Antioxidants and Osteoarthritis: Ali Mobasheri, Hans Konrad Biesalski, Mehdi Shakibaei, and Yves Henrotin

Antioxidants and Osteoarthritis
133
Ali Mobasheri, Hans Konrad Biesalski, Mehdi Shakibaei, and
Yves Henrotin
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2998
Musculoskeletal, Arthritic, and Rheumatic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3001
Osteoarthritis (OA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3002
ROS in Cartilage and OA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3003
“Nutrigenomics” and “Nutritargeting” Treatments for OA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3006
Chondrocyte Antioxidant Defenses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3008
Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3009
Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3011
Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3011
Vitamin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3011
Chondrocyte Antioxidant Defenses: Glutathione, Superoxide Dismutase (SOD),
Glutathione S-Transferase, Glutathione Peroxidase, and Catalase . . . . . . . . . . . . . . . . . . . . . . . . . . . 3014
A. Mobasheri (*)
Arthritis Research UK Centres for Pain, Musculoskeletal Ageing Research and Sport, Exercise and
Osteoarthritis, Faculty of Medicine and Health Sciences, The University of Nottingham,
Leicestershire, UK
Center of Excellence in Genomic Medicine Research (CEGMR), King Fahad Medical Research
Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
e-mail: ali.mobasheri@nottingham.ac.uk
H.K. Biesalski
Department of Biological Chemistry and Nutrition, Institute of Biological Chemistry and
Nutrition, University of Hohenheim, Stuttgart, Germany
e-mail: Hans-K.Biesalski@uni-hohenheim.de
M. Shakibaei
Musculoskeletal Research Group, Institute of Anatomy, Ludwig-Maximilian-University Munich,
Munich, Germany
Y. Henrotin
Bone and Cartilage Research Unit, Institute of Pathology, University of Liège, Liège, Belgium
I. Laher (ed.), Systems Biology of Free Radicals and Antioxidants, 2997

DOI 10.1007/978-3-642-30018-9_130, # Springer-Verlag Berlin Heidelberg 2014
2998 A. Mobasheri et al.
“Nutritargeting” with Antioxidants in OA: Systematic Reviews and Clinical Trials . . . . . . . 3015
Hormetic Effects of Antioxidants: Implications for the Prevention of
Inflammatory Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3018
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3019
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3022
Abstract
Oxidative stress produces reactive oxygen species (ROS) that play key roles in
the development of osteoarthritis (OA) and rheumatoid arthritis (RA). Meta-
bolic reactions in chondrocytes and synoviocytes produce free radicals, ROS,
and their derivatives. These dangerous chemicals can accumulate in the syno-
vial joint, causing extensive structural damage, inflammation, and cell death.
Antioxidants are naturally occurring reducing agents capable of inhibiting
ROS formation, scavenging free radicals, and removing ROS derivatives.
Antioxidant vitamins have major roles in modulating oxidative stress, regulat-
ing immune responses, and contributing to cell differentiation. Vitamin
C (ascorbic acid), vitamin E, thiols (glutathione), and plant polyphenols have
the capacity to neutralize ROS in joints and decrease the oxidative stress
associated with the progression of arthritis. There is a pressing need to under-
stand the contribution of antioxidants to OA, because they may provide
important insight into ameliorating the initiation and progression of the dis-
ease. The objective of this chapter is to examine ROS biology at the cellular
and tissue levels in the synovial joint with special emphasis on the biological
effects of ROS and naturally occurring antioxidants on chondrocytes. We
summarize and critically appraise the information published about antioxi-
dants and their potential for preventing and treating arthritic diseases such as
OA. The expectation is to relate the potential importance of dietary antioxi-
dants and their supplementation in OA patients. This knowledge will improve
the design of future clinical trials and interventional studies on OA and related
diseases.
Keywords
Antioxidant • Cartilage • Combination products • Glutathione • Inflammation •
Osteoarthritis • Supplements • Synovium • Vitamin A • Vitamin C • Vitamin E
Introduction
Antioxidants are naturally occurring reducing agents capable of inhibiting the

oxidation of biological molecules. Oxidation reactions in living cells produce
free radicals, reactive oxygen species (ROS), and their derivatives. These dan-
gerous and harmful chemical products can accumulate over time, causing exten-
sive structural damage or even cell death. The cytotoxic effects of ROS can
133 Antioxidants and Osteoarthritis 2999
cause a variety of health problems including inflammatory disease, tissue necro-

sis, organ failure, atherosclerosis, infertility, birth defects, premature aging,
mutations, and malignancy (Parke and Sapota 1996). ROS production initiates
an “inflammatory state” which unless quenched may result in chronic
inflammatory disease states, e.g., arthritis, hepatitis, nephritis, myositis, sclero-
derma, lupus erythematosus, and multiple system organ failure (Parke and
Sapota 1996).
ROS are involved in the initiation of inflammatory responses (Gloire et al.
2006). For example, ROS such as H2O2 can stimulate the transcription factor
NF-kB, which is crucial for cellular processes such as inflammation, immunity,
cell proliferation, and apoptosis (Schreck et al. 1991). Therefore, ROS-mediated
upregulation of NF-kB can cause dysregulation of many inflammatory responses.
ROS are also linked to mitochondria and the inflammasome (Zhou et al. 2011). The
inflammasome is a protein complex that stimulates caspase-1 activation to promote
the processing and secretion of proinflammatory cytokines (Ogura et al. 2006). This
multiprotein oligomer consists of caspase-1, PYCARD, NALP, and sometimes
caspase-5 (also known as caspase-11 or ICH-3). Inflammasome-dependent inflam-
matory responses are triggered by a variety of stimuli including infection, tissue
damage, and metabolic dysregulation (Tschopp 2011). Recent work suggests that
mitochondria are involved in integrating distinct signals and relaying information to
the inflammasome. Dysfunctional mitochondria generate ROS, which is required
for inflammasome activation. Interestingly, mitochondrial dysfunction has been
linked to osteoarthritis (OA) (Blanco et al. 2004; Terkeltaub et al. 2002). Analyses
of mitochondrial electron transport chain activity in chondrocytes from OA-
affected cartilage show decreased activity of complexes I, II, and III compared to
normal chondrocytes (Blanco et al. 2011). Therefore, it is possible that mitochon-
drial dysfunction in arthritis is exacerbated by ROS and catabolic processes that
alter cellular metabolism. The inflammasome is negatively regulated by autophagy,
which is a catabolic process that removes damaged or otherwise dysfunctional
organelles, including mitochondria (Tschopp 2011). Autophagy has been shown
to be a protective mechanism in normal cartilage, and its aging-related loss is linked
with cell death and OA (Carames et al. 2010). These studies suggest that the
connections between mitochondria, metabolism, and inflammation are important
for cell function and malfunctioning of this network is associated with many
chronic inflammatory diseases. ROS generation and inflammasome activation are
linked with mitochondrial dysfunction and may explain the frequent association of
mitochondrial damage with inflammatory diseases.
Antioxidants are thought to interfere with inflammatory reactions by inhibiting
ROS formation, scavenging free radicals, or removing ROS derivatives. They do
this by being oxidized themselves, so antioxidants are often reducing agents such as
vitamin C (ascorbic acid), vitamin E, thiols (glutathione), or a variety of plant
polyphenols. Living cells maintain a complex and interrelated protective
system of antioxidant vitamins, minerals such as selenium and manganese as
cofactors, and glutathione to protect themselves from the harmful effects of
ROS (Meister 1994a, b). Cells also use a variety of antioxidant enzymes such as
catalase, superoxide dismutase, and various peroxidases to quench and control
cellular levels of ROS. Deficiency in antioxidants or inhibition of the antioxidant
enzyme systems may cause oxidative stress and may damage or kill cells. Oxidative
stress is an important component of many diseases. Therefore, the biology of ROS
and antioxidants is widely investigated in the context of understanding the role of
these chemicals in chronic diseases characterized by oxidative stress.
Antioxidants are currently a key focus of nutritional research and are widely
used as ingredients in dietary supplements intended to support health. Epidemio-
logic data suggest that antioxidant vitamins may prevent cardiovascular
disease, with the clearest effect reported for vitamin E (Jha et al. 1995). Evidence
supporting the beneficial or harmful effects of antioxidants in other diseases is
either emerging or highly controversial. Taken together, antioxidants, present in
fruits and vegetables and edible oils, seem to protect the body from long-lasting
effects of oxidative stress. Oxidative stress defined as an imbalance between
oxidative processes and reduction equivalents (antioxidants) is involved in the
development of degenerative diseases. Data from epidemiological studies suggest
that a high dietary intake of antioxidants may indeed protect against several
degenerative diseases.
Musculoskeletal, arthritic, and rheumatic diseases are also characterized by oxi-
dative stress. The most up-to-date research suggests that oxidative stress and ROS
play key roles in the development of OA and rheumatoid arthritis (RA). For example,
many industrial workers with symptoms of systemic inflammation, resulting from
exposure to toxic chemicals, are diagnosed with RA, increased susceptibility to viral
infections, or microbial lesions, largely because their physicians are unaware that
exposure to certain chemicals can initiate inflammatory disease states (Parke and
Sapota 1996). However, this is still a relatively new area of research, and very few
studies have been conducted on the effectiveness of antioxidant vitamins, antioxidant
drugs, and nutritional supplements containing combination products for relieving the
symptoms of arthritis and slowing down disease progression. Nevertheless, because
of the clear connection between oxidative stress, ROS, and the pathogenesis of both
OA and RA, patients with either form of arthritis are advised to maintain a healthy
diet that consists of the naturally occurring antioxidants such as vitamin C, vitamin E,
and supplements such as N-acetylcysteine (NAC) that may support glutathione
antioxidant levels. Nutritional supplements containing antioxidants may also help
obese and overweight individuals with arthritis, especially in patients with metabolic
syndrome.
The aim of this handbook is to focus on the systemic effects of free radicals and
antioxidants, with particular emphasis on the pharmacology, physiology, and patho-
biology of ROS. The primary objective of this chapter is to examine ROS biology at
the cellular and synovial joint levels with a focus on the biological effects of ROS and
naturally occurring antioxidants on chondrocytes. The secondary objective of this
chapter is to summarize and critically appraise the published information
about antioxidants and their potential for preventing and treating arthritic diseases
such as OA. The expectation is to relate the potential importance of antioxidants
to OA and improve study design in future interventional studies on OA. If antioxi-

dants have genuine benefits for bones and joints in arthritic diseases such as OA, the
primary emphasis should be prevention rather than treatment. Realistically the use of
antioxidants as adjunct treatments for OA may extend to both prevention and
treatment as they have the capacity to neutralize ROS in joints and decrease the
oxidative stress associated with the progression of OA. However, this is a highly
controversial area of research and is fraught with conceptual and practical difficulties.
Consequently, many of the studies that have been carried out to date thus far have
proved inconclusive.
Musculoskeletal, Arthritic, and Rheumatic Diseases
According to the United Nations (UN) (www.un.org/) and the World

Health Organization (WHO) (http://www.who.int/en/), musculoskeletal and
arthritic conditions are leading causes of morbidity and disability throughout the
world, giving rise to enormous healthcare expenditures and loss of work (Woolf and
Pfleger 2003) (sources: http://www.arthritis.org; http://www.who.int/healthinfo/
statistics/bod_osteoarthritis.pdf; http://whqlibdoc.who.int/bulletin/2003/Vol81No9/
bulletin_2003_81(9)_630.pdf). Many types of rheumatic diseases and arthritic con-
ditions are essentially “inflammatory” disorders where the inflammation facilitates
disease progression. The term “arthritis” characterizes a group of conditions
involving inflammatory damage to synovial joints (Di Paola and Cuzzocrea
2008). Arthritis literally means inflammation (itis) of the joints (arthr). It involves
pain, redness, heat, swelling, and other harmful effects of inflammation within the
joint. There are over 200 different forms of arthritis. The most common and
important form of arthritis is OA (also known as osteoarthrosis or degenerative
joint disease). The risk factors for OA are well known and include age, overweight/
obesity, underlying metabolic or endocrine disease, genetics, and joint trauma
(Lotz and Kraus 2010). Other forms of arthritis include psoriatic arthritis and
rheumatoid arthritis (RA), an autoimmune disease in which the body’s own
immune system attacks synovial joints. The risk factors for RA are sex, age, family
history, ethnic background, and smoking tobacco (Oliver and Silman 2009).
It is important to note that OA and RA are now considered to be systemic
disturbances. Although synovial joints are primarily affected in both arthritides,
these diseases can also wreak havoc in other organs. For example, in RA the
pancreas and the heart also undergo significant changes. Ultimately, the major
consequences of all forms of arthritis include disability, chronic pain, and signifi-
cant morbidity. Pain is a constant and daily feature in well-established forms of the
disease. Arthritis pain occurs due to the inflammation that occurs around and within
the joint. Disability in patients with arthritis is a consequence of degeneration in the
joint and surrounding tissues and is further enhanced by inflammation-induced
pain. Aside from analgesics, there are currently no effective pharmacotherapies
capable of restoring the structure and function of the damaged synovial tissues in
any form of arthritis.
Osteoarthritis (OA)
The incidence of age-related diseases is rising, seriously affecting the well-being of

millions of people around the globe. OA is one of the most prevalent and chronic
diseases affecting the elderly (Aigner et al. 2004). More than 20 million Americans
are estimated to have OA (http://www.niams.nih.gov). A 2005 study in the USA
estimated that OA is one of the top five causes of disability among nonhospitalized
adults (source: Centre for Disease Control (CDC), USA; http://www.cdc.gov/).
In 2006, it was estimated that around 35–40 million Europeans suffer from OA
and nearly 25 % of people aged 60 and above suffer from OA-induced disability. It
is also anticipated that by the year 2030, 20 % of adults will have developed
OA in Western Europe and North America. Therefore, OA is expected to
place a heavy economic burden on healthcare systems and community services
throughout the world.
OA is the most common form of joint disease, with the majority of the popula-
tion over 65 years of age demonstrating radiographic evidence of OA in at least one
joint. Although it is rare in people under 40, it becomes much more common with
age. The end-stage treatment for OA is surgery, either to modify or replace the joint.
With increasing life expectancy, growth in the elderly population, and an alarming
escalation of chronic, inflammatory, and age-related conditions (such as OA), there
is increased demand for new treatments and preventative approaches.
Although developing OA is a manifestation of aging, the disease may remain
latent and asymptomatic, taking many years to reach clinical relevance. OA is
not simply the common outcome of aging and joint injury; it is an active and
inflammatory joint disease. Symptoms and signs in the most frequently affected
joints include heat, swelling, pain, stiffness, and limited mobility. OA is often
a progressive and disabling disease, which occurs due to a variety of risk factors,
such as advancing age, obesity, and trauma (Abramson and Attur 2009).
Other sequelae include osteophyte formation and synovitis (Sutton et al. 2009).
These manifestations are highly variable, depending on joint location and disease
severity. OA can affect any synovial joint, but it primarily affects large load-
bearing joints such as the hip and knee. The disease is essentially due to daily
wear and tear of the joint. Its most prominent feature is the progressive destruction
of articular cartilage (Buckwalter et al. 2005). It is generally accepted that OA
begins in articular cartilage and eventually spreads to subchondral bone and other
synovial tissues. However, there is the opposing view that suggests OA is a disease
of subchondral bone and begins there. Despite the controversy regarding its
initiation, the current consensus is that OA is a disease involving not only articular
cartilage but also the synovial membrane, subchondral bone, and periarticular soft
tissues (Goldring and Goldring 2007). OA may occur following traumatic injury to
the joint, subsequent to an infection of the joint or simply as a result of aging and the
mechanical stresses associated with daily life.
The synovitis that occurs in both the early and late phases of OA is associated
with alterations in the adjacent cartilage – these changes are highly similar to those
seen in RA. Catabolic and proinflammatory mediators such as cytokines, nitric
oxide (NO), prostaglandin E2 (PGE2), and neuropeptides are produced by

the inflamed synovium which alter the balance of cartilage matrix degradation
and repair. These events lead to excess production of the proteolytic enzymes
responsible for cartilage breakdown (Sellam and Berenbaum 2010). Cartilage
alterations induce further synovial inflammation, creating a vicious circle. The
progressing synovitis will then exacerbate clinical symptoms and joint degradation
in OA (Sellam and Berenbaum 2010). Figure 133.1 outlines the major molecular
and cellular changes that occur in the synovial joint in OA and synovitis.
The management of OA primarily involves symptomatic pain relief with anal-
gesics such as nonsteroidal anti-inflammatory drugs (NSAIDs). However, pharma-
cotherapy with conventional drugs does not influence disease progression and can
be associated with significant side effects. Nutritional supplements have been
reported to improve symptoms and reduce NSAID usage but there is no conclusive
proof of efficacy. Nutraceuticals and food supplementation may serve as useful
adjuncts to OA therapy. A variety of nutritional supplements are produced and
marketed for consumption by OA patients. Some of these have been reported to
improve the symptoms of OA but no conclusive proof of efficacy for any nutritional
supplement has emerged to date.
ROS in Cartilage and OA
Chondrocytes exist in an avascular microenvironment, with low nutrient and

oxygen levels (Mobasheri et al. 2002, 2008). Although the majority of metabolic
functions in chondrocytes rely on glycolysis (Archer and Francis-West 2003), some
of the metabolic functions of these cells are oxygen-dependent (Henrotin and Kurz
2007; Henrotin et al. 2003). Oxygen is mainly supplied by diffusion from the
synovial fluid (Mobasheri et al. 2002; Pfander and Gelse 2007). Consequently,
the lack of oxygen means that chondrocytes display a metabolism adapted to
anaerobic conditions (Henrotin and Kurz 2007; Henrotin et al. 2003; Lafont
2010). There is little published information about the regulation of antioxidant
enzymes within cartilage. Equally little is known about the transport of antioxidants
from the circulation to chondrocytes. However, transport of nutrients, oxygen, and
antioxidants to chondrocytes is thought to occur by diffusion from subchondral
bone (Imhof et al. 2000) and the synovial microcirculation (Levick 1995). The role
of subchondral bone in the pathogenesis of cartilage damage has been
underestimated (Imhof et al. 2000). There is increasing evidence that vascular
pathology plays a role in the initiation and/or progression of OA (Findlay 2007).
In pathological conditions, oxygen tension in synovial fluid is subject to fluctuation
as blood flow may be reduced by venous occlusion and stasis, vascular shunt, and
fibrosis in synovium and/or by the development of microemboli in the subchondral
vessels (Findlay 2007). In response to oxygen variations induced through
ischemia/reperfusion injury, mechanical stress, immunomodulatory and inflamma-
tory mediators, chondrocytes produce abnormal levels of reactive oxygen species
(ROS) that are generally produced by immune cells (Henrotin et al. 1992; Henrotin
3004
e
membran
Synovial
INFLAMMATION
l fluid
ovia Degradative
Subchondral Syn products
bone and Macrophages
Articular Microcrystals
cartilage MMPs Fibroblasts
ROS
TNF-α T-cells
Synovial membrane Degradation and loss
of collagen II and lL-1β
glycosaminoglycan
Articular cartilage
Bone
Synovial fluid -Cartilage degradation

-Cartilage repair
subchondral
-Matrix mineralization Fibrillation of cartilage
bone formation
Osteoblast
IGF-1 TGF-β
uPA and IGF-1 PGE2
BP proteolysis lL-6
IGF-1
Osteoblast Osteophyte
Chondrocyte
apoptosis
Fig. 133.1 (continued)

A. Mobasheri et al.
and Kurz 2007; Henrotin et al. 2003). The main ROS produced by chondrocytes are
NO and superoxide anion that generate derivative radicals, including peroxynitrite
and hydrogen peroxide (H2O2) (Hiran et al. 1997, 1998). NO is synthesized by
nitric oxide synthase (NOS) enzymes. Chondrocytes express both endothelial
(eNOS) and inducible (iNOS) forms of the enzyme. NO production is stimulated
by cytokines (i.e., IL-1b, TNF-a), interferons (i.e., interferon g (IFN-g)), and
lipopolysaccharides (LPS). In contrast, NO production is inhibited by growth
factors such as transforming growth factor b (TGF-b). The enzyme complex
NADPH, which catalyzes the reduction of molecular oxygen to superoxide anion
radicals, produces superoxide anion radicals. Biochemical studies have shown that
chondrocytes express the large subunit of the flavocytochrome of NADPH oxidase
(Moulton et al. 1998) Even immortalized human chondrocyte-like cell lines express
various components of the NADPH oxidase complex (Moulton et al. 1997).
Articular chondrocytes also appear to express cell-specific components of
NADPH oxidase complex such as p22phox, p40phox, p47phox, p67phox, and
gp91phox (Moulton et al. 1998).
Responses to ROS generation are dependent on the cellular redox status. When
the oxidant level does not exceed the reducing capacities of cells, ROS are strongly
involved in the control of cellular functions including signal transduction.
In contrast, in some pathological situations, when the cellular antioxidant capacity
is insufficient to detoxify ROS, oxidative stress may occur degrading not only
cellular membranes and nucleic acids but also extracellular components including
proteoglycans and collagens. Furthermore, ROS can modify proteins by oxidation,
nitrosylation, nitration, or chlorination of specific amino acids, leading to impaired
biological activity, changes in protein structure, and accumulation of damaged
proteins in the tissue. A further point that needs to be made in connection with
oxidative stress is the fact that redox-sensitive transcription factors (e.g., NF-kB)
are upregulated, which might result in an uncontrolled inflammatory response.
Oxidative stress may also cause cell death and release of cellular contents into
Fig. 133.1 Summary of the major synovial, chondral, and subchondral changes observed in OA.
This schematic also highlights the actions of various white blood cells and inflammatory mediators
in OA. Chondral changes include cartilage fragmentation (fibrillation), cartilage degradation, and
loss of collagen type II and glycosaminoglycans, chondrocyte apoptosis (hypocellularity), and
matrix mineralization. Synovial membrane changes in OA include inflammation, synovial hyper-
trophy, recruitment and activation of T cells, macrophages and fibroblasts, production of matrix
metalloproteinases (MMPs), and reactive oxygen species (ROS). Synovial fluid alterations in OA
include accumulation of MMPs and ROS; release of IL-1b, TNF-a, and other proinflammatory
cytokines (IL-6, IL-8); release of inflammatory pain mediators such as prostaglandin E2 (PGE2);
and formation of degradative products and microcrystals. Subchondral alterations in OA include
subchondral sclerosis (i.e., eburnation), osteoblast-mediated subchondral bone formation, prote-
olysis (degradation) of IGF-I and IGF-I binding proteins, and increased production of some growth
factors and cytokines including transforming growth factor beta (TGF-b), PGE2, interleukin 6
(IL-6), and IGF-I
Fig. 133.2 Schematic representation of the major ROS involved in joint inflammation
(Reproduced with permission from OsteoArthritis and Cartilage (2003) 11, 747–755. # 2003
OsteoArthritis Research Society International. Published by Elsevier Ltd. (Henrotin et al. 2003))
the extracellular environment. Altogether, degradation products and cellular con-

tent containing oxidized molecules may contribute to the exacerbation of synovial
inflammation and form a vicious circle, constituted by newly formed ROS and
further degradation products (Fig. 133.2).
“Nutrigenomics” and “Nutritargeting” Treatments for OA
The interaction between the human body and nutrition is an extremely complex
process involving multiorgan physiology with molecular mechanisms on all
levels of regulation (genes, gene expression, proteins, metabolites) (Corthesy-
Theulaz et al. 2005). Gene expression is modulated by nutrients including
carbohydrates and fatty acids (Corthesy-Theulaz et al. 2005) as well as plant
polyphenols (Konstantinidou et al. 2010). The benefits associated with the con-
sumption of a traditional Mediterranean diet consisting of olive oil polyphenols
on cardiovascular risk have been shown to be mediated, although not exclusively,
through the direct effects of nutrients on genes – the so-called “nutrigenomic”
effects (Konstantinidou et al. 2010).
DNA – gene regulation, single

nucelotide polymorphisms (SNP’s),
transcription control, histone
interactions
RNA – translational control,

processing, stability, transport of
mRNA
FOOD HEALTH
COMPONENT EFFECT
Protein - receptor interactions,

signal transduction, gene
regulation, enzyme regulation,
protein inhibition, modification,
regulation of transport, channel
or pump interactions
Metabolite – multitudes of functions
Fig. 133.3 Nutrigenomics. The study of the effects of foods and food constituents on gene
expression
Nutrigenomics (see Fig. 133.3) is the study of the effects of foods and food
constituents on gene expression (van Ommen and Stierum 2002). This exciting field
of study has emerged because of the realization that the health effects of food-
derived substances start at the molecular level (van Ommen 2004; van Ommen and
Stierum 2002). Therefore, nutrigenomics is a form of personalized nutrition that
involves tailoring diets to an individual’s genetic makeup, considering genetic
variation, allergies, and intolerances (van Ommen 2007). The changes in gene
expression translate to changes in the proteome and metabolome and consequently
result in an altered metabolic state, which may have beneficial health effects. An
important aim of nutrigenomic research is defining the relationship between genes
and nutrients from basic biology to clinical states. We often overlook the fact that
nutrigenomics and systems biology apply the same set of tools and technologies. The
nutrigenomics approach extracts relevant differences, which become leads for further
hypothesis-driven and mechanistic research. The application of systems biology
approaches in nutritional research aims to describe the physiological responses of
culture models, experimental animals, and human subject by exploiting the datasets,
focusing on biochemical pathways, molecular targets for therapy, and potential
biomarkers.
In this nutrigenomic framework, the term “nutritargeting” can be applied.

Nutritargeting is defined as the targeting of a nutrient or nutrients to specific
“target” tissues and is analogous to the term “drug targeting” (Biesalski and
Tinz 2008). There is a good scientific rationale for this intuitive idea. Some tissues
are able to accumulate and utilize micronutrients selectively. For example, the
antioxidant vitamin C is selectively accumulated in astroglial cells in the brain
and in the lens (where it fulfils antioxidative and metabolic functions, facilitating
the formation of collagen structures) (Biesalski and Tinz 2008; Siegel et al. 1999).
Dehydroascorbic acid, the oxidized form of vitamin C, can enter the cell via the
glucose transporter GLUT1 (Troadec and Kaplan 2008). GLUT1 is expressed in
tissues as a consequence of low oxygen pressure leading to upregulation of HIF1-a
(a finding that is well documented in cancer cells (Airley and Mobasheri 2007).
These observations highlight the importance of vitamin C and its oxidized form
dehydroascorbate in clinical nutrition, particularly in critically ill patients
(Biesalski 2008; McGregor and Biesalski 2006).
Approximately 40 % of the body’s ascorbate is stored in skeletal muscle
because this tissue is relatively abundant and its cellular concentration is
tenfold higher than the plasma level. The concept of “nutritargeting” relates
to the gradual accumulation of micronutrients in target tissues using specific
“carriers” or removal of the main barriers to absorption and tissue accumulation.
For example, naturally occurring curcumin, which is poorly absorbed, exhibits
increased bioavailability when complexed with polysorbate (Y. Henrotin, per-
sonal communication). “Nutritargeting” may play an important role in the dis-
eases where either systemic absorption is not possible (e.g., malabsorption/
maldigestion) or where significant local deficits occur, which may not
adequately be supplied by the systemic application of that nutrient (Biesalski
and Tinz 2008).
One of the goals of nutrition research is to optimize health and prevent or delay
disease (van Ommen et al. 2009). Research that targets certain aspects of the
overarching drivers of health (metabolism, oxidation, inflammation, and stress
responses) may be instrumental in creating knowledge for maintaining health and
preventing disease through nutrition (van Ommen et al. 2009).
Chondrocyte Antioxidant Defenses
Chondrocytes are exquisitely sensitive to the effects of ROS, especially in

the growth plate (Fragonas et al. 1998). Thus, they need to have enzymatic and
nonenzymatic antioxidant defense systems to protect themselves. In the following
sections, we summarize the most relevant antioxidants relevant to the health
of chondrocytes in the synovial joint and then review the relevant literature that
claims to support their benefits in OA. The information published on
clinical trials of vitamins E and the combination product “ACE” is presented in
Tables 133.1 and 133.2 and captures details of several ongoing clinical trials
on vitamin D.
Vitamin C
Vitamin C (alternative names: ascorbic acid, dehydroascorbic acid) is a soluble

vitamin and a potent antioxidant. Vitamin C reacts with free radicals and acts as
a cofactor for hyroxylase enzymes in the synthesis of collagens in cartilage,
intervertebral disc, skin, tendons, ligaments, and blood vessels. Vitamin C is needed
for the growth and repair of tissues. It helps heal wounds and form scar tissue. It is
also needed for the repair and maintenance of cartilage, bones, and teeth. It also
promotes iron absorption. In humans, vitamin C must be ingested for health and
survival. Vitamin C is an electron donor, and this property accounts for all its
known functions. As an electron donor, vitamin C is a potent water-soluble
antioxidant in humans. Antioxidant effects of vitamin C have been demonstrated
in many experiments in vitro. In chondrocyte cultures, ascorbate has a general
anabolic effect. It stimulates and enhances matrix formation and assembly through
mechanisms other than its redox function.
A review of the biochemical functions of vitamin C is beyond the scope of this
chapter. We refer the readers to several comprehensive reviews on vitamin C and an
evaluation of its role in disease prevention (Englard and Seifter 1986; Padayatty
et al. 2003). The oxidized form of vitamin C dehydroascorbate is taken up by the
GLUT1 glucose transporter (Montel-Hagen et al. 2009). This has been reported in
many cell types including erythrocytes (May 1998), neurons (Castro et al. 2008),
glia (Astuya et al. 2005), leukocytes (Wolf 1996), osteoblasts (Wolf 1996),
and chondrocytes (Mobasheri et al. 2002). There is also evidence for the presence
of the sodium-dependent vitamin C transporter SVCT2 in chondrocytes
(McNulty et al. 2005b). Furthermore, dehydroascorbate transport in chondrocytes
is regulated by hypoxia and is a physiologically relevant source of ascorbic acid in
the joint (McNulty et al. 2005a). Clearly, vitamin C is an important antioxidant for
chondrocytes, which have multiple pathways for its uptake and subsequent cellular
accumulation and utilization.
There is evidence to suggest that systemic oxidative stress is associated
with reduced vitamin C levels. In critically ill patients, the rapid restoration of
depleted vitamin C levels with high-dose parenteral vitamin C has been proposed to
reduce circulatory shock and improve fluid homeostasis (McGregor and Biesalski
2006). However, high-dose intravenous vitamin C is not associated with an increase
of pro-oxidative biomarkers (Muhlhofer et al. 2004), and the impact of vitamin
C supplementation on oxidative stress-related diseases is moderate because of its
limited oral bioavailability and rapid clearance (McGregor and Biesalski 2006).
It is therefore possible to suggest that vitamin C supplementation could help
OA patients with other comorbidities.
Table 133.1 Completed clinical trials on the effects of antioxidant vitamins in arthritis. We refer the readers to a detailed systematic review of other
3010
antioxidants including ginger (Zingiber officinale), cat’s claw (Uncaria tomentosa, Uncaria guianensis), green tea (Camellia sinensis), and omega-3 fatty
acids by Rosenbaum and coworkers (Rosenbaum et al. 2010)
Description
of the Type and dose of Conclusion, limitations, and original
clinical trial antioxidant Patient demographics Primary outcome measures reference
A double- Vitamin E 500 IU/day 77 patients (men and women) aged The primary outcome measures were Conclusion: vitamin E shows no
blind, 40 years or more who fulfilled pain, stiffness, and function benefit for the management of
placebo- American Rheumatism Association dimensions as derived from symptomatic knee OA
controlled clinical diagnostic criteria 14 for WOMAC (Western Ontario and Reference: (Brand et al. 2001)
randomized knee OA and had radiographic McMaster Osteoarthritis Index)
trial evidence of osteophytes or joint
space narrowing were included
A double- Vitamin E 500 IU/day 136 patients with knee OA over 2 The primary outcome measure was Conclusion: vitamin E does not
blind, years change in knee cartilage volume appear to have a beneficial effect in
placebo- (measured by magnetic resonance the management of knee OA; it does
controlled imaging) not affect cartilage volume loss or
randomized symptoms
trial Reference: (Wluka et al. 2002)
A case- Vitamins E, C, and 40 patients newly diagnosed with The primary outcome was disease Conclusion: the study did not lead to
control trial A combined – the patients RA. Patients were randomly divided activity as measured by the a definite conclusion due to the
received a fixed-dose into two groups; one (n¼20) Rheumatoid Arthritis Disease limited number of cases included in
combination of vitamins received standard treatment Activity (RADA) Index (Stucki et al. this trial
A, E, and C (NSAIDs and steroids) and the other 1995) Limitations: the precise dose of
(n ¼ 20) received standard treatment antioxidants was not stated in the
plus a fixed-dose combination of the study. Patients received antioxidants
antioxidants vitamins A, E, and C. along with the conventional drugs
20 sex- and age-matched “normal for the same period
individuals” served as controls. Data Reference: (Jaswal et al. 2003)
were collected at baseline and after
12 weeks of treatment
A. Mobasheri et al.
Vitamin D
Vitamin D is a fat-soluble vitamin that is naturally present in very few foods. It is

added to foods and is available as a dietary supplement. It is produced in the skin
through the action of the sun’s ultraviolet rays. Vitamin D obtained from exposure
to the sun, food, and supplements is biologically inert and must undergo two
hydroxylations in the body for activation. The first of these reactions occurs in
the liver and converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known
as calcidiol. The second reaction occurs primarily in the kidney and forms the
physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as
calcitriol. Vitamin D is a membrane antioxidant (Wiseman 1993). Thus, far there
is just one completed clinical trial relating to vitamin D in OA (see Table 133.2).
The details of three ongoing clinical trials on vitamin D are also summarized in
Table 133.2.
Vitamin E
Vitamin E is a fat-soluble nutrient found in many foods. It plays an important role as

an antioxidant in lipid environments, helping to protect cells from the damage
caused by free radicals. It contributes to the integrity, stability, and function of
cellular membranes. There is, at present, no evidence to suggest that arthritis
patients are deficient in vitamin E. The role of vitamin E in preventing OA
progression is currently under investigation, but a double-blind, randomized, pla-
cebo-controlled study has suggested that vitamin E supplementation has no benefit
for the management of symptomatic relief of knee OA (Brand et al. 2001).
A subsequent 2-year double-blind, randomized, placebo-controlled study by the
same team concluded that vitamin E does not have a beneficial effect in the
management of knee OA and does not affect cartilage volume loss or symptoms
(Wluka et al. 2002) (see Table 133.1).
Vitamin A
Vitamin A is actually group of related compounds (carotenoids and retinoids) that

play an important role in maintaining vision, bone growth, reproduction, cell
division, and cell differentiation (Gerster 1997; Ross and Gardner 1994). Vitamin
A and related compounds have significant therapeutic utility and important roles in
the prevention of cancer and cardiovascular disease (Hinds et al. 1997). Vitamin
A also helps regulate the immune system (Semba 1998). There is significant interest
in vitamin A and diseases of bone and cartilage. However, a systematic review of
randomized clinical trials has revealed that there is presently no convincing evi-
dence that combinations of vitamin A, vitamin C, vitamin E, and selenium or the
combination product selenium ACE is effective in the treatment of any type of
arthritis (Canter et al. 2007) (see Table 133.1).
3012
Table 133.2 Ongoing clinical trials on the effects of antioxidant vitamins in arthritis. Further details may be obtained from ClinicalTrials.gov
(http://clinicaltrials.gov/ct2/home)
ClinicalTrials.gov identifier and Type and dose of Patient Primary outcome
brief description antioxidant demographics measures Secondary outcome measures Conclusion
NCT01176344 (http://clinicaltrials. 50,000 IU (1.25 mg) 400 individuals (men Loss of knee Progression of knee cartilage N/A
gov/ct2/show/NCT01176344? cholecalciferol capsules and women) aged cartilage volume defects; Loss of limb muscle
term¼NCT01176344&rank¼1) given once monthly 50–79 years strength; Enlargement of tibial
Randomized controlled trial bone area
NCT00306774 (http://clinicaltrials. Vitamin D – 2,000 IU 146 individuals (men Cartilage volume See website for extensive Completed: Low
gov/ct2/show/NCT00306774? per day for 2 years and women) aged loss (MRI); knee details Vitamin D levels
term¼NCT00306774&rank¼1) 45–90 years symptoms are associated
Double-blind, placebo-controlled (WOMAC Physical function; Quality of with greater pain
trial questionnaire) life; Pathological (MRI) and slow walking
severity global score speed in patients
with knee OA
NCT00599807 (http://clinicaltrials. Vitamin D – the study 287 community- Pain and function N/A
gov/ct2/show/NCT00599807? will compare 2,000 IU dwelling individuals of the operated
term¼NCT00599807&rank¼1) vitamin D3 per day to age 60 years or older and non-operated
2-year double-blind, randomized, 800 IU per day undergoing knee; rate of falls
controlled trial unilateral total knee
replacement due to
severe OA of the
knee
A. Mobasheri et al.
NCT01351805 (http://clinicaltrials. Vitamin D (in the form 20,000 men aged Prevention Interactions between the N/A
133
gov/ct2/show/NCT01351805? of vitamin D3 60 and women incident effects of vitamin D and those
term¼NCT01351805&rank¼1) [cholecalciferol]) aged 65 autoimmune of fish oils for each of the
NIH-funded, large, randomized, (2,000 IU a day) and diseases primary outcomes; safety of the
double-blind, placebo-controlled, marine omega-3 fatty Effects on supplements alone and in
2 2 factorial trial of “VITAL” acid (eicosapentaenoic biomarkers of combination for 5 years in an
acid [EPA] + systemic older American population
docosahexaenoic acid inflammation subgroup analyses: effects
[DHA]) supplements Effect upon according to age, effects in men
chronic frequent and women, effects in different
knee pain racial groups, and effects
according to body mass index
(BMI)
Antioxidants and Osteoarthritis
N/A not applicable – ongoing study

3013
Chondrocyte Antioxidant Defenses: Glutathione, Superoxide

Dismutase (SOD), Glutathione S-Transferase, Glutathione
Peroxidase, and Catalase
Glutathione or gamma-L-glutamyl-L-cysteinylglycine (GSH) is the main nonprotein

thiol found in cells. GSH is a critical antioxidant and is involved in diverse cellular
functions including apoptosis, disulfide bond formation, detoxification, antioxidant
defense, maintenance of thiol status, and modulation of cell proliferation.
Increased oxidative stress with aging reduces chondrocyte survival, and this
correlates with intracellular GSH levels (Carlo and Loeser 2003). Increased oxida-
tive stress makes chondrocytes much more susceptible to oxidant-mediated cell
death. This occurs through the dysregulation of the GSH antioxidant system (Carlo
and Loeser 2003). The reduction in the capacity of antioxidant buffering systems
such as GSH may represent an important contributing factor to the development of
OA in older adults (Carlo and Loeser 2003).
There have been a number of in vitro studies on GSH in chondrocytes.
N-acetylcysteine, a precursor of GSH, has been shown to protect growth plate
chondrocytes and temporomandibular joint chondrocytes from the effects of oxi-
dative stress in vitro (He et al. 2011; Ueno et al. 2011). N-acetylcysteine has been
shown to prevent NO-induced chondrocyte apoptosis and cartilage degeneration in
an experimental model of rabbit OA (Nakagawa et al. 2010). N-acetylcysteine
also activates extracellular signal-regulated kinase signalling pathway in articular
chondrocytes, which may provide a mechanism for the promotion of chondrocyte
survival by this thiol antioxidant (Li et al. 2000). When over-expressed, the
enzyme glutathione S-transferase can protect chondrocytes from the effects of
oxidative stress (Vaillancourt et al. 2008). GSH depletion and NO both decrease
insulin-like growth factor I (IGF-I) receptor function chondrocytes in vitro (Studer
2004). Insulin-like growth factor I (IGF-I) helps maintain healthy articular carti-
lage; however, arthritic cartilage becomes less responsive to the anabolic actions of
IGF-I. Thus, it is interesting that GSH depletion can reduce the responsiveness of
chondrocytes to this important anabolic growth factor.
ROS such as superoxide, hydrogen peroxide, and hydroxyl radical are typically
produced in mitochondria as electrons leak from the electron transport chain and
react with oxygen to form superoxide. It is estimated that 1–3 % of oxygen reduced
in cells may form superoxide in this way (Chakravarthi et al. 2006). Hydrogen
peroxide is formed from the dismutation of superoxide and by oxidases. These three
reactive species are controlled via multiple enzyme systems like superoxide
dismutase (SOD), catalase, glutathione S-transferase and thioredoxin. SOD
converts superoxide to hydrogen peroxide, which is then removed by glutathione
peroxidase or catalase and therefore has the capacity to prevent the formation
of highly aggressive ROS, such as peroxynitrite or the hydroxyl radical (Afonso
et al. 2007).
The production of hydrogen peroxide (H2O2) by inflammatory and synovial
cells is an important cause of cellular damage during joint inflammation. Effective
H2O2-metabolizing systems are important in the maintenance of normal
biosynthetic rates in cartilage during inflammation. In addition to the antioxidant

vitamins and GSH, chondrocyte antioxidant defenses include catalase, glutathione
S-transferase, and glutathione peroxidase. These enzymes afford protection against
H2O2-dependent inhibition of proteoglycan biosynthesis (Baker et al. 1988).
Immunohistochemical studies have identified superoxide dismutases, catalase,
and glutathione S-transferases in rat joints (Deahl et al. 1992). Interestingly, there
were no major age-related changes in antioxidant enzyme distribution in rat joints
(Deahl et al. 1992). Microinjection of antibodies against superoxide dismutase and
glutathione peroxidase has been shown to decrease their viability, whereas injection
of control (nonimmune) antibodies had no effect (Michiels et al. 1988). These
findings highlight the importance of glutathione peroxidase as an antioxidant and
the relative efficiency of SOD in the balance between free radical production and
the activity of the other antioxidant systems in chondrocytes.
“Nutritargeting” with Antioxidants in OA: Systematic Reviews

and Clinical Trials
Active and reactive oxygen species derived from various sources play a role in the
disease process. The reactive oxygen species (ROS) generated by cells within joints
can cause oxidative damage to various macromolecules and have been shown to
play a role in the pathogenesis of OA (Henrotin et al. 1992). The metabolism of
cells in articular joint tissues in normal and pathological conditions is subject to
complex environmental controls. In addition to soluble mediators such as cytokines
and growth factors, and physical factors such as mechanical stimuli, ROS emerge as
major factors in this regulation. ROS production has been found to increase in joint
diseases, such as OA and RA (Henrotin et al. 2003). In 2003, Henrotin and
coworkers reviewed the literature to examine role of ROS in cartilage homeostasis
and degradation in OA (Henrotin et al. 2003). They considered the role of NO,
peroxynitrite, and superoxide anion radicals in the signalling mechanisms impli-
cated in the main cellular functions of chondrocytes, (i.e., synthesis and degradation
of matrix components). The direct effects of ROS on cartilage matrix components
as well as their inflammatory and immunomodulatory effects were also considered.
This original literature review revealed that many intracellular signalling pathways
in chondrocytes are redox sensitive and ROS are not only deleterious agents
involved in cartilage degradation (i.e., by direct attack or indirectly by reducing
synthesis of matrix components, inducing apoptosis, or activating latent
metalloproteinases) but that they also act as integral factors of intracellular signal-
ling mechanisms. They concluded that antioxidant therapy could be helpful to treat
structural changes but not to relieve symptoms. Thus, the review of the literature
suggested that further investigation is required to support the concept of antioxidant
therapy in the management of OA (Henrotin et al. 2003). In 2007, the same group
reexamined the literature to determine and set out to determine if antioxidants can
be used to treat OA (Henrotin and Kurz 2007). Antioxidant supplements and drugs
with antioxidant properties have been developed to reinforce the cellular
antioxidant status. They concluded that there is no convincing evidence published

thus far to support the concept that supplemental antioxidants can relieve OA
symptoms or to prevent structural changes in OA cartilage.
Oxidative stress can promote cell senescence, and studies have shown a role for
oxidative stress in altering cell signalling pathways in chondrocytes that can disrupt
the response to growth factors (Loeser 2011). Free radical exposure is known to
promote cellular senescence and apoptosis, and ROS are thought to be involved in
inflammation, fibrosis control, and pain nociception (Ziskoven et al. 2011). The
relationship between oxidative stress and OA pathophysiology may provide a novel
approach for understanding and modifying disease progression and providing
symptom control (Ziskoven et al. 2011). Therefore, there is potential for diet to
lower the risk of developing OA. The arthritic disease process might be influenced
by appropriate treatment with antioxidants and free radical scavengers. Vitamin C,
vitamin E, and carotenoids are excellent antioxidants that protect cells from damage
by oxidants and whose blood concentrations are primarily determined by dietary
intake (Machlin and Bendich 1987). However, the fundamental question that needs
to be addressed is this: do antioxidants have the capacity to protect against the
development and progression of OA? If so, are the effects marginal, mild, or
moderate and can they be quantified? This question was addressed in part by
McAlindon and colleagues in an original study published in 1996 (McAlindon
et al. 1996). The authors examined usual dietary intake using the Food Frequency
Questionnaire in patients that participated in the Framingham Osteoarthritis Cohort
Study (patients that underwent knee evaluations by radiography between 1983 and
1993). The association of vitamin C, beta-carotene, and vitamin E intake, ranked in
sex-specific tertiles, with incidence and progression of OA was compared with that
of a panel of nonantioxidant vitamins, Bl, B6, niacin, and folate. The study found
no significant association of incident OA with any of the nutrients. A threefold
reduction in risk of OA progression was found for vitamin C intake. This related
predominantly to a reduced risk of cartilage loss. Patients with high vitamin
C intake also had a reduced risk of developing knee pain. A reduction in risk of
OA progression was also observed for beta-carotene and vitamin E but was
less consistent. No significant associations were observed for the nonantioxidant
nutrients. The study concluded that high intake of antioxidants, especially vitamin
C, may reduce the risk of cartilage loss and disease progression in human patients
with OA. Importantly, the study found no effect of antioxidant nutrients on incident
OA. Although these preliminary findings warrant further confirmation, they clearly
indicate that high levels of dietary antioxidants may help slow down disease
progression (see below).
There are more recent published studies that demonstrate pain reduction as
a consequence of moderate vitamin C intake, e.g., prior to joint prosthetic surgery
(Besse et al. 2009; Jaiman et al. 2011), arthroplasty (Zollinger et al. 2008), and the
development of complex regional pain syndrome. Furthermore, it has been pro-
posed that vitamin C as an antioxidant exerts antinociceptive effects (Kapoor 2012).
To elucidate whether vitamin C supplementation is protective against
OA development, Peregoy and Wilder carried out a longitudinal study
(from 1988 to 2010) in a large group of 1,023 participants initially free of radio-
graphic knee OA. Individuals without baseline OA who self-reported to use vitamin
C supplements were 11 % less likely to develop knee OA compared to those who
did not report vitamin C supplement usage (Peregoy and Wilder 2011). Although in
this prospective cohort study the authors found no evidence to support a protective
role for vitamin C in the progression of knee OA, after controlling for confounding
variables, their data suggests that vitamin C supplementation may be beneficial in
preventing incident knee OA (Peregoy and Wilder 2011).
Antioxidants in dietary foods may also lower the risk of OA development by
protecting against the subchondral bone changes associated with knee OA. A study
published by Australian researchers in Arthritis Research and Therapy in 2007
(Wang et al. 2007) demonstrated that middle-aged adults with higher dietary intake
of vitamin C were less likely to develop subchondral bone abnormalities associated
with developing OA. The authors recruited 293 healthy middle-aged men and
women with no OA pain at the study onset. The study participants were initially
asked to fill out a questionnaire about their diets. After 10 years, the participants
underwent knee magnetic resonance imaging (MRI), which suggested that higher
dietary levels of vitamin C correlated with lower risk of certain bone changes
10 years later. A higher dietary consumption of fresh fruit rich in antioxidants
correlated with lower risk of subchondral bone changes 10 years later. In addition,
the study found that certain carotenoids (i.e., lutein and zeaxanthin) in green
vegetables also correlated with a lower risk of cartilage defects (Wang et al.
2007). The authors suggest that fruit consumption and vitamin C intake
have beneficial effects as they are associated with a reduction in bone size and
the number of bone marrow lesions, both of which are important in the pathogenesis
of knee OA. They admit that their findings need to be confirmed by longitudinal
studies, but the study clearly highlights the potential for diet to modify the risk
of OA.
Canter and colleagues have systematically reviewed the evidence from random-
ized clinical trials (RCTs) for the effectiveness of the antioxidant vitamins
A, C, and E or selenium or their combination in the treatment of arthritis (Canter
et al. 2007). Their systematic review concluded that the clinical trials testing the
efficacy of vitamin E in the treatment of OA and inflammatory arthritis have been
methodologically weak and have produced contradictory findings. They suggest
that at present no convincing evidence exists that the combination product selenium
ACE is effective in the treatment of any type of arthritis (Canter et al. 2007).
In theory, antioxidants should protect cartilage and bone from accumulating
damage induced by oxidative stress. However, there may be other explanations for
this study’s findings. Individuals with diets rich in antioxidants may be otherwise
healthy, in ways, which could have a protective effect against OA. They may have
been lean and nonobese – obesity is a major risk factor for the development of OA
(Gabay et al. 2008; Griffin and Guilak 2008; Iannone and Lapadula 2010). Calorie
restriction, moderate exercise, and eating a healthy and balanced diet consisting
of a variety of fruits and vegetables may have provided protection against the
development of OA. Another argument in favor of antioxidant nutritargeting is
the possibility of intervention in cases where homoeostatic control mechanisms

have already been compromised. The connection between ROS, mitochondria,
metabolism, and inflammation is again relevant in this context, as malfunctioning
of this network is associated with many other chronic inflammatory diseases
(Tschopp 2011).
Hormetic Effects of Antioxidants: Implications for the

Prevention of Inflammatory Disease
An important property of living cells is their capacity to respond to stress. In this

context, “oxidative stress” generated by physical, chemical, or biological factors
initiates a series of homeostatic responses in order to counteract, adapt, and survive.
While successful and compensatory responses to low doses of stressors improve the
overall physiological responses of cells, tissues, and organs, an incomplete or failed
response may lead to the damaging and harmful effects of stress, including death.
Therefore, the novel idea has emerged that if biological systems are intentionally
exposed to mild and acute periods of stress, their physiological pathways of
maintenance and repair are appropriately challenged, activating responses
that should lead to achieving beneficial effects, including activation of repair and
longevity-promoting factors. A recent paper makes the radical suggestion that ROS
act as essential signalling molecules to promote metabolic health and longevity
(Ristow and Schmeisser 2011). Ristow and coworkers have proposed that various
nutritional, behavioral, and pharmacological interventions aimed at promoting
longevity may converge by causing an activation of mitochondrial oxygen con-
sumption to promote increased formation of ROS. These serve as molecular signals
to exert downstream effects to ultimately induce endogenous defense mechanisms
culminating in increased stress resistance and longevity, an adaptive response more
specifically named mitochondrial hormesis or mitohormesis (Ristow and
Schmeisser 2011). This concept is new and controversial, but it fits well with the
idea that exposure to mild forms of stress and low levels of ROS may be protective.
In the sixteenth century, the Swiss chemist and physician Paracelsus
(http://en.wikipedia.org/wiki/Paracelsus) wrote: “All things are poison and nothing
is without poison, only the dose permits something not to be poisonous.” This is
a fundamental concept that applies to almost all drugs that are derived from plants
and microorganisms including various treatments for infections, cancers, and pain.
Even synthetic drugs thought to act on a specific molecular target may exert
“off-target” or “hormetic” effects. Toxicologists use the term “hormesis” to describe
a biphasic dose response to an environmental agent or chemical characterized by
stimulation or beneficial effects at low doses or toxic and inhibitory effects at high
doses. The response of the cell or organism to the low dose of the toxin is considered
an adaptive compensatory process following an initial disruption in homeostasis.
Thus, a short working definition of hormesis is “a process in which exposure to a low
dose of a chemical agent or environmental factor that is damaging at higher doses
induces an adaptive beneficial effect on the cell or organism.” The prevalence in the
DIETARY INTAKE
DRUG INTAKE Vitamin E
NSAIDs Vitamin C
Anthraquinone Selenium
ASU Carotenoids
GS ASU
CS Polyphenols
Oxidative
INTRAARTICULAR Stress
INJECTION
SOD
HA
CS/HA ØAntioxidants
Corticosteroids ≠ROS
Fig. 133.4 The contribution of dietary factors, drugs, nutraceuticals, and intra-articular injections
to the oxidative status of articular cartilage and the perturbed balance between ROS and antiox-
idants in OA. Abbreviations ASU avocado soybean unsaponifiables, CS chondroitin sulfate, GS
glucosamine sulfate, HA hyaluronic acid, NSAIDs nonsteroidal anti-inflammatory drugs, SOD
superoxide dismutase
literature of hormetic dose responses to environmental toxins has been reviewed

comprehensively (Calabrese and Blain 2005), as have the implications of toxin-
mediated hormesis for understanding carcinogenesis and its prevention (Calabrese
2005). Several different terms are commonly used to describe specific types of
hormetic responses including “preconditioning” and “adaptive stress response.”
Hormesis in aging is defined as the life-supporting beneficial effects resulting from
the cellular responses to single or multiple rounds of mild stress. Thus, hormesis may
also have the capacity to modify the aging process (Rattan 2008). The dose–response
relationships for medical agents commonly display the same hormetic dose–response
relationships as their toxic counterparts. Many agents, such as antibacterials, anti-
fungals, antivirals, and tumor-fighting drugs, display hormetic dose responses. Recent
studies have also demonstrated that curcumin (diferuloylmethane) exerts hormetic
effects at the cellular and molecular levels in mammalian cells (Rattan and Ali 2007).
Conclusions
Researchers and clinicians are striving for novel, innovative treatment options for
OA. There is a growing interest in using antioxidant vitamins and naturally occur-
ring phytochemical products for the prevention and treatment of arthritic diseases
characterized by oxidative stress. Figure 133.4 summarizes the contribution of
dietary factors, drugs, nutraceuticals, and intra-articular injections to the oxidative
status of articular cartilage and the perturbed balance between ROS and antioxi-
dants in OA. Although this is a relatively new area of research, good evidence exists
for the beneficial effects of vitamin C and vitamin E. The area of phytochemicals is
much more controversial due to the problems associated with poor intestinal
absorption and bioavailability of natural products. The beneficial and detrimental
effects of polyphenols such as curcumin and resveratrol, discussed in detail in one
of our recent review articles (Henrotin et al. 2010), appear to be more pronounced
in vitro than in vivo due to the higher concentrations which can be achieved in vitro
(Rahman et al. 2006). This is likely due to poor bioavailability and absorption
following oral ingestion. Furthermore, interactions between various polyphenols
and other food additives require comprehensive analysis to ensure that the
effects of a single compound observed in vitro are in fact transferrable to the
in vivo situation when other compounds are present. Therefore, the use of antiox-
idants and phytochemicals as therapeutic agents for arthritic diseases requires
rigorous pharmacokinetic and toxicity studies, as well as clinical verification of
results obtained in vitro. Nevertheless, this is an exciting new area of research,
which holds much potential for the prevention and treatment of OA and other
arthritic diseases.
The excess formation of nitric oxide (NO) has been implicated in the develop-
ment of OA and is thought to be responsible for triggering chondrocyte apoptosis
and matrix destruction (Abramson 2008; Amin and Abramson 1998; Goggs et al.
2003; Mobasheri 2002). However, the validity of the long-held view that
“too much NO” is contributing to disease progression has recently been challenged
(Feelisch 2008). One of the conceptual difficulties that may prevent
us from developing new treatments for OA is our incomplete understanding
of the molecular pathogenesis of OA. Clearly inflammatory diseases are character-
ized by a shift to superoxide-dominated chemistries that trigger changes
in thiol-dependent redox signalling, hypoxia-induced gene expression, and mito-
chondrial dysfunction (Feelisch 2008). Therefore, the idea of using dietary antiox-
idants remains rational and realistic.
Although the majority of the European population enjoy a healthy and balanced
diet, the rise in obesity and insulin resistance is a major concern, especially in
relation to the incidence of OA and the rise in metabolic syndrome. At the present
time, there are few defined European groups with antioxidant and micronutrient
deficiencies (Biesalski et al. 2003). However, there is not enough information about
antioxidant levels in patients with various forms of arthritis. It is conceivable that
deficiencies in vitamins (i.e., vitamin C) may facilitate disease progression or
exacerbate the disease. New research and relevant data is needed to define potential
risk groups before any intervention with supplements can be justified. It is worth
noting that many of the clinical trials testing the efficacy of antioxidant vitamins in
the treatment of OA and inflammatory arthritis have been fundamentally weak and
have produced contradictory findings. Systematic reviews that have revealed these
limitations utilize explicit methods that limit bias in identifying and rejecting
studies. Conclusions drawn from such reviews are thought to be more reliable
and accurate because of the methods used, and large amounts of information can be
assimilated quickly reducing the delay between making research discoveries and
the implementation of effective remedies. However, systematic reviews have
important and significant flaws. They assume that the studies reviewed and the
data they contain are all valid; bad studies may be included, the data summarized
may not be homogeneous, and grouping different causal factors may lead to
meaningless estimates of effects. Nevertheless, systematic reviews have not pro-
vided convincing evidence supporting the use of combination supplements for the
treatment of any type of arthritis – the evidence available thus far cannot recom-
mend use of vitamin E alone or vitamins A, C, and E in combination (Rosenbaum
et al. 2010). Whether any of these antioxidant supplements can be effectively and
safely recommended to reduce NSAID or steroid usage remains unclear based on
currently published literature (Rosenbaum et al. 2010).
Antioxidant vitamins have major roles in modulating oxidative stress, partici-
pating in immune responses, and contributing to cell differentiation. There is
a pressing need to understand their contribution to OA, because they may provide
important insight into ameliorating the initiation and progression of the disease.
Animal models commonly used for the study of OA are inappropriate because most
animals can synthesize vitamin C. The disease itself is extremely heterogeneous,
and there is a need to define the numerous subsets of OA and the processes that
contribute to that heterogeneity. There is a fundamental problem associated with
the use of antioxidants for the treatment of OA; our diet is not able to separate
antioxidant vitamins into independent entities (Sowers and Lachance 1999). Many
fruits and vegetables are sources of vitamins C and A. Clearly a healthy and
balanced diet is unlikely to require supplementation with these vitamins. However,
individuals with gastrointestinal disease or malabsorption syndromes may be at risk
of having a deficiency in their antioxidant system, but clearly there are huge
variations and complexities that deny scientists the opportunity to advance our
understanding of the role of diet and disease processes in OA. For the present time,
these problems prevent us from determining whether supplementation with antiox-
idants is a real opportunity or a myth. Ambiguous results from systematic reviews
and meta-analyses or failure of human clinical trials can make matters worse.
However, there is still potential for doing high-quality basic research in this area
although subsequent clinical studies will need to select more homogeneous patient
populations with a risk of developing OA rather than large cohorts of patients with
the full-blown disease. More high-quality research is needed, but this area will
remain controversial if there is substantial commercial involvement in research and
in influencing publications.
Acknowledgments A. Mobasheri wishes to acknowledge the generous financial support of the

Wellcome Trust, the National Centre for the Replacement, Refinement and Reduction of Animals
in Research (NC3Rs) (grant number: Mobasheri.A.28102007), the Biotechnology and Biological
Sciences Research Council (BBSRC) (grants BBSRC/S/M/2006/13141 and BB/G018030/1), and
the Engineering and Physical Sciences Research Council (EPSRC).
Conflict of Interest Statement

This chapter was written by the authors within the scope of their academic and research positions
at their host institutions. None of the authors has a financial or personal relationship with other
people or organizations that could inappropriately influence or bias the content of this chapter.
References
Abramson SB (2008) Osteoarthritis and nitric oxide. Osteoarthr Cartil 16(Suppl 2):S15–S20
Abramson SB, Attur M (2009) Developments in the scientific understanding of osteoarthritis.
Arthritis Res Ther 11:227
Afonso V, Champy R, Mitrovic D, Collin P, Lomri A (2007) Reactive oxygen species and
superoxide dismutases: role in joint diseases. Joint Bone Spine 74:324–329
Aigner T, Rose J, Martin J, Buckwalter J (2004) Aging theories of primary osteoarthritis: from
epidemiology to molecular biology. Rejuvenation Res 7:134–145
Airley RE, Mobasheri A (2007) Hypoxic regulation of glucose transport, anaerobic metabolism
and angiogenesis in cancer: novel pathways and targets for anticancer therapeutics. Chemo-
therapy 53:233–256
Amin AR, Abramson SB (1998) The role of nitric oxide in articular cartilage breakdown in
osteoarthritis. Curr Opin Rheumatol 10:263–268
Archer CW, Francis-West P (2003) The chondrocyte. Int J Biochem Cell Biol 35:401–404
Astuya A, Caprile T, Castro M, Salazar K, Garcia Mde L, Reinicke K, Rodriguez F, Vera JC,
Millan C, Ulloa V, Low M, Martinez F, Nualart F (2005) Vitamin C uptake and recycling among
normal and tumor cells from the central nervous system. J Neurosci Res 79:146–156
Baker MS, Feigan J, Lowther DA (1988) Chondrocyte antioxidant defences: the roles of catalase
and glutathione peroxidase in protection against H2O2 dependent inhibition of proteoglycan
biosynthesis. J Rheumatol 15:670–677
Besse JL, Gadeyne S, Galand-Desme S, Lerat JL, Moyen B (2009) Effect of vitamin C on
prevention of complex regional pain syndrome type I in foot and ankle surgery. Foot Ankle
Surg 15:179–182
Biesalski HK (2008) Parenteral ascorbic acid as a key for regulating microcirculation in critically
ill. Crit Care Med 36:2466–2468
Biesalski HK, Brummer RJ, Konig J, O’Connell MA, Ovesen L, Rechkemmer G, Stos K,
Thurnham DI (2003) Micronutrient deficiencies. Hohenheim consensus conference.
Eur J Nutr 42:353–363
Biesalski HK, Tinz J (2008) Nutritargeting. Adv Food Nutr Res 54:179–217
Blanco FJ, Lopez-Armada MJ, Maneiro E (2004) Mitochondrial dysfunction in osteoarthritis.
Mitochondrion 4:715–728
Blanco FJ, Rego I, Ruiz-Romero C (2011) The role of mitochondria in osteoarthritis. Nat Rev
Rheumatol 7:161–169
Brand C, Snaddon J, Bailey M, Cicuttini F (2001) Vitamin E is ineffective for symptomatic relief
of knee osteoarthritis: a six month double blind, randomised, placebo controlled study. Ann
Rheum Dis 60:946–949
Buckwalter JA, Mankin HJ, Grodzinsky AJ (2005) Articular cartilage and osteoarthritis. Instr
Course Lect 54:465–480
Calabrese EJ (2005) Cancer biology and hormesis: human tumor cell lines commonly display
hormetic (biphasic) dose responses. Crit Rev Toxicol 35:463–582
Calabrese EJ, Blain R (2005) The occurrence of hormetic dose responses in the toxicological
literature, the hormesis database: an overview. Toxicol Appl Pharmacol 202:289–301
Canter PH, Wider B, Ernst E (2007) The antioxidant vitamins A, C, E and selenium in the
treatment of arthritis: a systematic review of randomized clinical trials. Rheumatology
(Oxford) 46:1223–1233
Carames B, Taniguchi N, Otsuki S, Blanco FJ, Lotz M (2010) Autophagy is a protective mech-
anism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis.
Arthritis Rheum 62:791–801
Carlo MD Jr, Loeser RF (2003) Increased oxidative stress with aging reduces chondrocyte
survival: correlation with intracellular glutathione levels. Arthritis Rheum 48:3419–3430
Castro MA, Angulo C, Brauchi S, Nualart F, Concha II (2008) Ascorbic acid participates in
a general mechanism for concerted glucose transport inhibition and lactate transport stimula-
tion. Pflugers Arch 457:519–528
Chakravarthi S, Jessop CE, Bulleid NJ (2006) The role of glutathione in disulphide bond formation
and endoplasmic-reticulum-generated oxidative stress. EMBO Rep 7:271–275
Corthesy-Theulaz I, den Dunnen JT, Ferre P, Geurts JM, Muller M, van Belzen N, van Ommen
B (2005) Nutrigenomics: the impact of biomics technology on nutrition research. Ann Nutr
Metab 49:355–365
Deahl ST 2nd, Oberley LW, Oberley TD, Elwell JH (1992) Immunohistochemical identification of
superoxide dismutases, catalase, and glutathione-S-transferases in rat femora. J Bone Miner
Res 7:187–198
Di Paola R, Cuzzocrea S (2008) Predictivity and sensitivity of animal models of arthritis.
Autoimmun Rev 8:73–75
Englard S, Seifter S (1986) The biochemical functions of ascorbic acid. Annu Rev Nutr 6:365–406
Feelisch M (2008) The chemical biology of nitric oxide – an outsider’s reflections about its role in
osteoarthritis. Osteoarthr Cartil 16(Suppl 2):S3–S13
Findlay DM (2007) Vascular pathology and osteoarthritis. Rheumatology (Oxford) 46:1763–1768
Fragonas E, Pollesello P, Mlinarik V, Toffanin R, Grando C, Godeas C, Vittur F (1998) Sensitivity
of chondrocytes of growing cartilage to reactive oxygen species. Biochim Biophys Acta
1425:103–111
Gabay O, Hall DJ, Berenbaum F, Henrotin Y, Sanchez C (2008) Osteoarthritis and obesity:
experimental models. Joint Bone Spine 75:675–679
Gerster H (1997) Vitamin A – functions, dietary requirements and safety in humans. Int J Vitam
Nutr Res 67:71–90
Gloire G, Legrand-Poels S, Piette J (2006) NF-kappaB activation by reactive oxygen species:
fifteen years later. Biochem Pharmacol 72:1493–1505
Goggs R, Carter SD, Schulze-Tanzil G, Shakibaei M, Mobasheri A (2003) Apoptosis and the loss
of chondrocyte survival signals contribute to articular cartilage degradation in osteoarthritis.
Vet J 166:140–158
Goldring MB, Goldring SR (2007) Osteoarthritis. J Cell Physiol 213:626–634
Griffin TM, Guilak F (2008) Why is obesity associated with osteoarthritis? Insights from mouse
models of obesity. Biorheology 45:387–398
He SJ, Hou JF, Dai YY, Zhou ZL, Deng YF (2011) N-acetyl-cysteine protects chicken
growth plate chondrocytes from T-2 toxin-induced oxidative stress. J Appl Toxicol 32(12):
980–985
Henrotin Y, Kurz B (2007) Antioxidant to treat osteoarthritis: dream or reality? Curr Drug Targets
8:347–357
Henrotin Y, Deby-Dupont G, Deby C, Franchimont P, Emerit I (1992) Active oxygen species,
articular inflammation and cartilage damage. EXS 62:308–322
Henrotin YE, Bruckner P, Pujol JP (2003) The role of reactive oxygen species in homeostasis and
degradation of cartilage. Osteoarthr Cartil 11:747–755
Henrotin Y, Clutterbuck AL, Allaway D, Lodwig EM, Harris P, Mathy-Hartert M, Shakibaei M,
Mobasheri A (2010) Biological actions of curcumin on articular chondrocytes. Osteoarthr
Cartil 18:141–149
Hinds TS, West WL, Knight EM (1997) Carotenoids and retinoids: a review of research, clinical,
and public health applications. J Clin Pharmacol 37:551–558
Hiran TS, Moulton PJ, Hancock JT (1997) Detection of superoxide and NADPH oxidase in
porcine articular chondrocytes. Free Radic Biol Med 23:736–743
Hiran TS, Moulton PJ, Hancock JT (1998) In situ detection of superoxide anions within porcine
articular cartilage. Br J Biomed Sci 55:199–203
Iannone F, Lapadula G (2010) Obesity and inflammation – targets for OA therapy. Curr Drug
Targets 11:586–598
Imhof H, Sulzbacher I, Grampp S, Czerny C, Youssefzadeh S, Kainberger F (2000) Subchondral
bone and cartilage disease: a rediscovered functional unit. Invest Radiol 35:581–588
Jaiman A, Lokesh M, Neogi DS (2011) Effect of vitamin C on prevention of complex regional pain
syndrome type I in foot and ankle surgery. Foot Ankle Surg 17:207
Jaswal S, Mehta HC, Sood AK, Kaur J (2003) Antioxidant status in rheumatoid arthritis and role of
antioxidant therapy. Clin Chim Acta 338:123–129
Jha P, Flather M, Lonn E, Farkouh M, Yusuf S (1995) The antioxidant vitamins and cardiovascular
disease. A critical review of epidemiologic and clinical trial data. Ann Intern Med
123:860–872
Kapoor S (2012) Vitamin C and its emerging role in pain management: beneficial effects in pain
conditions besides post herpetic neuralgia. Korean J Pain 25:200–201
Konstantinidou V, Covas MI, Munoz-Aguayo D, Khymenets O, de la Torre R, Saez G, Tormos
Mdel C, Toledo E, Marti A, Ruiz-Gutierrez V, Ruiz Mendez MV, Fito M (2010) In vivo
nutrigenomic effects of virgin olive oil polyphenols within the frame of the Mediterranean diet:
a randomized controlled trial. FASEB J 24:2546–2557
Lafont JE (2010) Lack of oxygen in articular cartilage: consequences for chondrocyte biology. Int
J Exp Pathol 91:99–106
Levick JR (1995) Microvascular architecture and exchange in synovial joints. Microcirculation
2:217–233
Li WQ, Dehnade F, Zafarullah M (2000) Thiol antioxidant, N-acetylcysteine, activates extracel-
lular signal-regulated kinase signaling pathway in articular chondrocytes. Biochem Biophys
Res Commun 275:789–794
Loeser RF (2011) Aging and osteoarthritis. Curr Opin Rheumatol 23:492–496
Lotz MK, Kraus VB (2010) New developments in osteoarthritis. Posttraumatic osteoarthritis:
pathogenesis and pharmacological treatment options. Arthritis Res Ther 12:211
Machlin LJ, Bendich A (1987) Free radical tissue damage: protective role of antioxidant nutrients.
FASEB J 1:441–445
May JM (1998) Ascorbate function and metabolism in the human erythrocyte. Front Biosci 3:
d1–d10
McAlindon TE, Jacques P, Zhang Y, Hannan MT, Aliabadi P, Weissman B, Rush D, Levy D,
Felson DT (1996) Do antioxidant micronutrients protect against the development and progres-
sion of knee osteoarthritis? Arthritis Rheum 39:648–656
McGregor GP, Biesalski HK (2006) Rationale and impact of vitamin C in clinical nutrition. Curr
Opin Clin Nutr Metab Care 9:697–703
McNulty AL, Stabler TV, Vail TP, McDaniel GE, Kraus VB (2005a) Dehydroascorbate transport
in human chondrocytes is regulated by hypoxia and is a physiologically relevant source of
ascorbic acid in the joint. Arthritis Rheum 52:2676–2685
McNulty AL, Vail TP, Kraus VB (2005b) Chondrocyte transport and concentration of ascorbic
acid is mediated by SVCT2. Biochim Biophys Acta 1712:212–221
Meister A (1994a) Glutathione-ascorbic acid antioxidant system in animals. J Biol Chem
269:9397–9400
Meister A (1994b) Glutathione, ascorbate, and cellular protection. Cancer Res 54:1969s–1975s
Michiels C, Raes M, Zachary MD, Delaive E, Remacle J (1988) Microinjection of antibodies
against superoxide dismutase and glutathione peroxidase. Exp Cell Res 179:581–589
Mobasheri A (2002) Role of chondrocyte death and hypocellularity in ageing human articular
cartilage and the pathogenesis of osteoarthritis. Med Hypotheses 58:193–197
Mobasheri A, Vannucci SJ, Bondy CA, Carter SD, Innes JF, Arteaga MF, Trujillo E, Ferraz I,
Shakibaei M, Martin-Vasallo P (2002) Glucose transport and metabolism in chondrocytes:
a key to understanding chondrogenesis, skeletal development and cartilage degradation in

osteoarthritis. Histol Histopathol 17:1239–1267
Mobasheri A, Bondy CA, Moley K, Mendes AF, Rosa SC, Richardson SM, Hoyland JA, Barrett-
Jolley R, Shakibaei M (2008) Facilitative glucose transporters in articular chondrocytes.
Expression, distribution and functional regulation of GLUT isoforms by hypoxia, hypoxia
mimetics, growth factors and pro-inflammatory cytokines. Adv Anat Embryol Cell Biol
200(1):1–84
Montel-Hagen A, Sitbon M, Taylor N (2009) Erythroid glucose transporters. Curr Opin Hematol
16:165–172
Moulton PJ, Hiran TS, Goldring MB, Hancock JT (1997) Detection of protein and mRNA of
various components of the NADPH oxidase complex in an immortalized human chondrocyte
line. Br J Rheumatol 36:522–529
Moulton PJ, Goldring MB, Hancock JT (1998) NADPH oxidase of chondrocytes contains an
isoform of the gp91phox subunit. Biochem J 329(Pt 3):449–451
Muhlhofer A, Mrosek S, Schlegel B, Trommer W, Rozario F, Bohles H, Schremmer D, Zoller
WG, Biesalski HK (2004) High-dose intravenous vitamin C is not associated with an increase
of pro-oxidative biomarkers. Eur J Clin Nutr 58:1151–1158
Nakagawa S, Arai Y, Mazda O, Kishida T, Takahashi KA, Sakao K, Saito M, Honjo K, Imanishi J,
Kubo T (2010) N-acetylcysteine prevents nitric oxide-induced chondrocyte apoptosis and
cartilage degeneration in an experimental model of osteoarthritis. J Orthop Res 28:156–163
Ogura Y, Sutterwala FS, Flavell RA (2006) The inflammasome: first line of the immune response
to cell stress. Cell 126:659–662
Oliver JE, Silman AJ (2009) What epidemiology has told us about risk factors and
aetiopathogenesis in rheumatic diseases. Arthritis Res Ther 11:223
Padayatty SJ, Katz A, Wang Y, Eck P, Kwon O, Lee JH, Chen S, Corpe C, Dutta A, Dutta SK,
Levine M (2003) Vitamin C as an antioxidant: evaluation of its role in disease prevention.
J Am Coll Nutr 22:18–35
Parke DV, Sapota A (1996) Chemical toxicity and reactive oxygen species. Int J Occup Med
Environ Health 9:331–340
Peregoy J, Wilder FV (2011) The effects of vitamin C supplementation on incident and progres-
sive knee osteoarthritis: a longitudinal study. Public Health Nutr 14:709–715
Pfander D, Gelse K (2007) Hypoxia and osteoarthritis: how chondrocytes survive hypoxic
environments. Curr Opin Rheumatol 19:457–462
Rahman I, Biswas SK, Kirkham PA (2006) Regulation of inflammation and redox signaling by
dietary polyphenols. Biochem Pharmacol 72:1439–1452
Rattan SI (2008) Hormesis in aging. Ageing Res Rev 7:63–78
Rattan SI, Ali RE (2007) Hormetic prevention of molecular damage during cellular aging of
human skin fibroblasts and keratinocytes. Ann N Y Acad Sci 1100:424–430
Ristow M, Schmeisser S (2011) Extending life span by increasing oxidative stress. Free Radic Biol
Med 51:327–336
Rosenbaum CC, O’Mathuna DP, Chavez M, Shields K (2010) Antioxidants and antiinflammatory
dietary supplements for osteoarthritis and rheumatoid arthritis. Altern Ther Health Med
16:32–40
Ross AC, Gardner EM (1994) The function of vitamin A in cellular growth and differentiation, and
its roles during pregnancy and lactation. Adv Exp Med Biol 352:187–200
Schreck R, Rieber P, Baeuerle PA (1991) Reactive oxygen intermediates as apparently widely
used messengers in the activation of the NF-kappa B transcription factor and HIV-1.
EMBO J 10:2247–2258
Sellam J, Berenbaum F (2010) The role of synovitis in pathophysiology and clinical symptoms of
osteoarthritis. Nat Rev Rheumatol 6:625–635
Semba RD (1998) The role of vitamin A and related retinoids in immune function. Nutr Rev 56:
S38–S48
Siegel GJ, Agranoff BW, Albers RW et al. (eds) (1999) Basic neurochemistry: molecular, cellular
and medical aspects, 6th edn. Lippincott-Raven, Philadelphia.
Sowers M, Lachance L (1999) Vitamins and arthritis. The roles of vitamins A, C, D, and E. Rheum
Dis Clin North Am 25:315–332
Stucki G, Liang MH, Stucki S, Bruhlmann P, Michel BA (1995) A self-administered
rheumatoid arthritis disease activity index (RADAI) for epidemiologic research.
Psychometric properties and correlation with parameters of disease activity. Arthritis Rheum
38:795–798
Studer RK (2004) Nitric oxide decreases IGF-1 receptor function in vitro; glutathione depletion
enhances this effect in vivo. Osteoarthr Cartil 12:863–869
Sutton S, Clutterbuck A, Harris P, Gent T, Freeman S, Foster N, Barrett-Jolley R,
Mobasheri A (2009) The contribution of the synovium, synovial derived inflammatory
cytokines and neuropeptides to the pathogenesis of osteoarthritis. Vet J 179:10–24
Terkeltaub R, Johnson K, Murphy A, Ghosh S (2002) Invited review: the mitochondrion in
osteoarthritis. Mitochondrion 1:301–319
Troadec MB, Kaplan J (2008) Some vertebrates go with the GLO. Cell 132:921–922
Tschopp J (2011) Mitochondria: sovereign of inflammation? Eur J Immunol 41:1196–1202
Ueno T, Yamada M, Sugita Y, Ogawa T (2011) N-acetyl cysteine protects TMJ chondrocytes from
oxidative stress. J Dent Res 90:353–359
Vaillancourt F, Fahmi H, Shi Q, Lavigne P, Ranger P, Fernandes JC, Benderdour M (2008)
4-Hydroxynonenal induces apoptosis in human osteoarthritic chondrocytes: the protective role
of glutathione-S-transferase. Arthritis Res Ther 10:R107
van Ommen B (2004) Nutrigenomics: exploiting systems biology in the nutrition and health
arenas. Nutrition 20:4–8
van Ommen B (2007) Personalized nutrition from a health perspective: luxury or necessity? Genes
Nutr 2:3–4
van Ommen B, Stierum R (2002) Nutrigenomics: exploiting systems biology in the nutrition and
health arena. Curr Opin Biotechnol 13:517–521
van Ommen B, Keijer J, Heil SG, Kaput J (2009) Challenging homeostasis to define biomarkers
for nutrition related health. Mol Nutr Food Res 53:795–804
Wang Y, Hodge AM, Wluka AE, English DR, Giles GG, O’Sullivan R, Forbes A, Cicuttini FM
(2007) Effect of antioxidants on knee cartilage and bone in healthy, middle-aged subjects:
a cross-sectional study. Arthritis Res Ther 9:R66
Wiseman H (1993) Vitamin D is a membrane antioxidant. Ability to inhibit iron-dependent lipid
peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to
anticancer action. FEBS Lett 326:285–288
Wluka AE, Stuckey S, Brand C, Cicuttini FM (2002) Supplementary vitamin E does not affect the
loss of cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo
controlled study. J Rheumatol 29:2585–2591
Wolf G (1996) The mechanism of uptake of ascorbic acid into osteoblasts and leukocytes. Nutr
Rev 54:150–152
Woolf AD, Pfleger B (2003) Burden of major musculoskeletal conditions. Bull World Health
Organ 81:646–656
Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome
activation. Nature 469:221–225
Ziskoven C, Jager M, Kircher J, Patzer T, Bloch W, Brixius K, Krauspe R (2011) Physiology and
pathophysiology of nitrosative and oxidative stress in osteoarthritic joint destruction.
Can J Physiol Pharmacol 89:455–466
Zollinger PE, Ellis ML, Unal H, Tuinebreijer WE (2008) Clinical outcome of cementless
semi-constrained trapeziometacarpal arthroplasty, and possible effect of vitamin C on the
occurrence of complex regional pain syndrome. Acta Orthop Belg 74:317–322

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Antioxidants and Osteoarthritis

I. Laher (ed.), Systems Biology of Free Radicals and Antioxidants, 2997

Antioxidants are naturally occurring reducing agents capable of inhibiting the

cause a variety of health problems including inflammatory disease, tissue necro-

to OA and improve study design in future interventional studies on OA. If antioxi-

Musculoskeletal, Arthritic, and Rheumatic Diseases

According to the United Nations (UN) (www.un.org/) and the World

The incidence of age-related diseases is rising, seriously affecting the well-being of

oxide (NO), prostaglandin E2 (PGE2), and neuropeptides are produced by

ROS in Cartilage and OA

Chondrocytes exist in an avascular microenvironment, with low nutrient and

Synovial fluid -Cartilage degradation

Fig. 133.1 (continued)

the extracellular environment. Altogether, degradation products and cellular con-

“Nutrigenomics” and “Nutritargeting” Treatments for OA

DNA – gene regulation, single

RNA – translational control,

Protein - receptor interactions,

Metabolite – multitudes of functions

In this nutrigenomic framework, the term “nutritargeting” can be applied.

Chondrocyte Antioxidant Defenses

Chondrocytes are exquisitely sensitive to the effects of ROS, especially in

Vitamin C (alternative names: ascorbic acid, dehydroascorbic acid) is a soluble

Vitamin D is a fat-soluble vitamin that is naturally present in very few foods. It is

Vitamin E is a fat-soluble nutrient found in many foods. It plays an important role as

Vitamin A is actually group of related compounds (carotenoids and retinoids) that

N/A not applicable – ongoing study

Chondrocyte Antioxidant Defenses: Glutathione, Superoxide

Glutathione or gamma-L-glutamyl-L-cysteinylglycine (GSH) is the main nonprotein

biosynthetic rates in cartilage during inflammation. In addition to the antioxidant

“Nutritargeting” with Antioxidants in OA: Systematic Reviews

antioxidant status. They concluded that there is no convincing evidence published

the possibility of intervention in cases where homoeostatic control mechanisms

Hormetic Effects of Antioxidants: Implications for the

An important property of living cells is their capacity to respond to stress. In this

literature of hormetic dose responses to environmental toxins has been reviewed

Acknowledgments A. Mobasheri wishes to acknowledge the generous financial support of the

Conflict of Interest Statement

a key to understanding chondrogenesis, skeletal development and cartilage degradation in

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