antioxidative e ects of some thiols.
Neuroendocrinol Lett 31(2): 101–104.
Valachová K, Hrabárová E, Gemeiner P, Šoltés L. (2008). Study of pro- and
anti-oxidative properties of d-penicillamine in asystem comprising high-
molar-mass hyaluronan, ascorbate, and cupric ions. Neuroendocrinol Lett
29: 697–701.
Valachová K, Hrabárová E, Juránek I, Šoltés L. (2011b). Radical degradation of
high-molar-mass hyaluronan induced by Weissberger oxidative system.
Testing of thiol compounds in the function of antioxidants. 16th Interdisci-
plinary Slovak-Czech Toxicolo gical Conference in Prague. Interdiscip Toxicol
4(2): 65.
Valachová K, Kogan G, Gemeiner P, Šols L. (2008b). Hyaluronan degrada-
tion by ascorbate: Protective e ects of manganese (II). Cellulose Chem.
Technol 42(9–10): 473 −483.
Valacho K, Kogan G, Gemeiner P, Šoltés L. (2009b). Hyaluronan degrada-
tion by ascorbate: protective e ects of manganese (II) chloride. In: Progress in
Chemistry and B iochemistry. Kinetics, Ther modynamics, Synthesis, Proper-
ties and Application, Nova Science Publishers, N.Y, Chapter 20, pp. 201–215.
Valachová K, Mendichi R, Šoltés L. (2010c). E ect of
-glutathione on high-mo-
lar-mass hyaluronan degradation by oxidative system Cu(II) plus ascorbate. In:
Monomers, Oligomers, Polymers, Composites, and Nanocomposites, Ed: R.
A. Pethrick P. Petkov, A. Zlatarov G. E. Zaikov, S. K. Rakovsky, Nova Science
Publishers, N.Y, Chapter 6, pp. 101–111.
Valachová K, Rapta P, Kogan G, Hrabárová E, Gemeiner P, Šoltés L. (2009a).
Degrad ation of high-mo lar-mass hyaluronan by ascorbate plus cup ric ions:
e ects of
-penicillamine addition. Chem Biodivers 6: 389–395.
Valachová K, Rapta P, Slováková M, Priesolová E, Nagy M, Mislovičová D, Drá
F, Bauerová K, Šoltés L. (2013a). Radical degradation of high-molar-mass hy-
aluronan induced by ascorbate plus cupric ions. Testing of arbutin in the func-
tion of antioxidant. In: Advances in Kine tics and Mechanism of Chemical Re-
actions, G. E. Zaikov, A. J. M. Valente, A. L. Iordanskii (eds), Apple Academic
Press, Waretown, NJ, USA , pp. 1–19.
Also available online on PubMed Central
Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125
Copyright © 2013 SETOX & Institute of E xperimental Pharmacol ogy and Toxicology, SASc.
Valachová K, Šoltés L. (2010b). E ects of biogenic transition metal ions Zn(II)
and Mn(II) on hyaluronan degradation by action of ascorbate plus Cu(II) ions.
In: New Steps in Chemical and Biochemical Physics. Pure and Applied Sci-
ence, Nova Science Publishers, Ed: E. M. Pearce, G. Kirshenbaum, G.E. Zai-
kov, Nova Science Publishers, N.Y, Chapter 10, pp. 153–160.
Valachová K, Vargová A, Rapta P, Hrabárová E, Drá F, Bauero K, Juránek
I, Šoltés L. (2011a). Aurothiomalate in function of preventive and chain-
breaking antioxidant at radical degradation of high-molar-mass hyaluro-
nan. Chem Biodivers 8: 1274–1283.
Vanos HC, Drogendijk AC, Fetter WPF. (1991). The in uence of contamination
of culture-medium with hepatitis-B virus on the outcome of in vitro fertil-
ization pregnancies. Am J Obstet Gynecol 165: 152–159.
Vazquez JR, Short B, Findlow AH. (2003). Outcomes of hyaluronan therapy in
diabetic foot wounds. Diabetes Res Clin Pract 59: 12 3–127.
Weigel PH, Hascall VC, Tammi M. (1997). Hyaluronan synthases. J Biol Chem
272: 13997–14000.
West DC, Hampson IN, Arnold F, Kumar S. (1985). Angiogenesis induced by
degradation products of hyaluronic acid. Science 228: 1324–1326.
Wilkinson LS, Pitsillides AA, Worrall JG, Edwards JC. (1992). Light microscopic
characterization of the  broblastlike synovial intimal cell (synoviocyte). Ar-
thritis Rheum 35: 1179–1184.
Worrall JG, Bayliss MT, Edwards JC . (1991). Morphological localization of hyal-
uronan in normal and diseased synovium. J Rheumatol 18: 1466–1472.
Worrall JG, Wilkinson LS, Bayliss MT, Edwards JC. (1994). Zonal distribution of
chondroitin-4-sulphate/ dermatan sulphate and chondroitin-6-sulphate in
normal and diseased human synovium. Ann R heum Dis 53: 35–38.
Yerushalmi N, Arad A, Margalit R. (1994). Molecular and cellular studies of hy-
aluronic acid-modi ed liposomes as bioadhesive carriers for topical drug-
delivery in wound-healing. Arch Biochem Biophys 313: 267–273.
Yerushalmi N, Margalit R. (1998). Hy aluronic a cid- mo di ed bioadhesive lipo-
somes as local drug depots: e ects of cellular and  uid dynamics on lipo-
some retention at target sites. Arch Biochem Biophys 349: 21–26.
Yun YH, Goetz DJ, Yellen P, Chen W. (2004). Hyaluronan microspheres for sus-
tained gene delivery and site-speci c targetting. Biomaterials 25: 147–157.
Zhu YX, Granick S. (2003). Biolubrication: hyaluronic acid and the in uence
on its interfacial viscosity of an antiin ammatory drug. Macromolecules 36:
... HA is a natural substance that occurs in the human body, in the skin, connective tissue (extracellular matrix), cartilage, synovial fluid, bones and vitreous body of the eye, among other places. It ensures elasticity in the tissues mentioned and has a high water binding capacity [42][43][44][45][46][47][48][49][50][51]. ...
... The first ophthalmic viscosurgical device containing HA was Healon ® , which was approved in 1980 by the FDA. Since then, several HA-derived eye preparations have reached the market, including eye drops to treat dry eye syndrome [42,43,46]. ...
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Controlling rheological properties offers the opportunity to gain insight into the physical characteristics, structure, stability and drug release rate of formulations. To better understand the physical properties of hydrogels, not only rotational but also oscillatory experiments should be performed. Viscoelastic properties, including elastic and viscous properties, are measured using oscillatory rheology. The gel strength and elasticity of hydrogels are of great importance for pharmaceutical development as the application of viscoelastic preparations has considerably expanded in recent decades. Viscosupplementation, ophthalmic surgery and tissue engineering are just a few examples from the wide range of possible applications of viscoelastic hydrogels. Hyaluronic acid, alginate, gellan gum, pectin and chitosan are remarkable representatives of gelling agents that attract great attention applied in biomedical fields. This review provides a brief summary of rheological properties, highlighting the viscoelasticity of hydrogels with great potential in biomedicine.
... Importantly, healthy cartilage tissue enables bone gliding, while simultaneously acting as an effective shock absorber [5]. Such intrinsic functional attributes of cartilage are normally enhanced by the local presence of synovial fluid (SF), naturally composed of lubricin and hyaluronic acid (HA), which provides additional cushioning and lubrication capacities to the load-bearing joints [3,6,7]. It is well established that qualitative pejoration of both SF composition/content and superficial chondral structures constitutes a key mechanism of knee OA progression [3,[6][7][8]. ...
... Such intrinsic functional attributes of cartilage are normally enhanced by the local presence of synovial fluid (SF), naturally composed of lubricin and hyaluronic acid (HA), which provides additional cushioning and lubrication capacities to the load-bearing joints [3,6,7]. It is well established that qualitative pejoration of both SF composition/content and superficial chondral structures constitutes a key mechanism of knee OA progression [3,[6][7][8]. Clinically, the affected patients develop localized joint pain, stiffness, motion limitation, and inflammation [3,9]. ...
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Thermo-responsive hyaluronan-based hydrogels and FE002 human primary chondroprogenitor cell sources have both been previously proposed as modern therapeutic options for the management of osteoarthritis (OA). For the translational development of a potential orthopedic combination product based on both technologies, respective technical aspects required further optimization phases (e.g., hydrogel synthesis upscaling and sterilization, FE002 cytotherapeutic material stabilization). The first aim of the present study was to perform multi-step in vitro characterization of several combination product formulas throughout the established and the optimized manufacturing workflows, with a strong focus set on critical functional parameters. The second aim of the present study was to assess the applicability and the efficacy of the considered combination product prototypes in a rodent model of knee OA. Specific characterization results (i.e., spectral analysis, rheology, tribology, injectability, degradation assays, in vitro biocompatibility) of hyaluronan-based hydrogels modified with sulfo-dibenzocyclooctyne-PEG4-amine linkers and poly(N-isopropylacrylamide) (HA-L-PNIPAM) containing lyophilized FE002 human chondroprogenitors confirmed the suitability of the considered combination product components. Specifically, significantly enhanced resistance toward oxidative and enzymatic degradation was shown in vitro for the studied injectable combination product prototypes. Furthermore, extensive multi-parametric (i.e., tomography, histology, scoring) in vivo investigation of the effects of FE002 cell-laden HA-L-PNIPAM hydrogels in a rodent model revealed no general or local iatrogenic adverse effects, whereas it did reveal some beneficial trends against the development of knee OA. Overall, the present study addressed key aspects of the preclinical development process for novel biologically-based orthopedic combination products and shall serve as a robust methodological basis for further translational investigation and clinical work.
... The synovial fluid protects the articular cartilage surface by reducing friction during movement and providing nutrition to the joint [42]. The rich proteinaceous nature of SF makes it an ideal substrate for the growth and aggregation of pathogens, promoting bacterial colonization of implants, which leads to PJI [43][44][45]. ...
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Metallodrugs have a potent application in various medical fields. In the current study, we used a novel Palladium(II) thiazolinyl picolinamide complex that was directly fabricated over the titanium implant to examine its potency in inhibiting dual-species biofilms and exopolysaccharides. Additionally, inhibition of mono- and dual-species biofilms by coated titanium plates in an in vitro joint microcosm was performed. The study was carried out for 7 days by cultivating mono- and dual-species biofilms on titanium plates placed in both growth media and artificial synovial fluid (ASF). By qPCR analysis, the interaction of co-cultured biofilms in ASF and the alteration in gene expression of co-cultured biofilms were studied. Remarkable alleviation of biofilm accumulation and EPS secretion was observed on the coated titanium plates. The effective impairment of biofilms and EPS matrix of biofilms on Pd(II)-E-coated titanium plates were visualized by Scanning Electron Microscopy. Moreover, coated titanium plates improved the adhesion of osteoblast cells, which is crucial for a bone biomaterial. The potential bioactivity of coated plates was also confirmed at the molecular level using qPCR analysis. The stability of coated plates in ASF for 7 days was examined with FESEM-EDAX analysis. Collectively, the present study provided an excellent anti-infective effect on Pd(II)-E-coated titanium plates without affecting their biocompatibility with bone cells.
... First, we showed that synovial fluid from OA patients is not toxic to ProtheraCytes ® and maintains their viability when incubated for 96 h at 37°C, 5% CO 2 . It is possible that factors present in the synovial fluid such as hyaluronan and proteoglycan 4 (Tamer, 2013), might be responsible for the protection for ProtheraCytes ® . This is encouraging data showing that synovial fluid would support the survival of ProtheraCytes ® if they were injected in the knee joint of OA patients. ...
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Knee osteoarthritis (OA) is a degenerative joint disease of the knee that results from the progressive loss of articular cartilage. It is most common in the elderly and affects millions of people worldwide, leading to a continuous increase in the number of total knee replacement surgeries. These surgeries improve the patient's physical mobility, but can lead to late infection, loosening of the prosthesis, and persistent pain. We would like to investigate if cell-based therapies can avoid or delay such surgeries in patients with moderate OA by injecting expanded autologous peripheral blood derived CD34+ cells (ProtheraCytes®) into the articular joint. In this study we evaluated the survival of ProtheraCytes® when exposed to synovial fluid and their performance in vitro with a model consisting of their co-culture with human OA chondrocytes in separate layers of Transwells and in vivo with a murine model of OA. Here we show that ProtheraCytes® maintain high viability (>95%) when exposed for up to 96 hours to synovial fluid from OA patients. Additionally, when co-cultured with OA chondrocytes, ProtheraCytes® can modulate the expression of some chondrogenic (collagen II and Sox9) and inflammatory/degrading (IL1β, TNF, and MMP-13) markers at gene or protein levels. Finally, ProtheraCytes® survive after injection into the knee of a collagenase-induced osteoarthritis mouse model, engrafting mainly in the synovial membrane, probably due to the fact that ProtheraCytes® express CD44, a receptor of hyaluronic acid, which is abundantly present in the synovial membrane. This report provides preliminary evidence of the therapeutic potential of CD34+ cells on OA chondrocytes in vitro and their survival after in vivo implantation in the knee of mice and merits further investigation in future preclinical studies in OA models.
... Infectious fluid is of low viscosity and proportional to the degree of local inflammation. 24 The finding of statistically higher (2.099, p=0.042) bacterial 16S rRNA gene quantity in the thick synovial fluid compared with thin fluid (p=0.002) ( Table 2) might be attributed to the lower concentration and molecular weight of synovial hyaluronan and the addition of various serum-derived proteins substantially increase the viscosity of SF as a result of inflammatory process in the joint affected with SA. 25 The finding of twenty-five (65.8 %) thin and less viscous SF seems to be attributed to the dilution of the SF with plasma from leaky synovial blood vessels, and the reduction of production of the hyluronans by the synoviocytes. Moreover, the production and release of degrading digestive enzymes into the fluid leads to the reduction of viscosity and poor clot formation. ...
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This study aims to determine the types of causative organism, the utility of synovial procalcitonin (PCT), C-Reactive Protein (CRP) and bacterial 16S rRNA gene-based RT-PCR and their comparison with conventional culture results in patients with clinically-suspected SA. A total of 38 patients were recruited in this cross-sectional study for performing synovial PCT and CRP assay, and bacterial gDNA quantification via RT-PCT. Records of culture results, WBC count, ESR, blood CRP, and antibiotic administration were obtained. Gross appearance and viscosity determination are significantly associated with the bacterial load. This study documents Acinetobacter radioresistens and Klebsiella pneumoniae bacteria as causative pathogens of SA in Malaysia. CRP and ESR showed a significant role in diagnosing SA. Reasons for finding no concordance between conventional culture methods and 16S rDNA RT-PCR as well as synovial PCT were comprehensively reviewed. Gross appearance and viscosity showed a significant relationship with the bacterial load. RT-PCR is useful in patients treated with antimicrobial therapy with negative culture results.RT-PCR has speed and accuracy compared to conventional culture. Awareness of Klebsiella pneumoniae and Acinetobacter radioresistens as causative bacteria should be prompted among clinicians particularly at local, regional as well as international levels. Developing guidelines for including 16S rRNA gene RT-PCR and introducing Digital PCR and next-generation sequencing to detect and identify bacterial species in diagnosing SA is recommended.
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In this study, we synthesize a hyaluronic acid-g-poly(N-isopropylacrylamide) (HPN) copolymer by grafting the amine-terminated poly(N-isopropylacrylamide) (PNIPAM-NH2) to hyaluronic acid (HA). The 5% PNIPAM-NH2 and HPN polymer solution is responsive to temperature changes with sol-to-gel phase transition temperatures around 32 °C. Compared with the PNIPAM-NH2 hydrogel, the HPN hydrogel shows higher water content and mechanical strength, as well as lower volume contraction, making it a better choice as a scaffold for chondrocyte delivery. From an in vitro cell culture, we see that cells can proliferate in an HPN hydrogel with full retention of cell viability and show the phenotypic morphology of chondrocytes. In the HPN hydrogel, chondrocytes demonstrate a differentiated phenotype with the upregulated expression of cartilage-specific genes and the enhanced secretion of extracellular matrix components, when compared with the monolayer culture on tissue culture polystyrene. In vivo studies confirm the ectopic cartilage formation when HPN was used as a cell delivery vehicle after implanting chondrocyte/HPN in nude mice subcutaneously, which is shown from a histological and gene expression analysis. Taken together, the HPN thermosensitive hydrogel will be a promising injectable scaffold with which to deliver chondrocytes in cartilage-tissue-engineering applications.
Healthy synovium is critical for joint homeostasis. Synovial inflammation (synovitis) is implicated in the onset, progression and symptomatic presentation of arthritic joint diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). Thus, the synovium is a promising target for the development of novel, disease-modifying therapeutics. However, target exploration is hampered by a lack of good pre-clinical models that accurately replicate human physiology and that are developed in a way that allows for widespread uptake. The current study presents a multi-channel, microfluidic, organ-on-a-chip (OOAC) model, comprising a 3D configuration of the human synovium and its associated vasculature, with biomechanical and inflammatory stimulation, built upon a commercially available OOAC platform. Healthy human fibroblast-like synoviocytes (hFLS) were co-cultured with human umbilical vein endothelial cells (HUVECs) with appropriate matrix proteins, separated by a flexible, porous membrane. The model was developed within the Emulate organ-chip platform enabling the application of physiological biomechanical stimulation in the form of fluid shear and cyclic tensile strain. The hFLS exhibited characteristic morphology, cytoskeletal architecture and matrix protein deposition. Synovial inflammation was initiated through the addition of interleukin-1β (IL-1β) into the synovium channel resulting in the increased secretion of inflammatory and catabolic mediators, interleukin-6 (IL-6), prostaglandin E2 (PGE2), matrix metalloproteinase 1 (MMP-1), as well as the synovial fluid constituent protein, hyaluronan (HA). Enhanced expression of the inflammatory marker, intercellular adhesion molecule-1 (ICAM-1), was observed in HUVECs in the vascular channel, accompanied by increased attachment of circulating monocytes. This vascularised human synovium-on-a-chip model recapitulates a number of the functional characteristics of both healthy and inflamed human synovium. Thus, this model offers the first human synovium organ-chip suitable widespread adoption to understand synovial joint disease mechanisms, permit the identification of novel therapeutic targets and support pre-clinical testing of therapies.
Background: Giant Cell Tumour of Tendon Sheath (GCTTS) is a slow growing benign soft tissue tumour arising from synovium of tendon sheath or joint. These tumours occur more frequently in upper limbs, especially hands. In the present study, we aimed to evaluate the cytomorphological spectrum of GCTTS. Methods: This retrospective study includes a total of 56 cases of GCTTS diagnosed over a period of 8 years. The clinical and radiological details of these cases were retrieved from the cytopathology records and detailed cytomorphological features were studied and analysed. Histopathological correlation was done in 16/56 cases, where follow-up was available. Results: The mean age of patients at the time of presentation was 32 years and were predominantly females (68%). The most common site of GCTTS was fingers (76%), followed by foot, wrist and toes. The most consistent finding on cytology was stromal cells (100%) of polygonal, spindle and plasmacytoid morphology with interspersed multinucleated osteoclastic giant cells (100%), followed by binucleated stromal cells (75%), xanthoma cells (61%) and hemosiderin laden macrophages (52%). Presence of proteinaceous fluid background was also observed in 50% of the cases. Conclusion: GCTTS can be diagnosed with certainty on FNAC based on characteristic cytomorphological features in an appropriate clinical and radiological setting. FNAC plays a pivotal role in diagnosing GCTTS and differentiating it from other giant cell rich lesions, thus obviating the need of tissue biopsy for diagnosis, which in turn helps the clinician in timely and adequate management of the patient.
HYBID is a new hyaluronan-degrading enzyme and exists in various cells of the human body. Recently, HYBID was found to over-express in the osteoarthritic chondrocytes and fibroblast-like synoviocytes. According to these researches, high level of HYBID is significantly correlated with cartilage degeneration in joints and hyaluronic acid degradation in synovial fluid. In addition, HYBID can affect inflammatory cytokine secretion, cartilage and synovium fibrosis, synovial hyperplasia via multiple signaling pathways, thereby exacerbating osteoarthritis. Based on the existing research of HYBID in osteoarthritis, HYBID can break the metabolic balance of HA in joints through the degradation ability independent of HYALs/CD44 system and furthermore affect cartilage structure and mechanotransduction of chondrocytes. In particular, in addition to HYBID itself being able to trigger some signaling pathways, we believe that low-molecular-weight hyaluronan produced by excess degradation can also stimulate some disease-promoting signaling pathways by replacing high-molecular-weight hyaluronan in joints. The specific role of HYBID in osteoarthritis is gradually revealed, and the discovery of HYBID raises the new way to treat osteoarthritis. In this review, the expression and basic functions of HYBID in joints were summarized, and reveal potential role of HYBID as a key target in treatment for osteoarthritis.
Osteoarthritis (OA) is the most prevalent rheumatic pathology. However, OA is not simply a process of wear and tear affecting articular cartilage but rather a disease of the entire joint. One of the most common locations of OA is the knee. Knee tissues have been studied using molecular strategies, generating a large amount of complex data. As one of the goals of the Rheumatic and Autoimmune Diseases initiative of the Human Proteome Project, we applied a text-mining strategy to publicly available literature to collect relevant information and generate a systematically organized overview of the proteins most closely related to the different knee components. To this end, the PubPular literature-mining software was employed to identify protein-topic relationships and extract the most frequently cited proteins associated with the different knee joint components and OA. The text-mining approach searched over 8 million articles in PubMed up to November 2022. Proteins associated with the six most representative knee components (articular cartilage, subchondral bone, synovial membrane, synovial fluid, meniscus, and cruciate ligament) were retrieved and ranked by their relevance to the tissue and OA. Gene ontology analyses showed the biological functions of these proteins. This study provided a systematic and prioritized description of knee-component proteins most frequently cited as associated with OA. The study also explored the relationship of these proteins to OA and identified the processes most relevant to proper knee function and OA pathophysiology.