Dimitrova Et Al-2012-Principles of Osteoarthritis - Its Definition, Character, Derivation And...

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23
How Important are Innate Immunity Cells in

Osteoarthritis Pathology
Petya Dimitrova and Nina Ivanovska
Department of Immunology, Institute of Microbiology
Bulgaria
1. Introduction
Osteoarthritis (OA) is a chronic degenerative bone disorder leading to cartilage loss,
frequently associated with the aging process. It is widely spread in society and often causes
disability. Joint swelling which attends OA is due to osteophyte formation or to synovial
fluid accumulation. Pathologically, focal damage of cartilage in load-bearing areas are
observed together with the formation of new bone at the joint margins, as well as with
changes in subchondral bone, and synovitis. Current diagnosis of OA is based on the clinical
history and on the radiographical data which occur late at the disease and are very
irreversible. Ideally, we wish to detect osteoarthritis at an early stage by following the
changes in expression of particular molecular markers, assuming that these markers are
sufficiently sensitive, specific, and quantitative for the disease. OA is no longer considered
an exclusively degenerative joint disorder because it is related to changes in the synovial
membrane as a result of more or less exerted inflammation (Hedbom & Hauselmann, 2002).
Trauma or some mechanical problem might be the primary reason for OA initiation. The
initiation and progression of OA is sometimes associated with synovial inflammation and
the production of proinflammatory and destructive mediators from the synovium causing
the invasion of chondrocytes into the cartilage. In early OA the influx of mononuclear cells
is enhanced simultaneously with overexpression of inflammatory molecules compared with
late OA (Benito et al., 2005). A fundamental question is which cell populations in OA
contribute to and maintain synovial inflammation and cartilage destruction.
2. Neutrophils as the main participants in the development of OA

2.1 Phenotype of OA neutrophils
Neutrophils are an essential part of the innate immune system, triggering the initial
inflammatory response and the development of host defense mechanisms. During
inflammation they leave the circulation and enter the tissues in which they are under the
influence of various local factors such as cytokines, endogenous growth factors, microbial
products etc. In a result, neutrophils adopt effector functions of great importance for
initiation and maintaining of many chronic inflammatory diseases (Duan et al., 2001;
Edwards & Hallett, 1997; Mitsuyama et al., 1994).
Neutrophils develop from progenitor cells in bone marrow. They have short lifespans of
several hours and then die via apoptosis. Constitutive apoptosis of neutrophils is
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520 Principles of Osteoarthritis – Its Definition, Character, Derivation and Modality-Related Recognition
regulated by two transcription factors: hypoxia-inducible factor 1 (HIF1) and forkhead

box O3A. When certain stimuli such as granulocyte-macrophage colony-stimulating factor
(GM-CSF), TNF- , IL-8 and IFN- are provided, the lifespan of blood neutrophils is
significantly prolonged (Brach et al., 1992; Kilpatrick et al., 2006). Increased neutrophil
survival is related with an enhanced expression of anti-apoptotic genes (Marshall et al.,
2007) and by death-inducing receptors belonging to the tumor necrosis factor
(TNF)/nerve growth factor (NGF) receptor super-family, such as Fas, TNF-related
apoptosis-inducing ligand (TNFSF10) receptors, TNFRSF9 (CD137), and the type I TNF
receptor (Simon et al., 2003).
It has been shown that RA synovial fluid counteracts neutrophil apoptosis and leads to
prolonged survival (Ottonello et al., 2002). Such inhibited apoptosis is characteristic for
the earliest phase of RA in contrast to other early arthritides (Raza et al., 2006), suggesting
that the suppression of apoptosis in RA patients at high risk is a possible therapeutic
approach. RA neutrophils are also functionally different from healthy neutrophils as it has
been demonstrated by up-regulated expression of complement receptors CR1, CR3 and
CR4 (Felzmann et al., 1991). They show an increased chemotaxis to synovium (Pronai et
al., 1991) promoted by TNF-, IL-17, IL-20 and IL-24 (Kragstrup et al., 2008; Shen et al.,
2005). Reports about apoptosis of neutrophils in OA are few and controversial. Bell et al.
showed that synovial fluid from OA patients contains factors inhibiting neutrophil
survival (Bell et al., 1995). There is also a hypothesis that pyrophosphate dihydrate
(CPPD) and basic calcium phosphate (BCP) crystals present in the OA joint fluid and
tissue can activate Ca2+ signal in neutrophils thereby prolonging their survival and
reducing their apoptosis (Rosenthal, 2011). Chakravarti et al. isolated a subset of blood
neutrophils which represents 8–17% of the total neutrophil population and persists
beyond 72 h after an exposure to GM-CSF, TNF- and IL-4. These neutrophils secrete IL-1,
IL-1Ra and IL-8, and interact strongly with resident stromal cells (Chakravarti et al., 2009).
The phenotype of “long-lived” neutrophils also differs from that of the circulating
neutrophils. Although they express the common neutrophil cell surface markers CD32,
CD18 and CD11b, they acquire new surface markers, such as HLA-DR and the co-
stimulation molecule CD80 (Cross et al., 2003).
Neutrophils participate actively in joint inflammation as proven by their depletion in an
experimental model of arthritis (Santos et al., 1997). They affect chemotaxis of macrophages
and dendritic cells by cleaving prochemerin to chemerin. Neutrophils produce TNF- and
other cytokines like IL-1, IL-6 that drive the differentiation and activation of dendritic cells
and macrophages. The destructive potential of neutrophils is related with their ability to
release reactive oxygen species and granules with myeloperoxidase, defensins and MMP-8,
MMP-9, MMP-25. MMPs are secreted in response to IL-8 and through ERK1/2 and Src-
family kinase pathways (Chakrabarti & Patel, 2005).
2.2 RANKL expression on OA neutrophils

The uncoordinated bone remodeling events in OA results from the impaired balance
between bone resorption mediated by mature osteoclasts and bone formation mediated by
osteoblasts. The receptor activator of nuclear factor-B ligand (RANKL) and its receptor
RANK are actively involved in osteoclast formation (Yasuda et al., 1998). Immature
osteoblasts express RANKL which binds to RANK on osteoclasts, initiating the
recruitment of osteoclast precursors in bone marrow and promoting their differentiation.
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How Important are Innate Immunity Cells in Osteoarthritis Pathology 521
Intracellularly, RANK interacts with TNF receptor-associated factor 6 (TRAF6), which

unlocks signaling through NF-B, p38 kinase, and c-Jun N-terminal kinase (Teitelbaum,
2000). OPG is released by osteoblasts and stromal cells and is expressed by macrophages
in synovial lining layer. Bone resorption is controlled by the balance between RANKL,
RANK and osteoprotegerin (Crotti et al., 2002). The inhibition of RANKL in serum
transfer model (Ji et al., 2002), in TNF--induced model (Keffer et al., 1991) and in
autoimmune type II collagen-induced arthritis (Kamijo et al., 2006) resulted in
amelioration of bone destruction.
Recently, Poubelle and co-workers reported that RA neutrophils express RANKL and are
activated through RANK/RANKL interaction (Poubelle et al., 2007). Despite the studies
in RA, there are no investigations showing the involvement of RANKL positive
neutrophils in the pathogenesis of OA. A little is known about the expression of RANKL
in active or inactive stages of OA. We have conducted a study on RANKL expression by
neutrophils in OA patients and in mouse models. OA patients have been divided into two
groups depending on the presence of active inflammatory process. The first group, with
active OA had swelling, local hyperthermia of one or more joints and high erythrocyte
sedimentation rate (ESR). The second group with inactive OA lacked above mentioned
painful swelling and local hyperthermia. A number of healthy controls have also been
included (Table 1).
healthy controls active OA inactive OA
No. of subjects (women/men) 10 (4/6) 12 (5/7) 14 (6/8)
Duration (years) not assessed 4.5 ± 1.2 2.5 ± 1.2
ESR (mm/h) <20 24.8 ± 6.2 14.0 ± 3.6
RF not assessed <20 <20
CRP <0.01 58.9 ± 30.4 <0.01
CRP – C reactive protein; ESR-erythrocyte sedimentation rate; OA-osteoarthritis; RF-rheumatoid factor;

Data are expressed as mean ± standard error of the mean
Table 1. Basic characteristics of healthy donors and OA patients
The intensification of OA symptoms at established phase of the disease can be due to
calcium-containing crystals. The basic calcium phosphate (BCP) and hydroxyapatite (HA)
crystals are often found in joint fluid and tissues of OA patients. The reason for their
accumulation is not clear but their contribution to the aggravation of inflammation is
obvious (Mebarek et al., 2011; Rosenthal et al., 2011). The elevated ESR might reflect their
action on innate immunity cells, inducing inflammatory signals and amplification of already
generated. Moreover, the increase of BCP concentration correlates with the severity of the
disease (Yavorskyy et al., 2008). To provoke an inhibition of crystal deposition or their
degradation represents a novel and tempting approach for application in chronic phase
which can limit joint damage.
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donors (0.8  0.4%). After their in vitro stimulation with TLR2 agonist, zymosan, they
In our study low percentage of RANKL positive blood neutrophils was detected in healthy
responded with an increased RANKL expression (8.22  0.07%). Significantly higher
(14.75  5.07 %; p<0.001 vs healthy) and inactive OA (9.77  2.16%; p<0.01 vs healthy) but
percentage of RANKL positive blood neutrophils were observed in patients with active OA
only inactive group responded to zymosan stimulation (Fig. 1).
30 P<0.001
RANKL positive cells (% )
P<0.001 P<0.05
20 P<0.05
10
0
Zy - + - + - +
healthy controls active OA inactive OA
Fig. 1. RANKL expression on neutrophils isolated from healthy controls and patients with
absence or presence of 10 g/ml of zymosan (Zy). After washing neutrophils were stained
active and inactive osteoarthritis (OA). Cells (1x106/ml) were incubated (370C, 2 h) in the
with rat antibody against human RANKL and isotype control, followed by secondary FITC-
conjugated anti-rat antibody. Data represent percentage of RANKL positive cells with the
median value in the group (see lines in each group).
Experimental osteoarthritis was induced according to a method described by Blom et al. (Blom,
et al. 2007). Mice received two intra-articular injections of collagenase (2 times x1U collagenase)
of 180 g (10 l) of zymosan. In both models BALB/c mice 10-12 week old with weight 20-22 g
at day 0 and 2. Arthritis onset occurs within 7 days. ZIA was induced by intra-articular injection
were used. Whole-blood samples were collected in heparin and neutrophils were isolated by
stimulated for 2 h with zymosan (10 g/ml). After washing neutrophils were stained with rat
dextran sedimentation followed by gradient centrifugation, resuspended at 1x106/ml and
antibody against mouse RANKL and isotype control, followed by secondary FITC-conjugated
anti-rat antibody. Data from one representative experiment shows the mean fluorescence
intensity and the percentage of RANKL positive cells.
Further, we have investigated RANKL expression on neutrophils in two mouse models:
collagenase-induced osteoarthritis and zymosan-induced arthritis. We found low
frequencies of RANKL positive neutrophils in blood of CIOA mice and a weak response to
in vitro zymosan stimulation (Fig. 2). Blood neutrophis from ZIA mice expressed RANKL
and responded to TLR2 engagement with increased RANKL expression (Fig. 2).
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Fig. 2. RANKL expression by blood neutrophils isolated from mice with zymosan-induced
arthritis (ZIA) and collagenase-induced osteoarthritis (CIOA) at day 30 of disease.
2.3 MRP8/MRP14 as a potential OA marker related to neutrophil recruitment

The rate of neutrophil and macrophage infiltration at the site of inflammation is associated
with myeloid-related proteins (MRP)-8 and -14, belonging to S-100 family of calcium
binding proteins. MRP8 and MRP14 are secreted by human monocytes after activation of
protein kinase C (PKC) (Rammes et al., 1997). In inflammation they are expressed by
infiltrating neutrophils, keratinocytes and monocytes in contrast to resting-tissue
macrophages and lymphocytes (Frosch et al., 2000; Kerkhoff et al., 1998). Increased
expression of these molecules has been established in various inflammatory disorders
including RA (Youssef et al., 1999), psoriasis (Kunz et al., 1992), inflammatory bowel disease
(Rugtveit et al., 1994), PsA (Kane et al., 2003). MRP8/MRP14 expression is very low in
normal tissues and in RA patients in clinical remission, but high in patients with active
disease (Brun et al., 1994). Similar levels of MRP8/MRP14 are found in synovial fluid from
patients with psoriatic arthritis, RA and spondyloarthritis without a correlation with disease
duration and clinical expression of arthritis activity (Bhardwaj et al., 1992). The proteins
enriched more the synovial fluid than the blood circulation as a result of infiltration and
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activation of neutrophils and macrophages in the joints of RA patients. Very scarce data are
available about MRP proteins in OA. It is supposed that the contact of phagocytes with
activated endothelium leads to release of MRP8/MRP14, which induces the switch from
selectin-mediated reversible adhesion to integrin-dependent tight contact (Frosch et al.,
2000).
However, MRP8/MRP14 levels might be reliable prognostic marker for disease activity
and for the effectiveness of immunosuppressive therapy. Methotrexate (MTX) treatment
resulted in reduced MRP8/MRP14 serum levels (Kane et al., 2003; Ryckman et al., 2003). It
is considered that in acute inflammation MRP8/14 and MRP14 are well represented,
while MRP8 is associated with chronic inflammatory conditions (Roth et al., 2003). In our
study we have included OA patients with or without an active inflammatory process in
one or more joints (Toncheva et al., 2009). We observed high MRP8 plasma level in 30% of
the patients with active OA (number of patients =37) and in 8% of the patients with
inactive OA (number of patients =19). In healthy donors MRP8 level was very low
(number of donors =31). Although our data suggest that the severity of OA might
correlate with MRP8 plasma level it will be important to continue such investigations in
larger groups of patients. The diagnostic value and advantage of MRPs over other disease
markers is that they are released immediately upon activation of the particular cell
population.
2.4 TLR2 expression by OA neutrophils

The progression of arthritic processes might be supported by the recognition of microbial or
host-derived ligands found in arthritic joints. It has been shown that TLR2 and TLR4, but
not TLR9, play distinct roles in disease pathogenesis (Abdollahi-Roodsaz et al., 2008).
Knockout (IL1rn-/-) mice spontaneously develop T cell-mediated arthritis dependent on
TLR activation since germ-free mice fail to develop arthritis. Activation of TLRs on
macrophages and dendritic cells leads to the production of proinflammatory cytokines,
including TNF- and IL-1 . The role of the innate immune system in RA and in
experimental models of RA has been the object of recent investigations. An increased
expression of TLR2 and TLR4 on peripheral blood monocytes and in the synovial tissues
from patients with RA has been observed (De Rycke et al., 2005; Iwahashi et al., 2004).
Limited data exist on the quantitative TLR2 and TLR4 expression by synovial macrophages,
but it is known that their expression was increased in RA compared with osteoarthritis or
normal synovial tissue (Radstake et al., 2004). TLRs through NF-κB activation provoke the
production of innate immunity mediators, like IL-1, IL-6, IL-8, and TNF- (Takeuchi et al.,
2000; Wang et al., 2001). Consequently, these molecules up-regulate TLR expression, e.g.
TNF- stimulates TLR2 gene expression in contrast to TLR4 (Matsuguchi et al., 2000). The
stimulation of cultured RA synovial cells with IL-1 and TNF- leads to an increase of TLR2
mRNA expression but such increase of TLR4 and TLR9 expression is not detected in the
absence or in the presence of stimuli (Seibl et al., 2003). These results are not specific for RA,
because cells derived from joints of patients with OA responded similarly to TNF-
stimulation.
Neutrophils express all known human TLRs except TLR3 (Hayashi et al., 2003). TNF- and
IL-6 production in neutrophils can be triggered upon the engagement of TLR2, TLR4, TLR9.
In neutrophils the ligation of TLRs results in activation of MAPK and NF-kB but not always
involves the adaptor protein MyD88. In respect to TLR4, recently it has been reported that
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LPS can induce different response in adherent and in suspended neutrophils. In adherent
cells TLR4 ligation triggers Jun activation and the release of the chemokine monocyte
chemoattractant protein-1, an activated protein-1-dependent gene product that is important
for monocyte recruitment. Adherent neutrophils interact with matrix proteins through
sheded CD43. CD43 (leukosialin) is a heavily sialylated molecule that is cleaved by
neutrophil elastase near the plasma membrane. In blood CD43 binds albumin that protects it
from the elastase action. In inflammatory conditions neutrophils secrete elastase enhancing
the spread and rolling of neutrophils. In RA the destruction of cartilage and bone might be
associated with the activation of synovial cells through TLR2. The ligands of TLR2 include
lipopetides and peptidoglycan (Aliprantis et al., 1999; Schwandner et al., 1999), and
zymosan acting in collaboration with TLR6 and CD14 (Ozinsky et al., 2000). While TLR4 is
weakly represented on the surface of human neutrophils, TLR2 and CD14 are well
expressed (Kurt-Jones et al., 2002).
To investigate the involvement of TLR2 in OA we followed its constitutive and Zy-induced
expression in blood neutrophils. Data in Fig. 3 show that the percentage of TLR2 positive
neutrophils from OA patients was approximately 4 fold higher compared to healthy donors.
Zymosan stimulation resulted in 2 fold enhancement of TLR2 expression on neutrophils
from all groups.
Fig. 3. TLR2 positive neutrophils from healthy donors and patients with active and inactive
10 g/ml of zymosan (Zy). Cells were collected, washed and stained with rat antibodies
osteoarthritis (OA). Cells (1x106/ml) were incubated (370C, 2 h) in the absence or presence of
against human TLR2 (3 g/ml), followed by secondary FITC-conjugated anti-rat antibody.

Neutrophils isolated from healthy and OA donors were in vitro simulated with zymosan
and the secretion of TNF- was determined. Neutrophils from patients with active OA
spontaneously release the cytokine in contrast to healthy and inactive OA groups. Zymosan
significantly enhanced TNF- secretion of healthy donors and inactive OA (Fig. 4A). The
spontaneous release of TNF- was higher in ZIA and CIOA groups compared to healthy
group. Neutrophils from arthritic mice did not respond significantly to zymosan
stimulation, while healthy group showed increased TNF- production (Figure 4B).
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Fig. 4. Spontaneous and zymosan-induced TNF- production by blood neutrophils. (A)
(1x106/ml) were incubated (370C, 24 h) in the absence or presence of 10 g/ml of zymosan.

Cells isolated from healthy donors and patients with active and inactive osteoarthritis
(B) Cells isolated from healthy mice and mice with zymosan-induced arthritis (ZIA,) and
(370C, 24 h) in the absence or presence of 10 g/ml of zymosan. TNF- concentration in the

collagenase-induced osteoarthritis (CIOA) at day 30 of arthritis (1x106/ml) were incubated
supernatants was determines by ELISA.

The up-regulation of TLR2 corresponds either to a response to an exposure to microbial
compounds or is secondary to the inflammatory milieu present in the rheumatoid joints.
TNF- is a key mediator in inflammatory joint diseases. We observed the activation state
of neutrophils at least in active OA, which was witnessed by their spontaneous ex vivo
TNF- release. Our previous results showed that TLR4 ligand LPS is able to trigger in
vitro TNF- release by neutrophils from patients with inactive OA (Toncheva et al., 2009).
Zymosan also enhanced TNF- production of neutrophils from inactive OA patients.
Probably in active OA, being in activated state cells has reached a threshold after which
they become unresponsive. The results from ZIA and CIOA point on such possibility if we
accept that ZIA is relevant to more severe inflammatory condition than CIOA. In synovial
explant cultures it has been proved that a monoclonal antibody against TLR2 can inhibit
the spontaneous release of TNF- , IFN- , IL-1 and IL-8. Such data are a good base for
future investigations on the use of TLR2 antagonists by clinicians, because the effect of
anti-TLR2 antibodies is comparable with that of the TNF inhibitor adalimumab (Nic An
Ultaigh et al., 2011).
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2.5 Activation of monocytes and macrophages during OA

Monocytes and macrophages play an important role in various inflammatory conditions,
depending on their stage of activation (Burmester et al., 1997; Tak et al., 1997). Monocytes
are subdivided into two different populations with distinct phenotype and functional
activity. While classical monocytes are CD14hiCD16- in humans and GR1+ in mouse, non-
classical monocytes are CD14lowCD16+ in man and GR1- in mouse. Classical monocytes
highly express the CC-chemokine receptor 2 (CCR2), CD62 ligand (CD62L) (Tacke et al.,
2007) and vascular cell adhesion molecule 1 (VCAM1 or CD106), and produce low levels of
proinflammatory cytokines like TNF- and IL-1. The latter mediators activate synovial
endothelial cells and other leukocytes and initiate inflammatory process. Non-classical
monocytes or “resident” monocytes express high level of CX3C-chemokine receptor 1
(CX3CR1) and are potent antigen-presenting cells. It has been shown that monocytes from
arthritic patients with active disease have reduced HLA–DR expression and decreased
capacity to stimulate T cells in vitro than healthy cells (Muller et al., 2009). Moreover, TNF-
inhibits HLA-DR synthesis in arthritic myeloid cells via the expression of class II
transactivator (CIITA). In comparison to RA, OA patients showed lower density of HLA-DR
expression on peripheral monocytes (Koller et al., 1999) suggesting their intrinsic functional
abnormality to act as antigen-presenting cells.
An accumulation of macrophages is found in the synovium of patients with early OA
(Benito et al., 2005). These resident tissue cells are CD68 positive. CD68+ macrophages in
OA synovium were restricted to the lining layer while in RA patients they were found in the
sublining layer and the areas around newly formed micro-vessels. In the study of Bloom et
al. macrophages are depleted prior the development of early OA by injection of clodronate
liposomes (Blom et al., 2004). The lack of macrophages reduced the size of osteophytes and
lining thickness, and inhibits chondrocyte ossification and fibrosis. Macrophage depletion
also down-regulates the expression of bone morphogenetic proteins, BMP2 and BMP4 in
synovium (van Lent et al., 2004). Both molecules are important regulators of bone
remodeling process and their inhibition has good therapeutic potential in OA as we have
observed in a model of CIOA (Ivanovska & Dimitrova, 2011).
Under OA conditions, CD68+ macrophages in synovial lining layer are persistently
activated via NF-κB, STAT and Pi3K signaling pathways. They are the source of inducible
nitric oxide and of proinflammatory cytokines like TNF- and IL-1 (Benito et al., 2005)
driving inflammatory process in OA and causing synovitis and bone erosion. Apart of this
role, macrophages can participate directly in cartilage degradation. They are capable to
produce enzymes degrading extracellular matrix macromolecules like disintegrin-
metalloproteinases with thrombospondin motifs and MMPs like MMP-2, MMP-3 and MMP-
9 (Smeets et al., 2003). While MMP-2 activates the expression of other MMPs in
chondrocytes, MMP-3 is directly involved in cartilage destruction. Serum level of MMP-3 is
associated with joint space narrowing in OA patients (Lohmander et al., 2005). MMP-3–
deficient mice show significantly decreased cartilage damage (Blom et al., 2007). In rabbit
model of experimental arthritis MMP-3 is initially up-regulated in the synovium
contributing to the appearance of cartilage lesions while MMP-3 derived from chondrocyte
exacerbate cartilage loss at late phases of OA (Mehraban et al., 1998). Blom et al. showed that
at early experimental OA synovial macrophages are responsible for the initial MMP-3
production (Blom et al., 2007). These data are based on the observation that MMP-3
expression in the synovium is strongly reduced in the absence of synovial macrophages.
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Secreted by macrophages MMPs are proteases that cleave not only collagen in bone matrix
but also can modify other molecules present in the OA synovium. For example MMP-9
cleaves chemokines CXCL1 and CXCL8 increasing their potency to attract neutrophils and
to amplify inflammation and bone erosion (Van den Steen et al., 2000).
Synovial macrophages can secrete pro-inflammatory mediators that increase MMP
expression by synovial cells or chondrocytes. Macrophages isolated from synovial lining
layer of OA patients produce spontaneously IL-1 and TNF-. In synovial cell co-cultures
macrophages stimulate the synovial fibroblasts to produce MMPs and cytokines like IL-6
and IL-8 via a synergistic action of IL-1 and TNF- (Bondeson et al., 2006). IL-1 synthesis
in OA is independent of TNF- and correlates with OA severity. The biological activity of
IL-1 is regulated by the balance between the expression of the active receptor IL-1RI and
the inactive or decoy receptor IL-1RII. While the IL-1RI is highly expressed the decoy
receptor IL-1RII is little or missing in OA. This receptor imbalance in turn decreases the
 promotes osteoclast differentiation and bone resoption. It has been shown that IL-1 alone
ability of IL-1RII to neutralize completely and eliminate active IL-1. IL-1 together with TNF-
can induce osteoclastogensis but only in osteoclast precursors over-expressing IL-1R1 (Kim
et al., 2009). Several in vitro studies show that IL-1 inhibition by natural inhibitors such as IL-
1 receptor antagonist or soluble receptors decreases MMP expression and cartilage
destruction in OA (Jacques et al., 2006).
Macrophages can produce pro-inflammatory cytokine IL-18. The administration of IL-18 at
the initial and late phase of arthritis accelerates the development of disease. Despite that IL-
18 is detected at low amounts in OA synovium (Gracie et al., 1999) it can stimulate the
expression of MMP-3, MMP-13, aggrecanase-2, TIMP-1 in chondrocytes promoting bone
destructive process. Recently, it has been shown that IL-21 is a proinflammatory cytokine
that increases CXCL8 production by monocyte-derived macrophages. The receptor for IL-21
was detected on monocytes, monocyte-derived macrophages and on synovial macrophages
from RA patients (Jungel et al., 2004). IL-21R has limited expression in OA synovium but it
is expressed in the areas with enhanced catabolic processes and might participate in
destructive process.
Macrophages also release factors that are important for tissue repair and suppression of
inflammatory response. Among these factors are vascular endothelial growth factor CD106
(Haywood et al., 2003), prostaglandin E2, IL-10 and TGF- . TGF- expression from
macrophages can be triggered by lipoxin A4 produced by activated neutrophils. TGF-
inhibits T cell proliferation and inflammatory responses. The anti-inflammatory cytokine IL-
10 regulates the synthesis of IL-4, and inhibits IFN- production in T cells and TNF- and
IL-1 production in macrophages. The important role of anti-inflammatory cytokines IL-10
and IL-4 in OA has been well described in studies on experimental OA where these cytokine
are administrated. The combined treatment with low dosages of IL-4 and IL-10 has potent
anti-inflammatory effects and markedly protected against OA cartilage destruction.
Improved anti-inflammatory effect was achieved with IL-4/prednisolone treatment
(Joosten et al., 1999).
The progression of OA might result in an inappropriate differentiation of resident tissue
macrophages, and expression of functionally distinct phenotype (Mantovani et al., 2007; Xu
et al., 2005). Macrophage functions are tightly regulated by reversible histone acetylation
with acetylases (HAT enzymes) and deacetylation with deacetylases (HDAC enzymes)
(Grabiec et al., 2010).
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Resident macrophages in different tissues such as lung, liver and synovium express Z39Ig
(CRIg) protein (Helmy et al., 2006). The Z39Ig is a receptor for complement fragments C3b
and iC3b and is a type 1 transmembrane protein of the immunoglobulin superfamily
member. Significant Z39Ig staining is detected in macrophage-enriched areas in the lining
and sublining areas of RA synovium (Lee et al., 2006). In OA synovial tissue the number of
cells expressing Z39Ig was lower and the positive staining was restricted to the lining-layer
macrophages. A significant number of Z39Ig+CD11c+cells observed in some cases of OA
and PsA points that Z39Ig+CD11c+cells deserve extended investigations to clarify their
functional activity in OA (Tanaka et al., 2008).
It has been shown that prostaglandin E2 secreted by macrophages contributes to pain
hypersensitivity by promoting sensory neurons hyperexcitability. Tissue-resident
macrophages constitutively express receptor P2X4 and the stimulation via P2X4R triggers
calcium influx and p38 MAPK phosphorylation and COX-dependent release of PGE2
(Ulmann et al., 2010). These data suggest that synovial lining macrophages might be
important effectors that control pain relieve in OA patients.
Osteoclasts and monocytes are not only derived from a common myeloid progenitor but
their activity might be influenced by common mediators (Ross, 2000). Activation of CD40
signaling in monocytes/macrophages results in up-regulation of nitric oxide generation
(Tian et al., 1995), and induction of metalloproteinase production (Malik et al., 1996).
Recently, it was found that except CD40L, the known activator of
monocytes/macrophages, also OPGL can express such function (Andersson et al., 2002).
Mice deficient in CD40L expression display a deficiency in T cell-dependent
macrophage-mediated immune responses (Stout et al., 1996). The development of
osteoclasts is strongly dependent on the interactions between two members of TNF
superfamily, OPGL and its receptor RANK (Lacey et al., 1998; Yasuda et al., 1998). One
of the pathways for triggering inflammatory processes by OPGL is through p38 MAPK
and p42/44 ERK and inducing cytokine and chemokine secretion (Suttles et al., 1996).
Results from in vivo application of RANK-Fc in a model of antibody-mediated arthritis
showed that it blocked OPGL activity and ameliorated arthritis development (Seshasayee
et al., 2004).
3. TLR9 expression in OA
Toll-like receptors are involved not only in pathogen recognition but they can participate in
triggering the inflammatory and joint destructive process in arthritis or they can enhance the
progression of already established synovitis. TLR-mediated inflammatory response may
induce further tissue damage and can provoke a self-sustaining inflammatory loop
responsible for chronic progression of arthritis processes. The expression of TLR9 in the
joints was assessed in chronic phase (day 30) of ZIA and CIOA. In healthy mice no
detectable expression of TLR9 was found in the synovium in contrast to CIOA and ZIA,
where synovial lining was extensively stained (Fig. 5A).
We observed stronger TLR9 positive staining in the bone and bone marrow of ZIA than of
CIOA, in comparison to healthy mice showing only single positive cells (Fig. 5B). Most
intensive accumulation of TLR9 positive cells was established in ZIA mice, especially well
exerted in the sites of osteophyte formation (Fig. 5C)
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synovium
bone and bone

marrow
osteophyte
formation
Fig. 5. Histological analyses of TLR9 expression in the joint. Dissected ankle joints were
and embedded in paraffin. Sections (6 m thickness) were blocked with 5% bovine serum
fixed in 10% paraformaldehyde/PBS, decalcified in 5% nitric acid for 1 week, dehydrated
albumin/PBS for 1 h and the endogenous peroxidase was blocked with 0.3% H2O2 in 60%
temperature with antibodes against mTLR9 (10 g/ml). Isotype anti-mouse IgG was used as
methanol for 10 min. After washing, the sections were incubated for 40 min at room
a background staining control. Then, the joint sections were incubated for 10 min with
biotinylated anti-mouse IgGs and streptavidin-peroxidase was added for 10 min. The
sections were washed and incubated with DAB solution kit (3',3'diaminobenzididne kit,
Abcam) for 10 min and counterstained with Gill’s hematoxylin. Arrows show positive TLR9
staining (magnification 40x).
The different TLR9 expression might be due to the difference in both models. Zymosan-
induced arthritis is an example for proliferative arthritis, which is restricted to the joint
injected with zymosan (Bernotiene et al., 2004). Using this model we found that
histologically, joint sections showed cell infiltration into cartilage, capsule, osteoid and
surrounding soft tissue and synovial hyperplasia without aggressive pannus formation.
Proteoglycan depletion in cartilage, detected by loss of safranin O staining intensity, and
changes in joint architecture were observed at late stage of arthritis. Interestingly, we
observed the immunoreactivity for TNF-R and C5aR in cartilage, along with C5aR positive
inflammatory cells in the areas of bone and synovium. At the onset of ZIA, TNF- plays a
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dominant role in inflammation. In the synovial extracts were found increased levels of IL-6
and C5a that can regulate the expression of C5aR on infiltrating neutrophils (Dimitrova et
al., 2010; Dimitrova et al., 2011). CIA was provoked by intraarticular injections of
collagenase, leading to acute ligament instability and prolonged inflammatory cartilage
erosion over a period of six weeks. The model is relevant to human osteoarthritis pathology.
In order to look for correlation between elevated TLR expression and the severity of arthritis
we investigated the changes of TLR9 expression by macrophages from different origin in
established ZIA. Data showed high presence of TLR9 positive cells in peritoneal exudates
and PLNs in arthritic animals, while such elevation was not established for spleens (Fig. 6).
These results deserve further experiments on the role of macrophages in the maintenance of
inflammation in different organs. The elevation in lymph node population might be due to
the fact that PLN is located most closely to the site of zymosan injection in inflamed joint.
healthy
60
P<0.001 ZIA
TLR9 positive cells (%)
P<0.001
40
20
peritoneal M  splenic M  PLN M 

0
Fig. 6. TLR9 expression in macrophages isolated from different compartments at day 30 of

ZIA. Differentiated macrophages isolated from peritoneal exudates (peritoneal M), spleens
stained with antibodies against mouse TLR9 (1 g/ml), followed by secondary FITC-
(splenic M) and popliteal lymph nodes (PLN M) of healthy and ZIA mice (1x106/ml) were
conjugated anti-mouse antibody and subjected to FACS analysis.
4. Natural killer cells

Natural killer cells are firstly described by their capacity to limit the growth of malignant
cells and to eliminate virus-infected cells. They are innate immune effectors that produce
immunoregulatory cytokines, such as interferon (IFN)- and granulocyte macrophage–
colony-stimulating factor GM-CSF (Bancroft, 1993; Feng et al., 2006). Later, it became
evident that NK cells can play a critical role in various autoimmune diseases, including
rheumatoid arthritis by improving or exacerbating immune responses. They can play dual
role in autoimmune diseases, either support or suppress pathogenic processes. In animal
models it is established that NK cells are responsible for the induction and progression of
K/BxN serum transfer model, being engaged through activation of their FcgIII receptors
(Kim et al., 2006) and also being involved in the acceleration and exacerbation of CIA (Chu
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et al., 2007). The induction of CIA in NK-depleted mice reduces the severity of arthritis and
almost completely prevents bone erosion (Soderstrom et al., 2010). In these experiments,
also significantly reduced inflammation, pannus formation, and synovitis have been
observed. NK cells are enriched within the joints of RA patients but how they contribute to
disease pathology is currently not fully elucidated. In RA patients NK cells comprise 20 % of
the synovial fluid cells at the early phase of disease (de Matos et al., 2007; Tak et al., 1994).
These cells express CD56 and CD94/NKG2A phenotype, but failed to express CD16
similarly to peripheral RA NK cells.
Two distinct subsets of mature NK cells have been recognized, CD56bright and CD56dim.
CD56bright subset is the source of IFN- , TNF- , IL-10, IL-13, and GM-CSF, whereas the
CD56dim NK cell subset produces significantly less of these cytokines in vitro (Cooper et al.,
2001). The CD56bright NK cells express a chemokine receptor pattern similar to that of
monocytes including high-affinity receptors for IL-15 (Carson et al., 1994). This subset has
been identified in the joints of patients with early synovitis in RA. Several studies have
shown that IL-15 is a critical factor for the development of human and murine NK cells
(Kennedy et al., 2000; Mrozek et al., 1996). This might be due to its stimulation of M-CSF and
RANKL expression by NK cells. IL-15 alone did not change the ability of monocytes to
enhance osteoclast formation, while this process was dramatically supported in the presence
of both NK cells and IL-15, indicating that the effect of IL-15 is mediated through NK cells
(Soderstrom et al., 2010).
NK cells may be implicated in the initiation, the maintenance or the progression of autoimmune
diseases directly or through their interaction with dendritic cells, macrophages or T
lymphocytes. Whether neutrophils are capable to regulate and influence the activity of NK cells
is not well defined. Generally, data on neutrophils and NK cells concern RA and are focused
mainly on cytokines. There are no available investigations in OA in regard to remodeling events
and the participation of these cells in OA has been underestimated. The investigations of NK-
cell functions in patients with OA will improve our capacity to monitor these cells as possible
markers for disease activity and will provide new prospects for NK-cell–directed therapies.
5. Mast cells
Nearly two decades ago available data show that when compared with healthy individuals,
patients with OA had elevated numbers of intact and degranulated mast cells in the
synovium and synovial fluid of diseased joints. Histological studies confirmed significant
numbers of mast cells in both RA and OA synovium (Dean et al., 1993; Kopicky-Burd et al.,
1988). Moreover, the numbers of mast cells in OA are comparable with those in RA when
clinically active arthritis is envisaged. Prednisone used as anti-rheumatic drug lowered
synovial mast cell number (Bridges et al., 1991). Mast cells containing triptase (MCT)
expanded in the SF of OA patients (Buckley et al., 1998), while cells containing triptase and
chimase (MCTC) expand in RA but not in OA (Gotis-Graham et al., 1998). When mast cell
numbers in RA and OA patients are compared without respect to mast cell distribution in
the subsynovial layer or the stratum fibrosum, no statistical differences between the diseases
could be observed (Fritz et al., 1984). Synovial fluid collected from patients with hand OA
expressed elevated number of mast cells in correlation with high content of histamine and
elevated levels of tryptase and NO (Renoux et al., 1996). Such data support the hypothesis
that in OA the increase of mast cells may participate in the pathological process, at least they
can contribute in concert with other inflammatory cells.
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6. Adipokines as potential participants in OA

Although leptin has been discovered fifteen years ago, the investigations on adipokines as
potential participants in arthritic diseases are now at its beginning. Innate immunity cells
appeared to be a source of adipokines as well as an object of their action. Leptin realizes its
action as a proinflammatory cytokine through modulation of monocytes, macrophages,
neutrophils, basophils, eosinophils, natural killer and dendritic cells ( Otero et al., 2005). It
seems to play a role in auto immune diseases such as RA and OA, by expressing harmful as
well protective action on joint structures in RA (Lago et al., 2007). Leptin has been detected in
SF obtained from patients with OA, and it was strongly overexpressed in human OA cartilage
and in osteophytes (Dumond et al., 2003). The administration of exogenous leptin in rats
increases IGF1 and TGF 1 production suggesting that high circulating leptin levels might
protect cartilage from osteoarthritic erosion but it also can induce osteophyte formation.
Although adiponectin was discovered almost at the same time as leptin, its role in obesity-
related dis orders has now begun to be investigated. In joint disorders adiponectin might play
proinflammatory role beimg involved in matrix degradation. The pathogenic role of
adiponectin is largely unknown in concern to RA and OA. Recent data proved that in chronic
RA patients adiponectin plasma levels are higher compared to healthy controls, but lower
plasma levels than in OA (Laurberg et al., 2009). Another member of this group is resistin
(FIZZ3) which is found in adipocytes, macrophages and other cell types. It has been
determined in the plasma and the synovial fluid of RA patients. The injection of resistin into
mice joints induces an arthritis-like condition, with typical leukocyte infiltration in the
synovium and tissue hypertrophy (Bokarewa et al., 2005). There are not enough data to make
firm conclusions about the exact role of adipokines in arthritic processes. Their physiological
role in RA or OA and their use as disease markers deserve to be a subject of further studies.
7. Conclusions
In the hope of defining novel therapeutic targets in OA much attention has been paid on
degenerative processes of cartilage and secondary bone damage. But in recent years, the
synovium, and in particular the participation of synovial cells and their mediators are under
intensive study. Macrophages, neutrophils and lymphocytes act together with resident
fibroblasts in the destructive phases of arthritis through liberation of proinflammatory
molecues. Activated macrophages produced chemoattractants such as chemoattractant
protein 1, RANTES, MIP-2 and epithelial neutrophil activator (Choy & Panayi, 2001).
Many studies have been devoted to investigating various signaling pathways involved in
proinflammatory cytokine production from OA synovial macrophages. The promising
results of anticytokine therapies in RA prompted that such approach might be used in OA
(Bondeson, 2010). Major population of infiltrated cells in synovium are neutrophils. This is
valid for the early phase of inflammation as well as for its maintenance. The injection of anti-
neutrophil antibodies ameliorated the established disease in collagen-LPS-induced model
and K/BxN model (Nandakumar et al., 2003; Tanaka et al., 2006). Instead of
macrophage/monocyte or neutrophil depletion which can impair host resistance,
neutralizing antibodies blocking their chemotaxis might be used. Promising results in
animal models have been obtained with ant-MIP-1 antibodies (Kagari et al., 2003) and
pertussis toxin blocking of signals from G protein-coupled receptors (GPCRs) (Becker et al.,
1985; Painter et al., 1987; Spangrude et al., 1985).
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There is a large unmet need for reliable biochemical markers that will predict the subset of
patients who are at risk of the disease progression and will be used to find molecular targets
in future therapies. Elevated RANKL levels in synovium and circulation, and particularly
increased RANKL expression by neutrophils in OA, makes it a suitable candidate for
disease prognosis.
The ability of known TLR agonists to activate neutrophil functions supports the notion that
TLRs are an important pattern recognition receptors in the function of these cells.
Consequently, while producing chemokines they trigger migration of other immune cells,
such as more neutrophils, monocytes, macrophages, NK cells, and immature dendritic cells.
These results prompt a possible correlation between the increase of TLR2 positive blood
cells, including neutrophils and existing OA condition and strongly support the idea that
OA inflammation might be influenced through TLR2. Also, elevated TLR9 expression is
detected in the joints of arthritic mice. Whether TLRs involvement is similar for both
inactive and active OA is a question to be resolved. TLR-dependent mechanisms may
contribute to the activation of synovial cells, possibly leading to the destruction of cartilage
and bone in the pathogenesis of RA and OA.
8. Acknowledgments
This work has been supported by the project BG051PO001/3.3-05-001 „Science and
Business, financed by Operating Program “Development of human resources” to European
Social Fund.
9. Abbreviations
CIOA – collagenase-induced osteoarthritis; ERK – extracellular signal-regulated kinase;
FITC - fluorescein isothiocianate; GM-CSF - granulocyte-macrophage colony-stimulating
factor; IFN- - interferon gamma; IL – interleukine; MAPK-mitogen-activated protein
kinase; MIP-2 - macrophage inflammatory protein; MMP - matrix metalloproteinase; MRPs -
myeloid-related proteins; NF-kB – nuclear factor-kappa B; NK cells – natural killer cells; OA
– osteoarthritis; OPG - osteoprotegerin ; Pi3K - phosphatidylinositol 3-kinases; RA –
rheumatoid arthritis; RANK – receptor activator of nuclear factor-kappa B; RANKL -
receptor activator of nuclear factor-kappa B ligand; RANTES - Regulated upon Activation,
Normal T-cell Expressed, and Secreted; STAT - Signal Transducer and Activator of
Transcription; TGF- – transforming growth factor beta; TIMP-1 - TIMP metallopeptidase
inhibitor 1; TLR – Toll-like receptor; TNF - tumor necrosis factor; Z39Ig - Immunoglobulin
superfamily protein Z39IG; ZIA – zymosan-induced arthritis
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Principles of Osteoarthritis- Its Definition, Character, Derivation
and Modality-Related Recognition
Edited by Dr. Bruce M. Rothschild
ISBN 978-953-51-0063-8
Hard cover, 590 pages
Publisher InTech
Published online 22, February, 2012
Published in print edition February, 2012
This volume addresses the nature of the most common form of arthritis in humans. If osteoarthritis is inevitable
(only premature death prevents all of us from being afflicted), it seems essential to facilitate its recognition,
prevention, options, and indications for treatment. Progress in understanding this disease has occurred with
recognition that it is not simply a degenerative joint disease. Causative factors, such as joint malalignment,
ligamentous abnormalities, overuse, and biomechanical and metabolic factors have been recognized as
amenable to intervention; genetic factors, less so; with metabolic diseases, intermediate. Its diagnosis is based
on recognition of overgrowth of bone at joint margins. This contrasts with overgrowth of bone at vertebral
margins, which is not a symptomatic phenomenon and has been renamed spondylosis deformans.
Osteoarthritis describes an abnormality of joints, but the severity does not necessarily produce pain. The
patient and his/her symptoms need to be treated, not the x-ray.
How to reference
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Petya Dimitrova and Nina Ivanovska (2012). How Important are Innate Immunity Cells in Osteoarthritis
Pathology, Principles of Osteoarthritis- Its Definition, Character, Derivation and Modality-Related Recognition,
Dr. Bruce M. Rothschild (Ed.), ISBN: 978-953-51-0063-8, InTech, Available from:
http://www.intechopen.com/books/principles-of-osteoarthritis-its-definition-character-derivation-and-modality-
related-recognition/how-important-are-innate-immunity-cells-in-osteoarthritis-pathology
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How Important are Innate Immunity Cells in

2. Neutrophils as the main participants in the development of OA

regulated by two transcription factors: hypoxia-inducible factor 1 (HIF1) and forkhead

2.2 RANKL expression on OA neutrophils

Intracellularly, RANK interacts with TNF receptor-associated factor 6 (TRAF6), which

healthy controls active OA inactive OA

No. of subjects (women/men) 10 (4/6) 12 (5/7) 14 (6/8)

Duration (years) not assessed 4.5 ± 1.2 2.5 ± 1.2

ESR (mm/h) <20 24.8 ± 6.2 14.0 ± 3.6

RF not assessed <20 <20

CRP <0.01 58.9 ± 30.4 <0.01

CRP – C reactive protein; ESR-erythrocyte sedimentation rate; OA-osteoarthritis; RF-rheumatoid factor;

responded with an increased RANKL expression (8.22  0.07%). Significantly higher

only inactive group responded to zymosan stimulation (Fig. 1).

healthy controls active OA inactive OA

2.3 MRP8/MRP14 as a potential OA marker related to neutrophil recruitment

2.4 TLR2 expression by OA neutrophils

against human TLR2 (3 g/ml), followed by secondary FITC-conjugated anti-rat antibody.

Fig. 4. Spontaneous and zymosan-induced TNF- production by blood neutrophils. (A)

(1x106/ml) were incubated (370C, 24 h) in the absence or presence of 10 g/ml of zymosan.

(370C, 24 h) in the absence or presence of 10 g/ml of zymosan. TNF- concentration in the

supernatants was determines by ELISA.

2.5 Activation of monocytes and macrophages during OA

bone and bone

peritoneal M  splenic M  PLN M 

Fig. 6. TLR9 expression in macrophages isolated from different compartments at day 30 of

conjugated anti-mouse antibody and subjected to FACS analysis.

4. Natural killer cells

6. Adipokines as potential participants in OA

stimulating factor is caused by inhibition of programmed cell death. Blood, Vol.80,

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