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The pathophysiology of osteoarthritis

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DOI: 10.1016/j.jopr.2013.01.008

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Review Article

The pathophysiology of osteoarthritis

Zahra Ashkavand a,*, Hassan Malekinejad b, Bannikuppe S. Vishwanath a

a
Department of Studies in Biochemistry, Manasagangotri, Mysore University, Mysore 570006, India
b
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Urmia University, Iran

article info abstract

Article history: Osteoarthritis is a chronic, inflammatory joint disease in the world. In India more than 20%
Received 1 December 2012 of total population is suffering from arthritis, although the main cause of disease is un-
Accepted 9 January 2013 known, morphological changes observed in OA include cartilage erosion as well as
Available online 4 February 2013 inflammation. Complex network of risk factors and biochemical parameters, including
cytokines, proteolytic enzymes trigger the disease, by knowing the exact mechanism of
Keywords: progressive of disease, it may help in finding the new drug for reducing pain and curing of
OA the joint disease. In the present review, we described the most important risk factors and
Morphological changes morphological changes in the cartilage and bone during the development of OA.
Cytokines Copyright ª 2013, JPR Solutions; Published by Reed Elsevier India Pvt. Ltd. All rights
reserved.

1. Introduction
Osteoarthritis (OA) is degenerative joint disease, which affects
millions of people in the world. It is a complex disease whose
pathogenesis, changes the tissue homeostasis of articular
cartilage and subchondral bone, determine the predominance
of destructive processes. A key role in the pathophysiology of
articular cartilage is played by cell/extra-cellular matrix (ECM)
interactions.
which is released from sensory neurons in the spinal cord con-
tribute to hyperalgesia and pain in the affected area.4 Several
studies have found that there is no correlation between radio-
logical images and pain parameters, but the medial side of the
knee showed most sensitization in patients with strong/severe
knee OA, the degree of pain can be measured with temporal
summation of pressure pain instrument.5
2.2. Joint stiffness

The concept of joint stiffness in arthritis and related pathol-

2. Signs and symptoms
Findings from studies indicate that age, gender, joint impair-
ment, reduced range of motion (ROM), joint stiffness, and
pain, contribute to increased disability.1,2
ogy diseases was introduced in the early 1960s.6,7 It is revealed
that surface-active phospholipid (SAPL) (synovial surfactant)
capable of reducing friction to the very low levels and provide
lubricant in normal joint moreover, this lining is deficient in
osteoarthritis and lead to stiffness of joint.8,9

2.1. Pain 2.3. Muscle weakness

The most common symptom is a chronic pain,3 during devel- Quadriceps muscle strengthening is an important protective
opment of knee joint inflammation the concentration of Exci- function at knee joints. Cross-sectional studies suggest that
tatory amino acids (EAA) especially Glutamate is increased strength is correlate with physical function and that

* Corresponding author. Tel.: þ91 9986744608 (mobile).

E-mail address: zahraash90@yahoo.in (Z. Ashkavand).
0974-6943/$ e see front matter Copyright ª 2013, JPR Solutions; Published by Reed Elsevier India Pvt. Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jopr.2013.01.008
 j o u r n a l o f p h a r m a c y r e s e a r c h 7 ( 2 0 1 3 ) 1 3 2 e1 3 8
increasing quadriceps strength reduces pain and improves
function. Evidence suggests that thigh muscle strength may
protect against knee joint damage and progression of existing
OA.10,11 Arthrogenic muscle inhibition (AMI) is a presynaptic,
constant reflex inhibition of musculature surrounding a joint
after damage to joint as it restricts full muscle activity and
prevent the quadriceps strengthening, weaker quadriceps
have been associated with an increased rate of loading at the
knee joint.12 AMI is caused by activity in multiple inhibitory
pathways, its severity may vary according to the degree of
joint damage.13
2.4. Bone enlargement and swelling
Due to pathological changes of articular cartilage in knee joint
resulted from many causes leads to blockage and edema of
soft tissues, disturbance of blood circulation, erosion and
injury of chondrocyte, and even increase of bony density and
formation of cystic changes, resulting in swelling and pain.14
3. Risk factors of knee osteoarthritis
OA has a multifactorial etiology, can be considered the prod-
uct of interaction between systemic and local factors.
4. Systemic risk factors for OA
4.1. Age
It is most important factor for development of osteoarthritis;
with increasing age the tensile property of cartilage in artic-
ular cartilage is decreased results in accumulation of glycation
which causes mechanical failure.15
4.2. Gender
Women have a higher level of pain and disability than men.16
A hospital-based study revealed rates of osteoarthritis is as
high as 68% in women and 58% of men aged 65 and older.17
4.3. Genetics hormones
Classic study of monozygotic (MZ) twins aged 48 to 70 years,
having identical genes showed 65% influence of genetic fac-
tors in developing of osteoarthritis.18 Between 39% and 65% of
osteoarthritis in the general population can be attributed to
genetic factors, women after menopause are more susceptible
to knee arthritis because of increasing level of osteocalcin and
bone resorption.19 Levels of osteocalcin, a marker of bone
turnover, were lower in women with knee osteoarthritis.20
4.4. Diet
Rapid changes in diet and lifestyle by consumption of unre-
fined carbohydrates and Junk foods increased the rate of
chronic diseases.21
Furthermore, chondrocytes are powerful sources of reac-
tive oxygen species, which may damage cartilage collagen and
133
synovial fluid hyaluronate, since micronutrient antioxidants
provide defense against tissue injury, high dietary intake of
these micronutrients could be helpful to protect against
osteoarthritis.20
5. Local risk factors
5.1. Joint injury and trauma
Articular cartilage tolerates loading from daily physical ac-
tivities, in joints injuries and trauma the cartilage loses its
flexibility, kills the cells and decrease the loading of the sub-
chondral bone.22
5.2. Obesity
People with an elevated body mass index (BMI) as a measure
of relative weight for obesity, has a positive association be-
tween obesity and knee OA results in substantial overloading
and damage to the knee joint.23
5.3. Occupation
The lifting of heavy loads was found mainly in farmers, fish-
ermen, construction site workers, and general laborers.
Walking up stairs was experienced mainly by general laborers;
all of these stress activities causes the strong association be-
tween knee injury and osteoarthritis.24
5.4. Physical activity/Sports
In china women practicing gymnastic or kung fu (traditional
Chinese martial arts) regularly were at the risk of Knee
injury.25 Schematic diagram of risk factors in osteoarthritis is
shown in Fig. 1.
6. General changes in bone and cartilage
in OA
OA is a complex disorder, its initiation, progression and
severity may be influenced by multiple factors. The concept of
subchondral bone stiffening and increasing bone density in
OA is date back to 1970 to suggestion of first investigators
Radin and Paul.26 There is a correlation between subchondral
bone changes and articular cartilage degeneration, the bone
volume and trabecular thickness significantly increase with
the higher stage of cartilage degeneration.27 In OA the bone
becomes stiffer; it may be less able to absorb impact loads,
which may lead to more stresses in the cartilage.28 The com-
mon features of osteoarthritis are loss of cartilage, joint space
narrowing, hypertrophic bone changes, osteophye formation,
osteophytes were defined as outgrowth of the bone and car-
tilage occurring at the joint margins, the previous study shows
that direction of osteophyte at all sites except the lateral tibia
and medial patella alters with size; similarly strong associa-
tion was observed between osteophyte size and local cartilage
narrowing, especially in the medial TFJ and lateral PFJ. Bio-
mechanical factors support the osteophyte development.29
134 j o u r n a l o f p h a r m a c y r e s e a r c h 7 ( 2 0 1 3 ) 1 3 2 e1 3 8

Local Risk Factors Systemic Risk Factors

Severity of
Obesity
Osteoarthritis Age
Occupation
Gender
Physical Activity/Sports
Genetics and hormones
Injury
Diet

Pain
Joint stiffness
Muscle weakness

Disability

Fig. 1 e Schematic diagram of risk factors for osteoarthritis.

One of the mechanisms of articular cartilage damage is stiff-
ness of subchondral bone, if the bone becomes stiffer; it may
be less able to absorb impact loads, which may in turn lead to
increased stresses in the cartilage.28 Softening of articular
cartilage in the patella, frequently described as chondropathy
or chondromalacia of the patella, causes to erosion of the
cartilage.30 Although chondromalacia of the patella is a com-
mon phenomenon, its aetiology is unclear; in addition to
several functional and morphological changes in OA, studies
has shown different inflammatory mediators, proteinases,
Cell proliferation, biochemical parameters in development of
disease.31
7. Cytokines and osteoarthritis
Chondrocytes are the only cells in cartilage responsible for
synthesis and breakdown of matrix which regulated by cyto-
kines and growth factors, under arthritis condition their bal-
ance may be disturbed.32
Cytokines which have an impact on articular cartilage
metabolism are classified in three groups including, catabolic
(IL1a, IL1b, TNF a), regulatory and enzyme inhibitory (IL-6, Il-8,
IL-4, IL-10, IFNg) and anabolic (Growth factors, IGF, COMPs,
TGF b).33 It is generally accepted that IL-1 is the key cytokine at
early and late stages of OA; the interleukin-1 (IL-1) family in-
cludes two agonists, IL-1a and IL-1b, are produced by two
different genes34 and a specific receptor antagonist, IL-1Ra.35
Interleukin-l is a multifunctional pro inflammatory cyto-
kine that affects most cell types and results in several effects
including lymphokine production, cartilage breakdown,
interfering with the activity of growth factors such as insulin-
like growth factor, or decreasing the synthesis of key matrix
components such as aggregan and proliferation of fibroblast
have a crucial role in arthritis disease.35,36 The presence of
activated macrophages will release the IL which has a role in
destruction of cartilage.37
NF- kb (nuclear factor kappa-light-chain-enhancer of acti-
vated B cells) is one of the key regulatory mechanisms involved
in regulating and controlling expression of cytokines are criti-
cal in immune function, inflammation.38 It is known that
stimulus of NF-kb leads to expression of TNFa and IL1b.39,40
The TNF superfamily is a group of cytokines with impor-
tant functions in immunity and inflammation, among these,
TNF a is effective proinflammatory cytokine that plays an
important role in inflammation, and matrix degradation by
stimulating proteolytic enzyme secretion from chondrocytes
and synovial fibroblasts.41 TNF induces fever initially by
increasing prostaglandin E2synthesis in the hypothalamus
and subsequently production of IL-1and IL6.42 Interleukin-1
(IL-1) and tumor necrosis factor a (TNFa) both induce pro-
duction of IL-6, increased levels of these cytokines may, in
turn, contribute to the development of OA.43 Once inflam-
mation is initiated, IFN-g is produced and subsequently acts
through various pathways to deepen the inflammatory pro-
cess like arthritis.44
IL-1b also induces ROS and lipid peroxidation which have
been linked to cartilage matrix degradation.45 IL-1 and TNF
a stimulate NO production a potent mediator produced by
articular chondrocytes during inflammatory reactions by inhib-
iting proteoglycan (PG) synthesis, enhancing MMP production or
increasing oxidant stress to arthritis disease in joints.46,47
Interferon g (IFNg) is a cytokine with multiple biological and
pathological functions diseases such as multiple sclerosis,
arthritis and diabetics have been shown to be related with IFN g
signaling enhancing influence on collagen by producing CD4þT
Regulatory cells,48 and associated with TNF a.49 Transforming
growth factor beta (TGF-b) belongs to a large family of structur-
ally related cytokines50 involved in vital biological processes,
including development, ECM synthesis, cell proliferation and
tissue repair of articular chondrocytes in the joint,51,52 elevated
level of TGF-b activity has been found in the synovial fluid of OA
patients,53 in addition TGF-b released by tissue damage and
inflammation triggers cells to form osteophytes.54
 j o u r n a l o f p h a r m a c y r e s e a r c h 7 ( 2 0 1 3 ) 1 3 2 e1 3 8 135

Cartilage oligomeric matrix protein (COMP) is 524-kd non-

collagenous pentameric glycoprotein related to the thrombo-
Subchondral Bone
spondin family found abundance in articular cartilage, high
concentration of COMP have been detected in synovial fluid of
Proteinase
knee OA.55,56 Tamura57 reported that NO enhanced the matrix Aggrecanase
metalloproteinase activity. Synovial ADAMTS
NO
MMPS
Cytokines
8. Proteinases are responsible for aggrecan
and collagen degradation in OA (IL1, , IL6)
Growth factors
Aggrecan is the most of predominant proteoglycans (PGs) Inflammatory cells
found in articular cartilage; it functions in load distribution in Cartilage
joints during movement and providing hydration and elas- Degradation
ticity to cartilage tissue.58,59 Almost 90% of aggrecan mass is
comprised of substituted Glycosaminoglycan (GAG) chains.60
Loss of aggrecan is the event in OA The major aggrecanase
in cartilage is ADAMTS-5.61 DuPont in 1999 reported the first
and second aggrecan called aggrecanase 1, a disinterring and Fig. 2 e Potential targets for development of osteoarthritis
metalloprotease with thrombospondin motifs 4 (ADAMTS-4) in knee joint.
and aggrecanase2 (ADAMTS-5),62 out of 19 members of
ADAMTS family63 in osteoarthritis ADAMTS-4 and ADAMTS-5
expression is more.64 ADAMTS-4 is a member of the “dis-
ROS are capable of inducing degradation of collagen and
integrin and metalloproteinase with thrombospondin-like
aggrecan in chondrocytes.84,85
repeat family of proteins, an exposure to TNF-a or IL-1b and
Nitric oxide is a short lived radical synthesized via the
TGF-b, increases the activity of ADAMTS-4 in arthritis join-
oxidation of arginine by a family of nitric oxide synthases
ts65e67 whereas the expression of ADAMTS-5 is not affected by
(NOS),86 NO’s role in joint diseases was first reviewed by,87e89
neutralization of IL-1b or TNF-a.68 Aggrecan degradation is
chondrocyte and macrophyges can produce NO and prosta-
associated with upregulation of ADAMTS and matrix metal-
glandins consecutively in response to cytokines,88e90 ROS can
loproteinases (MMPs).69
reduce synthesis of hyaluronic acid (HA) main component
Matrix metalloproteinases (MMPs) are members of an
of ECM.91
enzyme family that require a zinc ion in their active site for
catalytic activity, active at neutral pH and neutral proteases is
able to degrade, The enzymic activities of these MMPs are
controlled by specific inhibitorsdthat is, tissue inhibitors of 10. Lipid peroxidation
metalloproteinases (TIMP).70,71 There are twenty members of
MMPs including the collagenases (MMP-1, MMP-8, MMP-13), Lipid peroxidation refers to oxidation of polyunsaturated fatty
gelatinases (MMP-9), stromelysins (MMP-3).72e74 MMPs are acids (PUFA) leading to a variety of hydroperoxide and alde-
involved in regulating cellular migration, ECM protein trans- hyde products that are highly reactive with components of the
formation, ECM degradation and apoptosis in the growth cell and the extracellular matrix and mediate collagen
plate.75,76 Overexpression of MMPs (e.g. MMP-9 and MMP-13) are degradation.45,92,93
considered to be crucial in the development of OA.62 Moreover, Taken together, it is indicated that the distribution of lipids
Cytokines also stimulate chondrocytes in OA cartilage to secret in cartilage changing during aging and OA.94,95
high levels of matrix metalloproteinase 13 or collagenase-3 Fig. 2 shows the brief schematic diagram of development of
(MMP-13), require zinc and calcium for their activity.77 OA in joint.

9. Role of ROS in arthritis

11. Conclusion
The ROS formed by reduction of oxygen are the radical su-
Treatment of osteoarthritis (OA) is mainly based on the
peroxide (O2.L), hydroxyl radical (OH.), peroxyl (ROO.), alkoxyl
pathophysiological events that alter the initiation and pro-
(RO.) and hydroperoxyl (HO.2), nitric oxide (NO) and nitrogen
gression of OA. Understanding the mechanism and Modula-
dioxide (NO.2) and non radical such as hydrogen peroxide
tion of cytokines and MMPs would be a main target for
(H2O2), hypochlorous acid (HOClL), Ozone (O3), singlet oxygen
treatment and prevention of Osteoarthritis.
(O2) and peroxynitrite (ONOOL).78 Recent studies showed that
chondrocytes produce reactive oxygen species (ROS), includ-
ing superoxide anions, hydrogen peroxide, hydroxyl radicals,
and large amount of nitric oxide in response to inter- Conflicts of interest
leukin1,79e81 ROS are generated by activated macrophages
and neutrophils participate in inflammatory responses.78,82,83 All authors have none to declare.
136 j o u r n a l o f p h a r m a c y r e s e a r c h 7 ( 2 0 1 3 ) 1 3 2 e1 3 8

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