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Hyaluronan and synovial joint: Function, distribution and healing

September 2013
Interdisciplinary Toxicology 6(3):111-125

DOI:10.2478/intox-2013-0019

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PubMed

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Authors:

Tamer M Tamer

City Of Scientific Research And Technological Applications

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.

Articular cartilage main components and structure (adapted from Chen et al., 2006).

…

Normal, (healthy) and rheumatoid arthritis synovial joint.

…

Schematic degradation of HA under free radical stress (Hrabarova et al., 2012).

…

Evaluation of antioxidative eff 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).

…

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Content uploaded by Tamer M Tamer

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interdisciplinary

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

ABSTRACT

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.

E-MAIL: ttamer85@gmail.com

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

Introduction

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

Cartilage

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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REVIEW ARTICLE

Cartilage

Joint cavity with

synovial uid

Ligament forming

joint capsule

Synovium

Figure 1. Normal, healthy synovial joint (adapted from Kogan,

2010).

112

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

COMP

Decorin Type IX collagen

Chondrocyte

Fibromodulin

Type II collagen

Aggrecan

Biglycan

Link protein

Fibronectin

S–S

Hyaluronan

Integrin

Figure 2. Articular cartilage main components and structure (adapted from Chen et al., 2006).

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Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125

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

2•–

, 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.

Hyaluronan

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

Cartilage Loss

Tendon

Synovium

Inamed Synovium

Synovial Fluid

Joint Capsule

Swollen Joint Capsule

Bone

Bone Loss

(Generalized)

Bone Loss/Erosion

Muscle

NORMAL JOINT

JOINT AFFECTED BY

RHEUMATOID ARTHRITIS

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

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Tamer Mahmoud Tamer

Hyaluronan and synovial joint

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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

(~c

3.3

) (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

C H

OC O H

OOH

OH O

Figure 4. Structural formula of hyaluronan – the acid form.

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Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125

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)

ORTHOVISC® (Anika, USA)

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

Ophthalmic

Increased ocular residence of drug,

which can lead to increased

bioavailability

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

bioavailability

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.

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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).

Lubrication

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

angiogenesis.

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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Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125

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

•

radical

formed via the Fenton-like reaction:

+ H

 Cu

+ 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

•

radical

attack.

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

macromolecule.

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

COOH O

CHO

HOOC

COOH O

CHO

HOOC

COOH O

CHO

HOOC

AHA

COOH O

CHO

HOOC

COOH O

CHO

HOOC

COOH

HOOC

COHO

Figure 5. Schematic degradation of HA under free radical stress

(Hrabarova et al., 2012).

118

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

HCH2OH

CH2OH

O−

HCH2OH

CH2OH

OOO

Cu (I)

HCH2OH

CH2OH

Cu (I)

+ Cu(II) + O2

+ Cu(II) + H2 O2

+ H+

060120180240300

Dynamic viscosity [mPa·s]

Time [min]

100

ABC

Time [min]

100

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).

119

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Interdisciplinary Toxicology. 2013; Vol. 6(3): 111–125

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

-antiproteinase

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

2•–

(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]

060120180240300

Time [min]

100

060120180240300

100

Time [min]

0 60 120 180 240 300

Dynamic viscosity [mPa·s]

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.,

2010).

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).

120

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).

Acknowledgements

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.

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Lubricant Strategies in Osteoarthritis Treatment: Transitioning from Natural Lubricants to Drug Delivery Particles with Lubricant Properties

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Effects of biogenic transition metal ions Zn(II) and Mn(II) on hyaluronan degradation by action of ascorbate plus Cu(II) ions

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Jan 2010

High-molar-mass hyaluronan (HA) degradation was initiated by two oxidative systems, i.e. ascorbate plus Fe(II) ions and ascorbate plus Cu(II) ions. By using the method of rotational viscometry, we observed dose-dependent degradation of HA by the above mentioned oxidative systems, which however differed in the reaction kinetics. The effects of two biogenic transition metal ions, i.e. Zn(II) and Mn(II) ions, on degradation of the high-molar-mass HA sample by the oxidative system ascorbate plus Cu(II) ions (Weissberger's oxidative system) were investigated. Two experimental settings were tested: Zn(II) or Mn(II) ions were added to the reaction system (i) before the reaction onset or (ii) 1 h after initiating the HA degradation. It was found that under the conditions specified in (i), Mn(II) and Zn(II) ions caused an inhibitory effect on HA degradation in a dose-independent manner up to a certain period of time (appr. 30 min). On the contrary, when the Mn(II) or Zn(II) ions were applied 1 h after the reaction onset (ii), a prooxidative effect of each element on degradation of the high-molar-mass HA chains was evidenced.

Molar mass - Intrinsic viscosity relationship of high-molar-mass hyaluronans: Involvement of shear rate

Article

Full-text available

Jan 2005

Empirical Kuhn - Mark - Houwink - Sakurada (KMHS) relationships for high-molar-mass hyaluronans, exhibiting non-Newtonian behaviour, are presented in 0.2 mol dm -3 NaCl at 25°C as a function of shear rate. Viscometric determination of the molar mass in conventional Ubbelohde viscometer of constant shear rate requires the proper use of KMHS relationship and concentration correction for moisture content of the hyaluronan sample characterized.

Impact of transition metals in the free-radical degradation of hyaluronan biopolymer

Article

Full-text available

Oct 2008
CELL CHEM TECHNOL

Due to their electronic configuration, transition metals readily participate in reductive-oxidative processes, thus contributing to the formation of free radicals, lipid peroxidation and oxidative DNA damage. In living (biogenic) organisms, there exist eight naturally-occurring transition metals, essential for the control of various metabolic and signaling pathways. In this overview, the role of these metals in physiological and pathophysiological processes is described, and their participation in the initiation and propagation of radical chain reactions - leading to oxidative stress and damage to the tissues - is critically assessed. Special attention is given to the involvement of biogenic transition metals in the catabolism of hyaluronan in the joint, where the oxidative degradation of this high-molar-mass glycosaminoglycan may lead to an impaired lubricating function of the synovial fluid, resulting in arthritic and inflammatory conditions.

Hyaluronan and synovial joint: Function, distribution and healing

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