Cytokine and Growth Factor Reviews 39 (2018) 71–91

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Cytokine and Growth Factor Reviews

journal homepage: www.elsevier.com/locate/cytogfr

Review article

Cytokines in the pathogenesis of hemophilic arthropathy T

a,b,c,⁎
Piotr Wojdasiewicz , Łukasz A. Poniatowski , Paweł Nauman , Tomasz Mandat , d e e,f

Agnieszka Paradowska-Goryckag, Katarzyna Romanowska-Próchnickaa,h, Dariusz Szukiewicza,

Andrzej Kotelai,j, Łukasz Kubaszewskik,l, Ireneusz Kotelaj, Iwona Kurkowska-Jastrzębskam,
Robert Gasikc
a
Department of General and Experimental Pathology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Pawińskiego 3C, 02-106
Warsaw, Poland
b
Department of Rheumaorthopaedics, Eleonora Reicher National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland
c
Department of Neuroorthopaedics and Neurology, Eleonora Reicher National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland
d
Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Banacha 1B, 02-097
Warsaw, Poland
e
Department of Neurosurgery, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland
f
Department of Neurosurgery, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, W. K. Roentgena 5, 02-781 Warsaw, Poland
g
Department of Biochemistry and Molecular Biology, Eleonora Reicher National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw,
Poland
h
Department of Systemic Connective Tissue Diseases, Eleonora Reicher National Institute of Geriatrics, Rheumatology and Rehabilitation, Spartańska 1, 02-637 Warsaw, Poland
i
Department of Orthopaedics and Traumatology, 1st Faculty of Medicine, Medical University of Warsaw, Lindleya 4, 02-005 Warsaw, Poland
j
Department of Orthopaedics and Traumatology, Central Clinical Hospital of the Ministry of the Interior and Administration, Wołoska 137, 02-507 Warsaw, Poland
k
Department of Spondyloorthopaedics and Biomechanics of the Spine, Wiktor Dega Orthopaedic and Rehabilitation Clinical Hospital, Poznań University of Medical
Sciences, 28 Czerwca 1956 135/147, 61-545 Poznań, Poland
l
Department of Orthopaedics and Traumatology, Wiktor Dega Orthopaedic and Rehabilitation Clinical Hospital, Poznań University of Medical Sciences, 28 Czerwca 1956
135/147, 61-545 Poznań, Poland
m
2nd Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland

A R T I C L E I N F O A B S T R A C T

Keywords: Hemophilic arthropathy (HA) is one of the most common and typical manifestation in the course of recurrent
Cytokines bleeding episodes in patients with hemophilia. Clinical and subclinical joint bleeding episodes gradually lead to
Hemophilic arthropathy irreversible changes manifesting themselves as pain, progressing ankylosis, marked limitation of the range of
Hemophilia motion, muscle atrophy and osteoporosis commonly concomitant with joint deformity resulting from chronic
Arthritis
proliferative synovitis and both cartilage and bone degeneration leading to the final functional impairment of the
Inflammation
Synovitis
joint. In spite of numerous studies, the pathophysiology of HA has not been fully elucidated, especially as regards
immunopathological mechanisms which are associated with the subclinical and early stage of the disease and to
be more precise, with chronic joint inflammation. It needs to be emphasized that the pathophysiological pro-
cesses occurring in a joint with HA are most probably highly mediated by interactions within the cytokine
network and other inflammatory mediators present in the tissues of affected joint. Among numerous compounds
participating in the induction of an inflammatory process in the pathogenesis of HA, cytokines seem to play a
leading role. The most important group controlling the disease seems to be well known inflammatory cytokines,
including IL-1β, TNFα and IL-6. The second group with antagonistic effect is formed by anti-inflammatory
cytokines such as IL-4 and IL-10. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis
of HA with respect to cellular and intracellular signaling pathways is still under investigation. This review,
summarizes and discusses the current knowledge about cytokine network in the pathogenesis of HA, indicating
possible molecular and cellular mechanisms that may provide potential new therapeutic directions.

⁎
Corresponding author at: Department of General and Experimental Pathology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Pawińskiego
3C, 02-106 Warsaw, Poland.
E-mail addresses: piotr.wojdasiewicz@wum.edu.pl (P. Wojdasiewicz), lukasz.poniatowski@gmail.com (Ł.A. Poniatowski), pnauman@ipin.edu.pl (P. Nauman),
tomaszmandat@yahoo.com (T. Mandat), paradowska_aga@interia.pl (A. Paradowska-Gorycka), katarzyna.prochnicka@gmail.com (K. Romanowska-Próchnicka),
dszukiewicz@hotmail.com (D. Szukiewicz), andrzejkotela@op.pl (A. Kotela), pismiennictwo1@gmail.com (Ł. Kubaszewski), ikotela@op.pl (I. Kotela),
ikurkowska@ipin.edu.pl (I. Kurkowska-Jastrzębska), robertgasik2@gmail.com (R. Gasik).

https://doi.org/10.1016/j.cytogfr.2017.11.003
Received 4 November 2017; Accepted 9 November 2017
Available online 13 November 2017
1359-6101/ © 2017 Elsevier Ltd. All rights reserved.
P. Wojdasiewicz et al. Cytokine and Growth Factor Reviews 39 (2018) 71–91

Fig. 1. Schematic representation of the coagulation cascade and simplified life cycle of FVIII and FIX including their domain structure and processing under physiological conditions.
Hemostasis mechanisms defined as a system of proteolytic reactions, are activated by two distinct pathways, through intrinsic pathway associated with the formation of ITC (FVIIIa/FIXa/
FX/PM/Ca2+) and by extrinsic pathway associated with the formation of ETC (FVIIa/FX/TF/PM/Ca2+). Both of these converge on the activation of common pathway associated with the
formation of PTC (FII/FVa/FXa/PM/Ca2+) and catalytic generation of FIIa which is essential for conversion of FI into FIa. Ultimately, FIa monomers polymerization along with platelet
aggregation leads to formation of a stable cross-linked fibrin clot. The tightly controlled process such a hemostasis can be disrupted by genetic deficiency or reduction in the activity of
FVIII or FIX. In this conditions assembly and functioning of ITC is impaired leading to prolonged bleeding (APTT ≥ 30–40 s). This types of congenital disturbances in hemostatic system
are known as hemophilia A and B. Abbreviations: APTT activated partial thromboplastin time, HMWK high molecular weight kininogen (Fitzgerald factor), PK prekallikrein (Fletcher
factor), K kallikrein, FXII coagulation factor XII (Hageman factor), FXIIa active coagulation factor XII, FXI coagulation factor XI (plasma thromboplastin antecedent), FXIa active
coagulation factor XI, FIX coagulation factor IX (Christmas factor), GLA gamma-carboxyglutamic acid-rich domain (1–40 aa), EGF1 epidermal growth factor 1-like domain (47–83 aa),
EGF2 epidermal growth factor 2-like domain (88–127 aa), AP activation peptide (146–180 aa), CAT catalytic domain (181–415 aa), FIXa active coagulation factor IX, FVIII coagulation
factor VIII (anti-hemophilic factor), A1 A1 domain (1–336 aa), a1 a1 acidic region (337–372 aa), A2 A2 domain (373–710 aa), a2 a2 acidic region (711–740 aa), B B domain (741–1648
aa), a3 a3 acidic region (1649–1689 aa), A3 A3 domain (1690–2019 aa), C1 C1 domain (2020–2172 aa), C2 C2 domain (2173–2332 aa), vWF von Willebrand factor, FVIIIHC coagulation
factor VIII heavy chain (A1-a1-A2-a2-B), FVIIILC coagulation factor VIII light chain (a3-A3-C1-C2), FVIIIa active coagulation factor VIII, PM phospholipid membrane, ITC intrinsic tenase
complex, PT prothrombin time, INR international normalized ratio, TF (FIII) tissue factor (coagulation factor III), FVII coagulation factor VII (proconvertin), FVIIa active coagulation
factor VII, ETC extrinsic tenase complex, TT thrombin time, FX coagulation factor X (Stuart factor), FXa active coagulation factor X, FV coagulation factor V (proaccelerin), FVa active
coagulation factor V, PTC prothrombinase complex, FII prothrombin, FIIa thrombin, FI fibrinogen, FIa fibrin, FXIII coagulation factor XIII (fibrin-stabilizing factor), FXIIIa active
coagulation factor XIII.

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P. Wojdasiewicz et al.
1. Introduction
Hemophilia is a congenital coagulation disorder caused by the re-
duced activity or the lack of plasma glycoproteins such as coagulation
factor VIII (FVIII), which leads to the development of hemophilia A, and
analogous reduction in the activity or the absence of coagulation factor
IX (FIX), which leads to the development of hemophilia B (Christmas
disease) [1,2]. Both hemophilia A and B are sex-linked disorders de-
termined by the presence of alleles on chromosome X (Xh), inherited in
a monogenic recessive pattern, where females (46,XX) are carriers
(46,XhX), and the disease is present in males (46,XY) having a complete
expression of the recessive gene (46,XhY) [2]. Around 1/3 of the cases
are caused by spontaneous mutations (de novo), without no prior fa-
mily history of hemophilia [1]. The reduced activity of FVIII and FIX
oscillating around the reference values may be commonly observed in
hemophilia gene carriers and in some rare cases the carriers may also
suffer from hemophilia (46,XhXh) [1,2]. Moreover, the clinically ob-
servable picture of the disease may be also affected by other genetic
factors leading to a multifactorial disease [3]. The analysis of currently
available data from long-term epidemiological research shows that
hemophilia is a disease carrying a heavy economic burden with its di-
rect and indirect costs [4]. It is also associated with limiting the health-
related quality of life (HRQoL) [4].
Taking into consideration global epidemiological data on hemo-
philia, according to the monitoring by the Centers for Disease Control
and Prevention (CDC) and World Federation of Hemophilia (WFH) the
prevalence of hemophilia A is around 1 in 5000 male births, and 1 in
30000 male births for hemophilia B and occurs in approximately 1 out
of 7500 live male births, affecting all racial and socioeconomic groups
equally [5–8].
The disturbances of hemostasis that are considered to be associated
with the reduction of activity or absence of FVIII and FIX are related to
the impairment of intrinsic tenase complex (ITC) functioning in the
activation of coagulation factor X (FX) to active FX (FXa) [9] (Fig. 1).
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Cytokine and Growth Factor Reviews 39 (2018) 71–91
Active FIX (FIXa), and acting as a cofactor active FVIII (FVIIIa), parti-
cipate in ITC forming in the presence of phospholipid membrane (PM)
and calcium ions (Ca2+) [9,10]. The kinetics of ITC complex in the
catalytic generation of FXa is approximately 50-fold more efficient
(kcat/Km) than extrinsic tenase complex (ETC) and therefore, its in-
sufficiency results in inhibition of assembly of prothrombinase complex
(PTC) and the impairment of thrombin (FIIa) production
(VITC→FXa ≥ 50 x VETC→FXa) [11,12]. Depending on the level of FVIII
and FIX in the serum, we distinguish the following forms of the disease:
severe < 0.01 IU/mL (< 1% of normal level), moderate 0.01–0.05 IU/
mL (1–5% of normal level) and mild > 0.05 to < 0.40 IU/mL (> 5%
to < 40% of normal level) [13].
The main phenotypic manifestations of the mutations on chromo-
some X are hemorrhages which are a part of the comprehensive clinical
picture in hemophilia patients. The type, location and severity of he-
morrhages are directly connected with factors including the type and
level of coagulation factor deficiency, patient’s age and a potentially
introduced treatment, however, the majority of cases are heterogenous
bleeding phenotypes [14]. According to the WFH, the most common
and typical manifestations in the course of severe hemophilia are non-
traumatic (spontaneous) hemorrhages within the musculoskeletal
system, with spontaneous intraarticular bleeding (hemarthrosis) ac-
counting for 70–80% of all the hemorrhages, and intramuscular he-
morrhages (the second largest group) accounting for 10–20% of all the
hemorrhages occurring in patients [15]. Bleeding episodes are most
frequently reported in large synovial joints, like the elbow, knee and
ankle [15]. Less frequently in multiaxial joints such as the shoulder and
the hip joint [15]. Recurrent clinical and subclinical joint bleeding
episodes gradually lead to irreversible changes manifesting themselves
as pain, progressing ankylosis, marked limitation of the range of motion
(ROM), muscle atrophy and osteoporosis commonly concomitant with
joint deformity resulting from chronic proliferative synovitis (syno-
vium-mediated component) and cartilage degeneration (cartilage-
mediated component) leading to the final functional impairment of the
Fig. 2. Radiographs showing the advanced hemo-
philic arthropathy of the knee in anteroposterior (A)
and lateral (B) view. In this case, we can observe
symmetrical full-thickness articular cartilage loss at
both femoral and tibial condyle associated with
subchondral bone destruction resulting in cyst for-
mation.
P. Wojdasiewicz et al. Cytokine and Growth Factor Reviews 39 (2018) 71–91

Fig. 3. Schematic overview of the potential cellular and molecular mechanisms by which IL-1β and its associated signaling pathways are involved in expression and functional regulation
of various genes involved in inflammatory and catabolic processes in the pathogenesis of hemophilic arthropathy. Abbreviations: IL-1β interleukin 1 beta, IL-1RA interleukin 1 receptor
antagonist, anti-IL-1β antibodies against interleukin 1 beta, IL-1R1 (CD121a) interleukin 1 receptor type 1, IL-1R2 (CD121b) interleukin 1 receptor type 2, IL-1RAcP interleukin 1 receptor
accessory protein, D1 immunoglobulin-like domain 1, D2 immunoglobulin-like domain 2, D3 immunoglobulin-like domain 3, TIR Toll/IL-1R homology domain, MyD88 myeloid
differentiation primary response 88 protein, IRAK4 interleukin 1 receptor associated kinase 4, IRAK2 interleukin 1 receptor associated kinase 2, IRAK3 interleukin 1 receptor associated
kinase 3, IRAK1 interleukin 1 receptor associated kinase 1, TRAF6 TNF receptor associated factor 6, IKKα inhibitor of nuclear factor kappa B kinase subunit alpha, NEMO nuclear factor
kappa B essential modulator, IKKβ inhibitor of nuclear factor kappa B kinase subunit beta, IκB inhibitor kappa B kinase complex, p50 nuclear factor kappa B subunit 1, p65 nuclear factor
kappa B p65 subunit, TAB2 TGF-β activated kinase 1/MAP3K7 binding protein 2, TAK1 mitogen-activated protein kinase kinase kinase 7, TAB3 TGF-β activated kinase 1/MAP3K7
binding protein 3, ERK1/2 extracellular signal-regulated kinase 1/2, JNK c-Jun N-terminal kinase, p38 p38 mitogen-activated protein kinase, AP-1 activator protein 1, MMP-1 interstitial
collagenase, MMP-3 stromelysin 1, MMP-13 collagenase 3, ADAM-TS4 a disintegrin and metalloproteinase with thrombospondin motifs 4, TNFα tumor necrosis factor alpha, IL-6
interleukin 6, IL-8 interleukin 8, CCL5 C-C motif chemokine ligand 5, PLA2 phospholipase A2, COX-2 cyclooxygenase 2, PGE2 prostaglandin E2, iNOS inducible nitric oxide synthase,
ACAN aggrecan, COL2 collagen type II; ↑ increase of expression, ↓ decrease of expression.

74
P. Wojdasiewicz et al.
joint [16,17]. Hemophilic arthropathy (HA) is a syndrome connected
with blood-induced joint disease (BIJD) in the course of hemophilia
[17] (Fig. 2).
The correlation between hemorrhages occurring in the course of
hemophilia and arthritis was first reported by a German surgeon Franz
König in 1892, who was also the first to perform joint surgery in he-
mophilia patients [18]. The natural history of HA on an animal model
was first described by Margaret Swanton in 1959 [19]. While there is no
uniform consensus, it is considered that the annual joint bleeding rate
(AJBR) at the level of 2–3 predisposes to the development of irrever-
sible pathobiological and structural changes within the tissues of the
joint [20]. Regarding in vitro testing results, research conducted on
animals and histological analysis, it is assumed that the process may be
due to a single clinical episode of hemarthrosis and potentially occur-
ring subclinical bleedings [20]. According to Fisher et al. the median
age at the time of the first joint bleeding is 2.2 years (range: 0.2–5.8
years) and 90% of patients had experienced at least one joint bleeding
at the age of 4.4 years [21]. Although an effective prophylactic factor
replacement therapy (FRT) was developed which considerably reduces
the occurrence of joint bleeding episodes, there are still patients with a
clinically advanced form of HA (30–50%) in many regions of the world,
also in highly developed countries [15,22]. HA is the main cause of
morbidity in patients with hemophilia [15,23]. In the most severe types
of hemostasis disturbances associated with hemophilia even appro-
priate and regular use of prophylactic FRT may not prevent the de-
velopment of advanced forms of HA, which may be due to the devel-
opment of alloimmune antibodies directed against epitopes of infused
FVIII (anti-FVIII) or FIX (anti-FIX) known as inhibitors, occurring in
approximately 10–30% hemophilia A patients and 2–5% of hemophilia
B patients [24].
In spite of numerous studies, the pathophysiology of HA has not
been fully elucidated, especially as regards immunopathological me-
chanisms which are associated with the subclinical and early stage of
the disease and to be more precise, with intraarticular inflammation
[15,25]. The presence of extravasated blood in the joint is the trigger of
an inflammation which initiates BIJD [17]. The morphotic elements of
blood include numerous immune system cells, such as granulocytes,
monocytes and lymphocytes, and it needs to be emphasized that after
extravasation these elements remain active in the process of secretion of
inflammatory mediators [26]. Then, blood and its metabolites are
gradually absorbed by macrophages (MΦ) and synovial cells [17]. In
case of recurrent episodes of hemarthrosis, the potential of blood me-
tabolite removal by immune system cells present in the joint and the
synovial membrane gradually depletes [17]. It results in an extended
presence of toxic blood metabolites, such as erythrocyte-derived iron
(Fe2+) and deposition of hemosiderin in the synovium which is asso-
ciated with the production of reactive oxygen species (ROS) via the
Haber-Weiss/Fenton reaction (Fe2+ + H2O2 → Fe3+ + OH% + OH−)
and, additionally, induction of oxidative stress [27,28]. These processes
lead to pathological changes including cartilage and subchondral bone
destruction, increased fibroblast proliferation and angiogenesis within
the synovial membrane resulting in its hypertrophy which is also as-
sociated with overexpression of mouse double minute 2 homolog
(MDM2) and v-myc avian myelocytomatosis viral oncogene homolog
(c-MYC) [17].
It has already been mentioned that in case of HA and other arthritis-
associated diseases the direct process of intensified degeneration of
joint tissues is due to a chronic inflammation [25]. Among numerous
compounds participating in the induction of an inflammatory process in
HA pathogenesis cytokines seem to play a leading, but not fully eluci-
dated role [25]. Cytokines form a heterogeneous group of mediators
responsible for such processes as activation and proliferation of im-
mune system cells and the change of the metabolism of various types of
cells including, what is important in this context, cells which make up
the joint and potentially infiltrate its structures via blood vessels [29].
Cytokines and their individual, highly specific influence via positive
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Cytokine and Growth Factor Reviews 39 (2018) 71–91
and negative feedback exerted on cells and the production of other
cytokines forms a complex multilevel system of correlations known as
cytokine network [30]. It needs to be emphasized that the potential role
of cytokines and inflammatory mediators in the pathomechanism and
pathophysiology of numerous arthritis-associated diseases such as os-
teoarthritis (OA) and rheumatoid arthritis (RA) have been described
[31,32]. In this review, we describe the participation of the cytokine
network in the course of HA, and will analyse the role of inflammatory
and anti-inflammatory cytokine-driven processes occurring in HA-af-
fected joints, late sequelae and possible clinical implications.
2. Inflammatory cytokines
The role of inflammatory cytokines in the pathogenesis of HA
mainly involves promoting catabolic processes in joint-forming tissues
and intensifying an inflammatory response [17,25]. In the described
context catabolic processes are mainly seen in the cells and extra-
cellular matrix of the articular cartilage which, as a result of the dis-
ruption of its metabolic homeostasis, undergoes gradual atrophy and
destruction [33]. However, the intensification of immune response
should be associated with immune system cells which may be activated
and stimulated by cytokines as a result of autocrine, paracrine and
endocrine properties acting via pleiotropy, redundancy, synergy and
antagonism [30]. Periarticular tissues are also sensitive to in-
flammatory cytokine activity, especially the synovial membrane or its
vascular endothelial cells, which become a potentially dynamic re-
servoir of cells and mediators participating in an inflammation after the
activation of intracellular pathways propagating an inflammatory re-
sponse [34]. Currently, interleukin 1 beta (IL-1β), tumor necrosis factor
alpha (TNFα) and interleukin 6 (IL-6) are the best described in-
flammatory cytokines which take part in the pathogenesis of HA.
2.1. Interleukin 1 beta (IL-1β)
2.1.1. Overview of the IL-1β properties and its associated signaling
pathways
The activity of IL-1β as one of the main regulators of inflammatory
response consists of inducing catabolic processes in the articular carti-
lage and other elements making up the joint [17,25] (Fig. 3). IL-1β
belongs to interleukin 1 family (IL-1F), which consists of 11 ligand
members [35]. IL-1β precursor is synthesized as a cytosolic protein
(pro-IL-1β), which is composed of 269 amino acid residues [36]. After
the proteolysis by the cysteine-aspartic acid protease, caspase 1
(CASP1, ICE), a member of the multiprotein oligomer NLR family pyrin
domain containing 3 (NLRP3) inflammasome, the precursor is con-
verted into an active form composed of 153 amino acid residues, and
then secreted to the extracellular space [25,37]. It has an ability to
adhere to two types of receptors. One of them is interleukin 1 receptor
type 1 (IL-1R1, CD121a), belonging to Toll-like receptors (TLR) and
interleukin 1 receptor (IL-1R) superfamily, which has the affinity for
other cytokines from IL-1F family, such as interleukin 1 alpha (IL-1α)
and interleukin 1 receptor antagonist (IL-1RA) [38]. Another receptor is
interleukin 1 receptor type 2 (IL-1R2, CD121b), which includes the
same set of possible ligands as IL-1R1, with the reservation that IL-1R2
forms an inactive ligand-receptor complex which is unable to propagate
further signals of intracellular communication [39]. Intracellular
phosphorylation of subsequent proteins due to IL-1R1, leads to the
activation of nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-κB) transcriptive factor and other transcriptive factors such as
c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein ki-
nases (p38MAPK) [40]. As a result, there is an increased expression of
various genes responsible for the synthesis of enzymes, adhesion mo-
lecules or inflammatory mediators including cytokines and chemokines
[41].
P. Wojdasiewicz et al. Cytokine and Growth Factor Reviews 39 (2018) 71–91

HA hemophilic arthropathy, MNC mononuclear cells, RBC red blood cells, LPS lipopolysaccharide, F8-KO F8 gene knock-out, CD14+ cluster of differentiation 14 cells, ELISA enzyme-linked immunosorbent assay, IHC immunohistochemistry.
2.1.2. Biological functioning of the IL-1β in joint tissues

Reference
IL-1β may be synthesized within joint tissues both by synovial

[115]
[118]
[131]
[54]
[55]
[56]
[57]
[58]
[60]
[62]
[63]
membrane cells, chondrocytes, osteoblasts and mononuclear cells in the
course of an inflammation [42]. IL-1β demonstrates a multidirectional
effect on the articular cartilage via simultaneous intensification of its

of incubation
of incubation

of incubation
of incubation
of incubation
disintegration and inhibition of regenerative processes [43]. Under the
influence of IL-1β, chondrocytes increase the synthesis of enzymes from
matrix metalloproteinase (MMP) group, including interstitial col-
lagenase (MMP-1), stromelysin 1 (MMP-3), collagenase 3 (MMP-13),

cultures after 4 days

cultures after 4 days

cultures after 4 days

cultures after 4 days
cultures after 4 days
which influence the excessive degradation of extracellular matrix mo-

subchondral bone
lecules [44]. IL-1β also results in an increased proteolysis of aggrecan

synovial fluid
supernatants
supernatants
supernatants

supernatants
(ACAN) molecules by promoting the secretory activity of cartilage cells
in order to produce proteinases from a disintegrin and metalloprotei-
nase with thrombospondin motifs (ADAM-TS) family, and more pre-
cisely ADAM-TS4 [44]. In addition to catabolic processes affecting the

concentration in the
concentration in the
concentration in the

concentration in the
concentration in the

concentration in the
secretion by the cell
secretion by the cell

secretion by the cell

secretion by the cell
secretion by the cell
extracellular matrix, IL-1β also causes a significant reduction in the
synthesis of the substances like collagen type II (COL2) and ACAN,

Reported results/timing
which leads to a gradual loss of cartilage density and its mechanical
resistance [45]. The combination of IL-1β and TNFα led to a tendency
towards accelerated ageing process and more frequent induction of

of
of
of
of
of
of
of
of
of
of
of
apoptosis in chondrocytes [46]. This may be directly related to the

Increase
Increase
Increase
Increase
Increase
Increase
Increase
Increase
Increase
Increase
Increase
property of IL-1β to increase the production of ROS and induce oxi-
dative stress [47]. IL-1β generates the development of substances such
as hydroxyl radicals (OH%) and peroxides (H2O2) which have been
shown to destroy the structure of articular cartilage [47]. Thus, the

Methodology for quantification

catabolic properties of IL-1β are not only due to a direct influence on
chondrocyte metabolism, but also to the stimulation of the production
of inflammatory mediators in all types of cells which make up the joint
[48]. IL-1β triggers the synthesis of numerous inflammatory cytokines
such as TNFα, IL-6, interleukin 8 (IL-8), C-C motif chemokine ligand 5

Luminex xMAP
(CCL5, RANTES) and also induces self-secretion via an autocrine me-
chanism [49]. Moreover, it increases the production and causes the
ELISA
ELISA
ELISA
ELISA
ELISA

ELISA
ELISA
ELISA
ELISA
overexpression of inflammatory enzymes and molecules including
phospholipase A2 (PLA2), cyclooxygenase 2 (COX-2), prostaglandin E2 IHC
(PGE2) and inducible nitric oxide synthase (iNOS) [50–52].
Subchondral bone samples

2.1.3. Role of IL-1β in the pathogenesis of hemophilic arthropathy

Synovial tissue samples
Synovial tissue samples
Synovial tissue samples

Synovial tissue samples

Synovial fluid samples

Numerous studies implicate IL-1β production in the pathophy-

Method of sampling

Cartilage cultures
Cartilage cultures

Cartilage cultures
Cartilage cultures
Cartilage cultures

siology of HA [17,25,37,53] (Table 1). The level of IL-1β is markedly

elevated in the synovial membranes harvested via synovectomy or joint
replacement from patients with HA compared to the control group
[54,55]. Roosendaal et al. analysed cell cultures from synovial tissue of
Observational studies showing the expression pattern of IL-1β in hemophilic arthropathy.

patients with HA and reported that the supernatants had higher levels
of IL-1β compared to the control group [56]. A significantly elevated
level of IL-1β secretion was also observed in the supernatants of human
Cartilage co-cultured with whole blood, MNC, MNC + RBC or MNC + LPS

articular cartilage cell cultures which underwent a short-term contact

Cartilage co-cultured with whole blood, MNC + RBC or RBC + CD14+

with the blood [57,58]. It is also currently suggested that IL-1β in-
creased transferrin (TFN)-bound iron uptake into synovial fibroblasts
which was significant in the context of chronic synovitis associated with
F8-KO mouse with needle-induced knee joint hemarthrosis

deposition of hemosiderin and IL-1β autocrine secretion [59]. A de-

Cartilage co-cultured with whole blood or MNC + RBC

tailed study by Øvlisen et al. conducted on a mouse model of hemo-

philia A demonstrated changes in the concentration of numerous cy-
tokines, including IL-1β, in the synovial fluid [60]. The study group
included FVIII gene (F8) knock-out (F8-KO) mice and the control group
included C57Bl/6NTac mice, divided into four subgroups. The first
Cartilage co-cultured with whole blood
Cartilage co-cultured with whole blood

group did not receive any clotting factor, only a carrier (an excipient
administered with clotting factors) was administered into the tail vein.
The remaining groups received various clotting factors: the second
group – recombinant FVIII (rFVIII), the third group − recombinant
activated factor VII (rFVIIa) and the fourth group − rFVII analogue
Clinical trial/model

(NN1731). All the animals from the control and study group, then had a
Patients with HA
Patients with HA
Patients with HA

Patients with HA

Patients with HA

knee injury made with a needle. After 3 days, a post-mortem analysis

was performed, which included parameters like the level of cytokines in
the synovial fluid of injured joints. The level of IL-1β in the synovial
Table 1

fluid in F8-KO mice which received placebo was considerably higher

(18.0 ± 26.2 pg/mL) than in the mice from the healthy control group

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P. Wojdasiewicz et al. Cytokine and Growth Factor Reviews 39 (2018) 71–91

Fig. 4. Schematic overview of the potential cellular and molecular mechanisms by which TNFα and TNFR1 signaling complex are involved in expression and functional regulation of
various genes involved in inflammatory and catabolic processes in the pathogenesis of hemophilic arthropathy. Abbreviations: sTNFα soluble tumor necrosis factor alpha, mTNFα
membrane tumor necrosis factor alpha, anti-TNFα antibodies against tumor necrosis factor alpha, ADAM17 (TACE) a disintegrin and metalloproteinase domain 17 (tumor necrosis factor
alpha-converting enzyme), EGF epidermal growth factor-like domain, CR cysteine-rich domain, DS disintegrin domain, MP catalytic metalloproteinase domain, iRhom2 intramembrane
serine proteases rhomboid 5 homolog 2, TNFR1 tumor necrosis factor receptor 1, DD death domain, TRADD TNFRSF1A protein associated via death domain, FADD Fas associated via
death domain, CASP8 caspase 8, RIPK1 receptor interacting serine-threonine kinase 1, Ub ubiquitin, TRAF2 TNF receptor associated factor 2, cIAP1 baculoviral IAP repeat containing 2,
cIAP2 baculoviral IAP repeat containing 3, TAB2 TGF-β activated kinase 1/MAP3K7 binding protein 2, TAK1 mitogen-activated protein kinase kinase kinase 7, TAB3 TGF-β activated
kinase 1/MAP3K7 binding protein 3, ERK1/2 extracellular signal-regulated kinase 1/2, JNK c-Jun N-terminal kinase, p38 p38 mitogen-activated protein kinase, AP-1 activator protein 1,
IL-1β interleukin 1 beta, TNFα tumor necrosis factor alpha, IL-6 interleukin 6, C5a complement component 5a, VEGF vascular endothelial growth factor, FIIa thrombin, Hb hemoglobin,
Fe2+ erythrocyte-derived iron, MMP-1 interstitial collagenase, MMP-3 stromelysin 1, MMP-13 collagenase 3, ADAM-TS4 a disintegrin and metalloproteinase with thrombospondin motifs
4, IL-6 interleukin 6, IL-8 interleukin 8, CCL5 C-C motif chemokine ligand 5, SDF-1 stromal cell-derived factor 1, VEGF vascular endothelial growth factor, HIF-1α hypoxia inducible
factor 1 alpha, HIF-2α hypoxia inducible factor 2 alpha, ACAN aggrecan, COL2 collagen type II; ↑ increase of expression, ↓ decrease of expression.

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P. Wojdasiewicz et al. Cytokine and Growth Factor Reviews 39 (2018) 71–91

(1.0 ± 6.5 pg/mL). Administration of clotting factors markedly re-
duced the level of IL-1β in the synovial fluid, with rFVIII
(3.7 ± 18.7 pg/mL) being the most efficient in this context. The results
of the substitution of rFVIIa and NN1731 were comparable
(10.0 ± 19.0 pg/mL and 11.0 ± 30.9 pg/mL, respectively). Im-
portantly, the levels of IL-1β and other inflammatory cytokines
correlated with changes observed in the joint with visual bleeding score
(VBS) [61]. Control group mice and those after rFVIII administration
manifested significantly fewer cases of joint capsule oedema and he-
marthrosis than the mice that underwent the substitution of rFVIIa,
NN1731 and after receiving placebo. The last group had a distended,
oedematous joint capsule and hemarthrosis in almost every case.

Fig. 5. Schematic overview of the potential cellular and molecular mechanisms by which TNFα and TNFR2 signaling complex are involved in expression and functional regulation of
various genes involved in inflammatory and catabolic processes in the pathogenesis of hemophilic arthropathy. Abbreviations: mTNFα membrane tumor necrosis factor alpha, anti-TNFα
antibodies against tumor necrosis factor alpha, TNFR2 tumor necrosis factor receptor 2, TRAF1 TNF receptor associated factor 1, TRAF2 TNF receptor associated factor 2, ETK BMX non-
receptor tyrosine kinase, PI3K phosphatidylinositol-4,5-bisphosphate 3-kinase, AKT protein kinase B, mTOR mechanistic target of rapamycin, RIPK1 receptor interacting serine-threonine
kinase 1, Ub ubiquitin, TRAF3 TNF receptor associated factor 3, cIAP1 baculoviral IAP repeat containing 2, cIAP2 baculoviral IAP repeat containing 3, IKKα inhibitor of nuclear factor
kappa B kinase subunit alpha, NEMO nuclear factor kappa B essential modulator, IKKβ inhibitor of nuclear factor kappa B kinase subunit beta, IκB inhibitor kappa B kinase complex, p50
nuclear factor kappa B subunit 1, p65 nuclear factor kappa B p65 subunit, MAP3K mitogen-activated protein kinase kinase kinase, ERK1/2 extracellular signal-regulated kinase 1/2, JNK
c-Jun N-terminal kinase, p38 p38 mitogen-activated protein kinase, AP-1 activator protein 1, NIK nuclear factor kappa B-inducing kinase, p100 nuclear factor kappa B p100 subunit, RelB
transcription factor RelB, p52 nuclear factor kappa B p52 subunit, MMP-1 interstitial collagenase, MMP-3 stromelysin 1, MMP-13 collagenase 3, ADAM-TS4 a disintegrin and me-
talloproteinase with thrombospondin motifs 4, IL-1β interleukin 1 beta, IL-6 interleukin 6, IL-8 interleukin 8, CCL5 C-C motif chemokine ligand 5, SDF-1 stromal cell-derived factor 1,
VEGF vascular endothelial growth factor, HIF-1α hypoxia inducible factor 1 alpha, HIF-2α hypoxia inducible factor 2 alpha, ACAN aggrecan, COL2 collagen type II; ↑ increase of
expression, ↓ decrease of expression.

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Zhang et al. analysed the levels of IL-1β in subchondral bone de- within 8 h after the exposure of a colony to blood had a reduced effect
rived from femoral heads of patients with HA and RA [62]. The level of on extracellular matrix proteoglycan synthesis. In contrast, TNFαmAb
IL-1β was markedly elevated in the subchondral bone form patients had no significant effect on the synthesis of proteoglycans via inhibiting
with HA compared to the RA patients group. A study by Hooiveld et al. TNFα activity. Moreover, IL-1βmAb reduced the apoptotic activity of
corroborated the negative multidirectional effect of IL-1β on the ar- chondrocytes, whereas TNFαmAb did not. After four days of exposure
ticular cartilage on a study model which imitated intraarticular and adding IL-1RA, the expression of IL-1β and IL-6 was reduced, TNFα
bleeding, and reported a direct influence of IL-1β on the reduction of secretion was unaffected and no influence of TNFαmAb on the ex-
the synthesis of extracellular matrix proteoglycans (PG) of the articular pression of IL-1β was observed. Despite the limitations of an in vitro
cartilage by chondrocytes which was tested with liquid scintillation model, the authors concluded that IL-1β had a key role in the process of
analysis by measuring their rate of sulphate (35SO24−) incorporation cartilage destruction due to BIJD, a role that was not observed with
[63]. Moreover, as regards the pathomechanisms of HA, it was con- TNFα [65].
firmed that the cell membrane of erythrocytes (RBC) was damaged by
lysis, and stimulated monocytes/macrophages (CD14+) to secrete in-
2.2. Tumor necrosis factor alpha (TNFα)
flammatory cytokines, mainly IL-1β independent of inflammation [64].
It was also noted that the impaired secretion of extracellular matrix
2.2.1. Overview of the TNFα properties and its associated signaling
proteoglycans by chondrocytes had a longer lasting effect in case of a
pathways
synergistic activity of IL-1β with lysed RBC than if the factors acted
TNFα is another key inflammatory cytokine, a member of tumor
separately. After four days of the exposure of a colony of human
necrosis factor TNF superfamily with catabolic properties in articular
chondrocytes to isolated IL-1β, isolated lysed RBC and IL-1β combined
cartilage and joint tissues [66,67]. The activity of a protease from a
with lysed RBC, the respective levels of secreted extracellular matrix
disintegrin and metalloproteinase (ADAM) family, namely ADAM me-
proteoglycans were 50%, 37% and 31% of the level in the control
tallopeptidase domain 17 (ADAM17) or TNFα-converting enzyme
group, which was not subjected to the activity of any external factors.
(TACE) triggers the conversion of a homotrimeric transmembrane
Next, the researchers assessed the durability of the impairment of ex-
protein type II (mTNFα) into a soluble TNFα (sTNFα) form [68]. It is
tracellular matrix proteoglycans production by chondrocytes. All three
currently suggested that the signaling pathway associated with
assessed colonies were washed to eliminate pathogenetic factors. After
ADAM17 (TACE) and its regulator known as intramembrane serine
12 days the colonies were again assessed in terms of extracellular ma-
proteases rhomboid 5 homolog 2 (iRhom2) may have a role in HA pa-
trix proteoglycan production and compared to the control group. The
thogenesis [69]. TNFα binds two isotypes of membrane receptors,
result of the colony subjected to IL-1β activity was 90%. In the colony
tumor necrosis factor receptor 1 (TNFR1, TNFRSF1A, CD120a) and
incubated with lysed RBC the level of secretion returned to the level
tumor necrosis factor receptor 2 (TNFR2, TNFRSF1b, CD120b) [70]
observed in the control group. Third colony incubated with IL-1β
(Figs. 4 and 5). Both types of receptors are responsible for the stimu-
combined with lysed RBC indicated the secretion at the level of 56%.
lation of inflammatory and degenerative processes within the articular
Addition of dimethylsulphoxide (DMSO) free radical scavenger, in-
cartilage and other joint tissues; however the activity of TNFR1 re-
creased the production of proteoglycans and the disintegration of the
ceptor, which is sensitive to both forms of TNFα, seems to be sig-
extracellular matrix substances proving that oxidative radicals are in-
nificantly dominant [71]. The activation of TNFR2 receptor also affects
volved in pathological mechanism. A related study was proposed by van
the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT/mam-
Vulpen et al. that analysed the effects of anti-IL-1β monoclonal anti-
malian target of rapamycin (mTOR) angiogenic pathway, independent
body (IL-1βmAb), IL-1RA and anti-TNFα monoclonal antibody
of TNF receptor associated factor 2 (TRAF2) activation, induced with
(TNFαmAb) on the synthesis of extracellular matrix proteoglycans,
angiogenesis, which may be of pathophysiological significance in the
chondrocyte apoptosis and the expression of IL-1β, TNFα and IL-6 in
context of HA and HA-related chronic hypertrophy of the synovial
human colonies of chondrocytes incubated with blood [65]. After four
membrane [72,73].
days of the exposure of the colony to blood, the respective levels of
extracellular matrix proteoglycan secretion dropped by 75% and 76%
compared to the control colony with no blood added. Gradually added 2.2.2. Biological functioning of the TNFα in joint tissues
IL-1βmAb and IL-1RA substantially increased the synthesis to the level The properties of TNFα are related to the inhibition of proteoglycan
of 91% at a dose of 100 ng/mL of IL-1βmAb and 74% at a dose of and COL2 synthesis by chondrocytes [45]. However, the expression of
1000 ng/mL of IL-1RA. A rapid administration of IL-1βmAb and IL-1RA catabolic compounds, such as MMP-1, MMP-3, MMP-13 and ADAM-
TS4, is increased [44]. As regards the promotion of inflammatory

Table 2
Observational studies showing the expression pattern of TNFα in hemophilic arthropathy.

Clinical trial/model Method of sampling Methodology for Reported results/timing Reference

quantification

Patients with HA Synovial tissue samples ELISA Increase of concentration in the supernatants [55]
Patients with HA Synovial tissue samples ELISA Increase of concentration in the supernatants [56]
Cartilage co-cultured with whole blood or Cartilage cultures ELISA Increase of secretion by the cell cultures after [57]
MNC + RBC 4 days of incubation
Cartilage co-cultured with whole blood, MNC, Cartilage cultures ELISA Increase of secretion by the cell cultures after [58]
MNC + RBC or MNC + LPS 4 days of incubation
F8-KO mouse with needle-induced knee joint Synovial fluid samples Luminex xMAP No difference in concentration in the synovial [60]
hemarthrosis fluid
Patients with HA Subchondral bone IHC Increase of concentration in the subchondral [62]
samples bone
Cartilage co-cultured with whole blood Cartilage cultures ELISA Increase of secretion by the cell cultures after [115]
4 days of incubation
Patients with HA Synovial tissue samples ELISA Increase of concentration in the supernatants [131]

HA hemophilic arthropathy, MNC mononuclear cells, RBC red blood cells, LPS lipopolysaccharide, F8-KO F8 gene knock-out, ELISA enzyme-linked immunosorbent assay, IHC im-
munohistochemistry.

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P. Wojdasiewicz et al.
phenomena, TNFα stimulates cells to increase the secretion of IL-6, IL-
8, CCL5, stromal cell-derived factor 1 (SDF-1) and mediators re-
sponsible for the neoangiogenesis of substances like vascular en-
dothelial growth factor (VEGF), hypoxia inducible factor 1 alpha (HIF-
1α) and hypoxia inducible factor 2 alpha (HIF-2α) [17,46,49,74,75].
The regenerative abilities of the articular cartilage are inhibited due to
the induction of chondrocyte apoptosis and via the disruption of
chondrogenic progenitor cells (CPC) migration [46]. In the course of
arthritis, a distinct synergism between the activity of TNFα and IL-1β
may be observed [76]. The cytokines activate identical groups of in-
tracellular signaling pathways and are secreted by the same types of
cells, which is manifested by their increased concentration in the car-
tilage and synovial fluid, subchondral cortical bone layer and synovial
membrane [31].
2.2.3. Role of TNFα in the pathogenesis of hemophilic arthropathy
The significant role of TNFα and IL-1β in the pathogenesis of HA is
corroborated by several studies (Table 2). Studies by Roosendaal et al.
confirmed that the supernatants of cell cultures of synovial tissue of HA
patients have higher levels of TNFα compared to OA and RA study
groups and control groups, with the reservation that samples including
hemosiderin deposits had the highest level of TNFα, that may be as-
sociated with TNFα-induced TFN-bound iron uptake into synovial
macrophages [55,56,59]. Studies by Øvlisen et al. showed no sig-
nificant differences of TNFα levels in the synovial fluid collected from
study group and control group mice [60]. The effect of TNFα on ar-
ticular cartilage degeneration was shown by Sun et al., who compared
the influence of isolated FIX and FIX with TNFα receptor antagonist
(etanercept) in FIX gene (F9) knock-out mice (F9-KO) with knee he-
marthrosis triggered by needle puncture [77,78]. After 3–4 weeks the
degree of destruction of the knees in the FIX and etanercept group was
lower than in the group which received FIX substitution and the control
group. The results of the animal study are similar to the study by
Melchiorre et al. and demonstrate a positive clinical impact of admin-
istration of anti-TNFα antibody (adalimumab) [79]. TNFα also influ-
enced the process of hemostasis occurring directly in joint (Fig. 6).
Dargaud et al. demonstrated that TNFα alone, and in combination with
interleukin 17 (IL-17), in human synovial cells culture from HA pa-
tients, induced a substantial reduction of thrombomodulin (TM)
Fig. 6. Schematic overview of the model showing role of TNFα and IL-17 in the context of hemostasis mechanisms occurring directly in joint of patient with hemophilic arthropathy.
Upregulated levels of thrombomodulin and inflammatory cytokines may lead to additional disruption of coagulation processes in the tissues of the affected joint. In case of hemostasis
mechanisms occurring in joint of patient with hemophilic arthropathy, TNFα and IL-17 seem to have a procoagulant activity apart from their direct inflammatory effects. Abbreviations:
TNFα tumor necrosis factor alpha, IL-17 interleukin 17, TM thrombomodulin, PS protein S, C4b-BP complement component 4b binding protein, FIIa thrombin, PC protein C, APC
activated protein C, FVa active coagulation factor V, FVai inactive coagulation factor V, FVIIIa active coagulation factor VIII, A1 A1 domain (1–336 aa), a1 a1 acidic region (337–372 aa),
A2 A2 domain (373–710 aa), a2 a2 acidic region (711–740 aa), A3 A3 domain (1690–2019 aa), C1 C1 domain (2020–2172 aa), C2 C2 domain (2173–2332 aa), FVIIIai inactive
coagulation factor VIII.
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Cytokine and Growth Factor Reviews 39 (2018) 71–91
messenger RNA (mRNA) expression by synoviocytes [80]. Moreover,
TM levels were higher in the synovial fluid of patients with HA
(56 ± 25 ng/mL) compared to healthy controls (39 ± 21 ng/mL). In
natural conditions TM binds thrombin in 1:1 stoichiometric ratio, then
activates protein C (PC) [81]. PC is a zymogen which belongs to a group
of proteins which inhibit blood clotting via active coagulation factor V
(FVa) and FVIIIa degradation [81]. HA-related tendency of endothelial
cells, synovial membrane and immune system cells towards an ex-
cessive secretion of inflammatory cytokines, including TNFα, may lead
to additional disruption of coagulation processes, via an increased se-
cretion of TM, and the resultant excessive and inadequate activation of
PC [80,82]. As regards congenital coagulation disturbances the above
cascade of reactions appears to be a potentially aggravating factor of
the prognosis in patients with HA [82].
2.3. Interleukin 6 (IL-6)
2.3.1. Overview of the IL-6 properties and its associated signaling pathways
IL-6 is a multi-functional cytokine composed of 184 amino acid
residues of molecular weight of 21–28 kDa depending on the level of
glycosylation, with a post-translational four-α-helix bundle structure
[83,84] (Fig. 7). The biological activity of IL-6 is mediated through
binding to the IL-6 receptor (IL-6R), a type I transmembrane protein
and binding second membrane glycoprotein 130 (mgp130) that serves
as a signal transducer of IL-6 [85]. There are two forms of IL-6R such as
membrane IL-6R (mIL-6R) and soluble IL-6R (sIL-6R) [86]. Unlike other
cytokine receptors, both types of IL-6 receptor have activating proper-
ties [86]. The secretion of IL-6 is mainly induced by IL-1β, TNFα, in-
terferon gamma (IFNγ) and lipopolysaccharides (LPS) [49,87].
2.3.2. Biological functioning of the IL-6 in joint tissues
Numerous cell types produce IL-6, including: chondrocytes, osteo-
blasts, fibroblasts, macrophages and mononuclear cells [88]. Arthritis-
associated diseases caused by inflammation, such as OA and RA involve
an increased concentration of IL-6 both in the synovial fluid and in the
serum, with a positive correlation between clinical signs and the
radiographic evidence of the severity of the destructive lesions [88,89].
IL-6 inhibits the synthesis of COL2 by chondrocytes and increases the
synthesis of MMPs, IL-1β and TNFα by osteoblasts [90,91].
P. Wojdasiewicz et al. Cytokine and Growth Factor Reviews 39 (2018) 71–91

Fig. 7. Schematic overview of the potential cellular and molecular mechanisms by which IL-6 and its associated signaling pathways are involved in expression and functional regulation
of various genes involved in inflammatory and catabolic processes in the pathogenesis of hemophilic arthropathy. Abbreviations: IL-6 interleukin 6, anti-IL-6R antibodies against
interleukin 6 receptor, mIL-6R membrane interleukin 6 receptor, sIL-6R soluble interleukin 6 receptor, mgp130 membrane glycoprotein 130, JAK1 janus kinase 1, JAK2 janus kinase 2,
TYK2 tyrosine kinase 2, MAP3K mitogen-activated protein kinase kinase kinase, ERK1/2 extracellular signal-regulated kinase 1/2, JNK c-Jun N-terminal kinase, p38 p38 mitogen-
activated protein kinase, AP-1 activator protein 1, PI3K phosphatidylinositol-4,5-bisphosphate 3-kinase, AKT protein kinase B, mTOR mechanistic target of rapamycin, STAT3 signal
transducer and activator of transcription 3, P phosphate, MMP-1 interstitial collagenase, MMP-3 stromelysin 1, MMP-13 collagenase 3, ADAM-TS4 a disintegrin and metalloproteinase
with thrombospondin motifs 4, IL-1β interleukin 1 beta, TNFα tumor necrosis factor alpha, IL-6 interleukin 6, IL-8 interleukin 8, CCL5 C-C motif chemokine ligand 5, PLA2 phospholipase
A2, COX-2 cyclooxygenase 2, PGE2 prostaglandin E2, ACAN aggrecan, COL2 collagen type II; ↑ increase of expression, ↓ decrease of expression.

Additionally, IL-6 promotes the development of osteoclast formations
which stimulates the process of osseous tissue resorption, especially in
the subchondral layer [92]. However, some research questions the in-
flammatory role of IL-6 as regards the articular cartilage and periarti-
cular tissues [93]. Mice which lacked the gene coding IL-6 (IL-6−/−)
demonstrated a tendency towards developing much more advanced
degenerative changes in joints compared to wild-type (WT) mice [94].
Another study on IL-6−/− mice showed that intraarticular
administration of IL-6 had chondroprotective properties and reduced
the loss of proteoglycans during the acute stage of inflammation. Fur-
thermore, chronic administration of IL-6 produced an increased ten-
dency towards osteophyte formation [95]. Seemingly, there is an opi-
nion that IL-6 has a tendency towards regulating immunological
processes or may show anti-inflammatory properties at the physiolo-
gical level or during acute inflammation [96]. However, in case of a
chronic inflammatory process, the biological activity of IL-6 turns into

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P. Wojdasiewicz et al.
an inflammatory one [97]. Altogether these results indicate that IL-6
mediates anti-inflammatory properties during acute inflammation, but
inflammatory activity during chronic inflammation [96,97].
2.3.3. Role of IL-6 in the pathogenesis of hemophilic arthropathy
The inflammatory role of IL-6 seems to be confirmed in the patho-
genesis of HA (Table 3). Just like in case of IL-1β and TNFα, the su-
pernatants of cell cultures of synovial tissue in HA patients have higher
levels of IL-6 compared to OA and RA study groups and control groups
[55,56,59]. Øvlisen et al. reported a significantly higher level of IL-6 in
the synovial fluid in F8-KO mice (174 ± 319 pg/mL) than in healthy
mice and those which received the substitution of rFVIII [60]. Ad-
ditionally, the levels of IL-6 in the synovial fluid correlated with post
mortem examination showing a more marked distension of the joint
capsule and hemarthrosis. In the study of Narkbunnam et al. analysed
the effect of MR16-1, a rat monoclonal immunoglobulin G1 (IgG1)
antibody directed against mouse IL-6R (anti-IL-6R) on the knees of F8-
KO mouse with hemarthrosis [98]. The administration of isolated
MR16-1 insignificantly reduced the proliferation of the synovial mem-
brane, the presence of neovascularization, hemosiderin deposits, mac-
rophage infiltration and articular cartilage erosion compared to the
control group. Interestingly, the best anti-inflammatory activity to-
wards joints was observed in case of a substitution with MR16-1 com-
bined with FVIII. A 100% survival rate was observed until the last day
of the study in F8-KO mice which received the combined therapy. It is
noteworthy that supplementation with FVIII alone did not have such an
anti-inflammatory effectiveness as the combination of MR16-1 and
FVIII. It may indicate that in early stage of HA, the role of IL-6 is not so
important as regards the development of destructive lesions in the joint.
It confirms that the administration of isolated MR16-1 only slightly
inhibited degenerative processes. IL-6 seemed rather to specifically
strengthen immune processes which is confirmed by the observed high
chondroprotective effectiveness of the combined substitution of MR16-
1 and FVIII.
2.4. Other inflammatory cytokines
Other inflammatory cytokines which participate in the pathogenesis
of HA include chemokine C-C motif ligand 2 (CCL2, MCP-1) and che-
mokine C-X-C motif ligand 1 (CXCL1, KC) [60]. Their level in the sy-
novial fluid in mouse knees was significantly elevated in F8-KO mice
compared to healthy controls. CCL2 mediates monocyte and macro-
phage migration, and their infiltration to the site of inflammation [99].
CXCL1 is a strong chemoattractant for neutrophils, which potentially
contributes to the promotion of the immune response and secretion of
numerous inflammatory mediators including IL-1β, TNFα and IL-6 by
neutrophils and other cell types [100]. CXCL1 is an important cytokine
that influences the severity of an inflammatory process in injuries with
bleeding. Blocking its activity before the procedure of an artificially
stimulated bleeding in a mouse with anti-CXCL1 resulted in reduction
of neutrophil infiltration to liver and lung tissues and diminished the
oedema of these organs compared to the control group [101]. However,
there is a scarcity of studies concerning other inflammatory cytokines
which might have a role in the pathogenesis of HA. Individual studies
have not confirmed any significant effect of IL-17 or CCL5 on the
Table 3
Observational studies showing the expression pattern of IL-6 in hemophilic arthropathy.
Clinical trial/model Method of sampling
Patients with HA Synovial tissue samples
Patients with HA Synovial tissue samples
F8-KO mouse with needle-induced knee joint Synovial fluid samples
hemarthrosis
HA hemophilic arthropathy, F8-KO F8 gene knock-out, ELISA enzyme-linked immunosorbent assay.
Cytokine and Growth Factor Reviews 39 (2018) 71–91
development of HA, at least at the initial stage of the inflammation, in
which no significant activity of lymphocytes T CD4+ is observed [60].
3. Anti-inflammatory cytokines
Anti-inflammatory cytokines are associated with the regulation and
modulation of the immune response in two ways: they inhibit the
synthesis of inflammatory cytokines, which indirectly prevents cata-
bolic processes and they possess a direct anabolic activity on articular
structures via the stimulation of the secretion of growth factors and
selective regulatory proteins [102,103]. In the large group of anti-in-
flammatory cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10)
have been the best analysed in the context of HA pathogenesis.
3.1. Interleukin 4 (IL-4)
3.1.1. Overview of the IL-4 properties and its associated signaling pathways
IL-4 is a glycoprotein composed of 129 amino acid residues of
molecular weight of 15–20 kDa depending on the level of glycosylation,
with a post-translational four-α-helix bundle structure, additionally
stabilized by the presence of three disulfide bonds [104]. There are two
types of membrane receptors binding IL-4 (IL-4R) forming heterodimers
which are structurally a combination of two of the three receptor chains
[105]. Type I signaling complex contributes to the transfer of in-
tracellular signal via gradual phosphorylation of IL-4Rα/JAK1/STAT3/
STAT6 cascade [106,107]. The activation of type II signaling complex is
associated with triggering IL-4Rα/JAK2/STAT3 cascade and also IL-
13Rα1/TYK2/STAT1/STAT6 cascade in case of binding the second type
of receptor with IL-13 [106,107]. There is also a soluble form of a re-
ceptor for IL-4 (sIL-4R), which binds and inhibits the biological activity
of IL-4 [108].
3.1.2. Biological functioning of the IL-4 in joint tissues
IL-4 is mainly produced by Th2 lymphocytes which infiltrate the
synovial membrane of the joint via blood vessels [109]. Mast cells,
basophils and eosinophils also have the ability to express and secrete IL-
4 [110]. IL-4 is a cytokine with strong chondroprotective properties,
that blocks the degradation of proteoglycans of articular cartilage via
inhibiting the secretion of MMPs in patients at an advanced stage of OA
[42]. IL-4 also inhibits the synthesis of inflammatory mediators such as
PGE2, COX-2, PLA2 and iNOS via chondrocytes and fibroblasts
[42,111,112]. Moreover, fibroblast and chondrocyte cultures exposed
to IL-4 showed a reduction in the expression of inflammatory cytokines
such as IL-1β, TNFα and IL-6 [113]. Fu et al. studied mice with col-
lagen-induced arthritis which received recombinant murine IL-4 (rmIL-
4) with recombinant murine GM-CSF (rmGM-CSF) [114] and reported a
significant reduction in inflammation of the synovial membrane and
articular cartilage. Macrophages sampled from these mice showed a
diminished ability to express IL-1β and TNFα compared to the control
group. The effect of rmIL-4 with rmGM-CSF was also manifested by the
reduced proliferation of Th17 lymphocytes with the reduced in-
flammatory synthesis of IL-17 and increased secretion of IL-10 and
transforming growth factor beta (TGF-β) by regulatory T (Treg) cells.
Methodology for quantification Reported results/timing Reference
ELISA Increase of concentration in the supernatants [55]
ELISA Increase of concentration in the supernatants [56]
Luminex xMAP Increase of concentration in the synovial fluid [60]
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P. Wojdasiewicz et al. Cytokine and Growth Factor Reviews 39 (2018) 71–91

3.1.3. Role of IL-4 in the pathogenesis of hemophilic arthropathy

Reference
Studies on HA pathogenesis confirm the anti-inflammatory and

[115]

[118]
[131]
[132]

[133]
chondroprotective role of IL-4, as well as a decrease in disease devel-
opment (Table 4). In the study of van Meegeren et al. analysed the

Prevent of blood-induced cartilage damage

Prevent of blood-induced cartilage damage

Prevent of blood-induced cartilage damage
Prevent of blood-induced cartilage damage

Prevent of blood-induced cartilage damage

effect of single IL-4, IL-10, and IL-4 combined with IL-10 on human
chondrocyte cultures, exposed to blood for four days, to mimic the
natural evacuation time of blood from the joint [115,116]. IL-4 treat-
ment increased proteoglycan production by chondrocytes to complete
normalization. The combination of IL-4 and IL-10 (10 ng/mL) in a dose-
dependent manner further increased the normalization of proteoglycan
secretion. Moreover, IL-4 reduced the expression of IL-1β and TNFα,
and also markedly inhibited blood-induced apoptosis of chondrocytes.

Reported results
Additionally, some samples of cartilage which had been exposed to
blood showed the increased expression of mRNA for IL-4 receptor
subunit alpha (IL-4Rα) and interleukin 2 (IL-2) receptor common

IL-4 interleukin 4, IL-10 interleukin 10, IL-1β interleukin 1 beta, TNFα tumor necrosis factor alpha, IL-6 interleukin 6; ↑ increase in mentioned variable, ↓ decrease in mentioned variable.
gamma (IL-2Rγc) chains [42] (Fig. 8). The another study in F8-KO mice
administering IL-4 and IL-10 demonstrated a slower progression of ar-
ticular cartilage destruction compared to the control group. Similar

IL-6

↓
↓
↓
↓
↓
↓
↓
↓
results were obtained when the analysis included canine and human

Effect on production
cartilage, with a marked reduction in the production of IL-1β by human

TNFα
chondrocytes after adding IL-4 combined with IL-10 [118]. Optimal
chondroprotective activity and potential BIJD prevention occurred with

↓
↓
↓

↓
early administration of anti-inflammatory cytokines, preferably im-
mediately after hemarthrosis occurred and no later than 4–8 h after an

IL-1β
artificially induced injury [115,117,118]. Some authors also suggested

↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
the role of IL-4 in decreasing VEGF expression in the course of HA

Effect on chondrocyte apoptosis

[119]. It may be due to an intermediate activity of inhibiting the se-
cretion of IL-1β and TNFα which are indirectly responsible for in-
creased expression of VEGF [98,115,117–119]. Thanks to the limitation
of the pathological growth and permeability of blood vessels IL-4 and
other anti-inflammatory cytokines may contribute to the protection and
reduction of inflammatory and degenerative processes in the course of
HA [119]. Ravanbod et al. demonstrated that IL-4 deficiency enhanced
the tendency towards the development of destructive lesions in the
↓
↓
↓

joints of HA patients [120]. A therapeutic effect of mesenchymal stem

cells (MSC) on rabbit joints with hemarthrosis were analyzed. The re-
duced degenerative manifestations were accompanied with the in-
Observational studies implicating the role of IL-4 and IL-10 in the pathogenesis of hemophilic arthropathy.

Effect on proteoglycan turnover

creased expression of IL-4 and simultaneous reduction in the level of the

Release

expression of IL-1β and TNFα in the synovial membrane of study group

animals. It may indicate that maintaining healthy joints requires the
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
↓
constant presence of IL-4, and lowering its expression may be associated
with the progression of inflammatory changes related to BIJD. In this
case the use of MSC appears to be a promising therapeutic option in HA
Synthesis

patients [121]. Interestingly, presence of anti-FVIII in blood also in-

fluences the anti-inflammatory activity dependent on IL-4. Silveira
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑
↑

et al. reported changes in the activity of IL-4-positive cells in the per-

ipheral blood of patients with anti-FVIII [122]. These patients had a
and synovial tissue co-cultured with whole blood and IL-10

decreased level of IL-4 in CD4+ and CD8+ T cells compared to analo-

gous cells isolated from the peripheral blood of HA patients who lacked
co-cultured with whole blood and IL4-10 synerkine

co-cultured with whole blood and IL4-10 synerkine

anti-FVIII. Similar results are observed as regards B cells. Moreover, it

co-cultured with whole blood and IL-4 + IL-10
co-cultured with whole blood and IL-4 + IL-10

co-cultured with whole blood and IL-4 + IL-10

co-cultured with whole blood and IL-4 + IL-10

was demonstrated that the presence of anti-FVIII is associated with

decreased frequencies of IL-4-positive neutrophils. Some researchers
co-cultured with whole blood and IL-10

co-cultured with whole blood and IL-10

co-cultured with whole blood and IL-10

co-cultured with whole blood and IL-4

co-cultured with whole blood and IL-4

co-cultured with whole blood and IL-4

suggest that there is a relationship between level of anti-FVIII secretion

and an anti-inflammatory activity and regulatory pattern of IL-4
[123,124]. The study showed a correlation between the presence of
anti-FVIII and the reduced expression of IL-4, which may provide a
rationale for deteriorated prognosis in HA patients [122].

3.2. Interleukin 10 (IL-10)

Clinical trial/model

3.2.1. Overview of the IL-10 properties and its associated signaling

pathways
IL-10 is a homodimer of the total molecular weight of 37 kDa, built
Cartilage
Cartilage
Cartilage
Cartilage
Cartilage
Cartilage
Cartilage
Cartilage
Cartilage
Cartilage
Cartilage
Cartilage
Cartilage

of monomers composed of 160 amino acid residues of the molecular

Table 4

weight of 18.5 kDa, after post-translational modifications the homo-

dimer becomes a six-α-helix bundle structure [125,126]. The receptor

83
P. Wojdasiewicz et al. Cytokine and Growth Factor Reviews 39 (2018) 71–91

Fig. 8. Schematic overview of the potential cellular and molecular mechanisms by which IL-4 and IL-13 signaling complexes are involved in expression and functional regulation of
various genes involved in anti-inflammatory and anabolic processes in the pathogenesis of hemophilic arthropathy. Abbreviations: IL-4 interleukin 4, IL-13 interleukin 13, IL-4Rα
interleukin 4 receptor subunit alpha, IL-2Rγc interleukin 2 receptor common gamma, IL-13Rα1 interleukin 13 receptor subunit alpha 1, IL-13Rα2 interleukin 13 receptor subunit alpha 2,
JAK1 janus kinase 1, JAK3 janus kinase 3, STAT6 signal transducer and activator of transcription 6, P phosphate, TYK2 tyrosine kinase 2, STAT3 signal transducer and activator of
transcription 3, MMPs metalloproteinases, IL-1β interleukin 1 beta, TNFα tumor necrosis factor alpha, IL-6 interleukin 6, PGE2 prostaglandin E2, COX-2 cyclooxygenase 2, PLA2
phospholipase A2, iNOS inducible nitric oxide synthase, VEGF vascular endothelial growth factor, ACAN aggrecan, COL2 collagen type II; ↑ increase of expression, ↓ decrease of
expression.

for IL-10 (IL-10R) is a heterodimer composed of two chains such as IL-
10 receptor subunit 1 (IL-10R1) and IL-10 receptor subunit 2 (IL-10R2)
[126]. The immune system cells which may secrete IL-10 include CD4+
T lymphocytes (Th1, Th2, Th17, Treg), CD8+ T lymphocytes, B lym-
phocytes, monocytes, macrophages, myeloid dendritic cells (mDC),
eosinophils and mast cells [127]. Moreover, numerous other cell types
are capable of secreting IL-10, which makes them able to take part in
the regulation of inflammatory response, such as keratinocytes, epi-
thelial cells or fibroblasts [128].
3.2.2. Biological functioning of the IL-10 in joint tissues
IL-10 has multifunctional protective and anti-inflammatory prop-
erties as regards articular cartilage cells and periarticular tissues [42]
(Fig. 9). IL-10 increases the synthesis of COL2 and ACAN by chon-
drocytes and also leads to an intensified general proteoglycan synthesis
and their increased percentage proportion in the extracellular matrix in
in vitro conditions [42]. Just like IL-4, IL-10 exerts an inhibiting effect
on chondrocyte apoptosis and MMPs production [42]. These processes
are also influenced by triggering IL-1RA expression, a possible me-
chanism stimulated by IL-10, and tissue inhibitor of metallopeptidase 1
(TIMP-1) [129]. IL-10 is also antagonistic to TNFα activity towards

84
P. Wojdasiewicz et al. Cytokine and Growth Factor Reviews 39 (2018) 71–91

Fig. 9. Schematic overview of the potential cellular and molecular mechanisms by which IL-10 and its associated signaling pathways are involved in expression and functional regulation
of various genes involved in anti-inflammatory and anabolic processes in the pathogenesis of hemophilic arthropathy. Abbreviations: IL-10 interleukin 10, IL-10R1 interleukin 10 receptor
subunit 1, IL-10R2 interleukin 10 receptor subunit 2, JAK1 janus kinase 1, TYK2 tyrosine kinase 2, STAT3 signal transducer and activator of transcription 3, P phosphate, MMPs
metalloproteinases, TIMP-1 tissue inhibitor of metallopeptidase 1, IL-1RA interleukin 1 receptor antagonist, TNFα tumor necrosis factor alpha, IL-4Rα interleukin 4 receptor subunit
alpha, PLA2 phospholipase A2, COX-2 cyclooxygenase 2, PGE2 prostaglandin E2, BMP-2 bone morphogenetic protein 2, BMP-6 bone morphogenetic protein 6, ACAN aggrecan, COL2
collagen type II; ↑ increase of expression, ↓ decrease of expression.

fibroblasts of the synovial membrane via inhibiting the secretion of
PGE2, COX-2 and PLA2 [111]. Moreover, IL-10 impedes binding TNFα
to specific receptors via inhibiting their expression on the surface of
fibroblasts [111]. It was also demonstrated that IL-10 induces the ex-
pression of numerous growth factors, including bone morphogenetic
protein 2 (BMP-2) and bone morphogenetic protein 6 (BMP-6) which
belong to TGF-β family and are responsible for chondrogenesis reg-
ulation involving an appropriate transformation of mesenchymal cells
into chondrocytes [130]. IL-10 is viewed as a well-known cytokine with
protective and anti-inflammatory properties towards joints in the
course of OA and RA [42].
3.2.3. Role of IL-10 in the pathogenesis of hemophilic arthropathy
Numerous studies have investigated the role of IL-10 in the patho-
genesis of HA and its possible therapeutic activity (Table 4). Jansen
et al. demonstrated that chondrocyte and synovial membrane cell cul-
tures collected from patients with advanced HA lesions increased the
production of proteoglycans and decreased their degradation after IL-
10 administration [131]. IL-10 also reduced the expression of IL-1β and
TNFα in culture supernatants. Van Meegeren et al. confirmed these
observations, but showed that IL-4 had stronger anti-inflammatory
properties compared to IL-10 [115]. As mentioned before, IL-10 showed
the strongest protective activity when combined with IL-4 [117,118].
From these results, van Meegeren and van Vulpen et al. analysed the
effect of fusion protein consisting IL-4 and IL-10 (IL4-10 synerkine) on
human chondrocyte cultures [132,133]. The IL4-10 synerkine pre-
vented blood-induced cartilage damage similar to the combination of
the individual components in a dose-dependent manner
(0.0001–100 ng/mL), and the use of IL4-10 synerkine also appeared to
be a potent therapeutic option in HA patients. Interestingly, Silveira
et al. demonstrated that the patients with hemophilia who developed
anti-FVIII had increased frequencies of IL-10-positive neutrophils, B and
T cells [122]. It may be associated with polymorphism in the IL-10
gene. Apparently, a polymorphism in the IL-10 gene (134 allele in

85
P. Wojdasiewicz et al.
cytosine-adenine repeat microsatellites of the IL-10 promoter) directly
carries a significantly higher risk of anti-FVIII development [124]. IL-10
is known to stimulate plasma cells to secrete numerous antibodies and
cytokines. Presence of allele 134 markedly increases this tendency.
Most probably, the presence of this polymorphism in IL-10 gene con-
tributes to an intensified and permanent secretion of IL-10, and also
anti-FVIII in hemophilia patients. Interestingly, polymorphisms in IL-1β
and IL-4 genes demonstrated no correlation with a higher risk of anti-
FVIII development [124]. Therefore, it needs to be emphasized that
although IL-10 has a protective role in the pathogenesis of HA as re-
gards the joint and periarticular tissues, its overexpression propably
results in anti-FVIII development, which may ultimately lead to prog-
nosis deterioration and a considerable limitation of therapeutic options.
3.3. Other anti-inflammatory cytokines
Interleukin 11 (IL-11) deserves a particular attention as regards the
remaining anti-inflammatory cytokines [134]. No studies have analysed
the direct effect of IL-11 on joints in the course of HA. However, it has
been proved to have an effect on the increase of FVIII level in the blood
serum, Ragni et al. stated that the subcutaneous administration of re-
combinant human IL-11 (rhIL-11) is an effective and safe alternative to
desmopressin (DDAVP) administration [135]. Patients with mild and
moderate forms of hemophilia A and von Willebrand disease (vWD)
who received 25 μg/kg of rhIL-11 subcutaneously for four subsequent
days demonstrated approximately 1.5–2.0-fold higher levels of FVIII in
the serum on the last day of the study compared to the respective
baseline levels. According to the authors it resulted in the reduction of
blood loss during menstruation and made the conducted surgeries safer.
Similar results had been obtained previously on a mouse model by
Denis et al. [136]. The expression of IL-11 in joints and periarticular
tissues has not been studied more precisely in patients with HA. The
data might be useful in the determination of the exact role of this cy-
tokine in the pathophysiology of HA. TGF-β and bone morphogenetic
protein (BMP) family are indicated to be promising directions in the
treatment of intraarticular bleeding in the course of HA [78]. They have
an anti-inflammatory and anabolic effect towards tissues which form
the joint [137]. Until recently, their significance was demonstrated in
non-hemophilia subjects in the treatment of bone union disorders and
promotion of differentiation of articular cartilage cells [78,138]. It may
be an interesting direction in the treatment of BIJD patients, however, it
still needs to be experimentally developed. The anti-inflammatory role
of IL-13 should not be disregarded in HA pathophysiology [139]. It
occurs via the possibility of activating type II signaling complex which
triggers IL-13-specific IL-13Rα1/TYK2/STAT1/STAT6 cascade, which
is associated with anti-inflammatory and chondroprotective activity in
various arthritis-associated diseases [106] (Fig. 8).
4. Summary and future perspectives
The pathophysiology of HA has not been fully elucidated, especially
in terms of mechanisms responsible for the development of an in-
flammation and catabolic processes in the joint. It is believed that cy-
tokines play a key role in promoting these phenomena, as they act as a
part of a complex system known as cytokine network. It is suggested
that the development of an inflammation is due to the imbalance be-
tween the biological activity of inflammatory and anti-inflammatory
cytokines [140]. The main factor which triggers and causes the im-
balance is blood and its metabolites appearing in the joint. Recurrent
joint bleeding episodes strengthen the tendency towards promoting
inflammatory phenomena, which causes a gradual degeneration of
joints and periarticular tissues. Consequently, the patients are con-
siderably impaired and the mortality rate increases [141]. The present
treatment methods mainly involve the use of prophylactic FRT in-
cluding new bypassing agents, and in advanced cases – the use of highly
specialized orthopaedic procedures [142]. However, the methods may
86
Cytokine and Growth Factor Reviews 39 (2018) 71–91
not be viewed in some cases as fully effective and satisfactory [143].
The use of prophylactic FRT is associated with the risk of inhibitor
development which considerably impedes the prophylaxis of articular
lesions [144]. At the same time, orthopaedic procedures, due to their
specificity, carry a high perioperative risk and if conducted at a young
age, they do not provide a long-term solution to the problem, but only a
short-term relief, depending on the severity of the disease [143].
Therefore, it is important to continue the search for new sustainable
therapies which would help prevent the development of the disease and
avoid the surgical treatment of patients with HA [145]. The regulation
and modulation of relationships occurring within the cytokine network
are considered to be very promising directions in such therapy. In order
to achieve this goal it is necessary to determine the role of specific
cytokines in the immunopathological mechanisms involved in HA.
The present paper presents the current knowledge on inflammatory
and anti-inflammatory cytokines involved in the pathogenesis of HA.
The cytokines mainly associated with NF-κB signaling pathway are key
cytokines responsible for the clinical presentation of HA with a proven
inflammatory and catabolic activity associated with BIJD development
[146]. The inflammatory cytokines whose activity has been very well
elucidated are ones described in this paper such as IL-1β, TNFα, IL-6,
CCL2 and CXCL1. As regards the articular cartilage cells they affect the
disintegration and reduction in the synthesis of extracellular matrix,
including COL2 and ACAN, they contribute to chondrocyte apoptosis.
They are also responsible for forming free radicals and promoting the
synthesis of catabolic and inflammatory factors, such as MMP-1, MMP-
3, MMP-13, ADAM-TS4, PLA2, COX-2, PGE2, iNOS and, reciprocally,
the synthesis of other cytokines. They also increase VEGF and TM se-
cretion. VEGF is responsible for the growth of endothelium in the sy-
novial membrane affected with an inflammation, while TM contributes
to the activation of PC, a factor which degrades FVa and FVIIIa. Their
activity also manifests itself via inhibiting anti-inflammatory cytokine
synthesis by numerous cell types, especially immune system cells and
synovial membrane cells. Inflammatory cytokines may also disturb the
differentiation of progenitor cells into chondroblasts and osteoblasts
and promote osteoclastogenesis. The reciprocal stimulation of synthesis
leads to a broadened, frequently complementary catabolic activity of
inflammatory cytokines, which causes the development of a full-blown
form of HA in a short period of time.
On the other hand, the main anti-inflammatory cytokines which
play a role in the pathogenesis of HA are IL-4 and IL-10. They inhibit
the degeneration of proteoglycans and the synthesis of substances with
a strong inflammatory potential such as MMPs, PGE2, COX-2, PLA2,
iNOS by chondrocytes and fibroblasts. They inhibit the synthesis of
inflammatory cytokines and prevent blood-induced chondrocyte
apoptosis. They also reduce VEGF synthesis, therefore, the pathological
neovascularization within the synovial membrane may be limited.
Ravanbod et al. reported that the treatment of a typical HA-related
deficit of anti-inflammatory cytokines with MSC led to a considerable
reduction in IL-β synthesis and inhibited the progression of degen-
erative lesions occurring after hemarthrosis on an animal model [120].
The HA treatment with anti-inflamamtory cytokines and growth factors
seems also to be promising direction. Growth factors such as TGF-β and
ligands from BMP family may prove helpful in the regeneration of joints
and periarticular tissues in patients with HA. However, we cannot rule
out their possible negative effect, such as on the development of neo-
plastic lesions, the stimulation of angiogenesis and synovial membrane
cell proliferation [147]. Additionally, the treatment with IL-10 may
contribute to the production of anti-FVIII in patients with hemophilia
via the stimulation of plasma cells to produce numerous types of anti-
bodies [124,133]. At the same time, the prolonged exposure of tissues
to IL-4 activity may potentially lead to the activation of macrophages
and increased erythrophagocytosis in the liver, spleen and bone marrow
intensifying the general inflammatory response [148]. But in most
cases, the supplementation of IL-4 or IL-10 directly or indirectly via
MSC appears to be rather safe. Taking into consideration these facts the
P. Wojdasiewicz et al.
use of IL4-10 synerkine appears to be the most promising therapeutic
option due to pharmacokinetics and bioactivity properties [132]. Time
is also an important therapeutic criterion. The sooner anti-in-
flammatory cytokines are administered to the injured joint after
bleeding occurred, the better the chondroprotective effect. Another
promising treatment method of lesions typical of HA is the use of an-
tibodies against inflammatory cytokines, such as etanercept and adali-
mumab, which block the biological activity of TNFα. Preliminary re-
sults of their effectiveness in the course of HA treatment appear to be
promising [77,79]. Novel approaches, currently under investigation
(phase 4), include targeted agents such as bevacizumab (anti-VEGF)
used in intraarticular injections (NCT02060305) which seem to be a
potential promising direction of effective therapies for HA patients with
chronic proliferative synovitis [74]. Such conclusions may not be
viewed as final due to insufficient research conducted on the effect of
inflammatory and anti-inflammatory cytokines on immunopathological
mechanisms involved in HA. Moreover, numerous cytokines and pro-
teins related to the pathomechanism of HA have not been studied yet.
This group includes progranulin (PGRN), iRhom2, IL-17, CCL5, IL-11,
IL-13 and especially CX3CL1 (fractalkine). Apart from chemotactic
properties typical of chemokines, CX3CL1 has the ability to induce
leukocyte migration through the vascular endothelium independent of
selectins and integrins [149]. Therefore, leukocytes which have
CX3CR1 receptor on the surface are able to pass through the vascular
wall to the site of inflammation in an alternative way. Overexpression
of CX3CL1 results with hypertrophy of the synovial membrane and the
proliferation of vascular endothelium in many joint diseases [150].
Therefore, CX3CL1 impact on the development of HA need to be par-
ticularly investigated.
Exploring the role of cytokine network in HA seems to be justified,
as it shifts the center of gravity from symptomatic to causative treat-
ment. It may result in a shorter duration of treatment, reduction in the
general treatment costs. Most importantly, it may lower mortality rates
and cause a long-lasting improvement of the quality of life in patients
with HA.
Conflict of interest
None.
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M. Theobald, et al., Interleukin-10 protects against blood-induced joint damage,
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Osteoblasts and stromal cells isolated from femora in rheumatoid arthritis (RA)
and osteoarthritis (OA) patients express IL-11, leukaemia inhibitory factor and
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P. Wojdasiewicz et al. Cytokine and Growth Factor Reviews 39 (2018) 71–91

[135] M.V. Ragni, E.M. Novelli, A. Murshed, E.P. Merricks, M.T. Kloos, T.C. Nichols, Łukasz A. Poniatowski was graduated and obtained his
Phase II prospective open-label trial of recombinant interleukin-11 in desmo- MD from the Medical University of Warsaw in 2016.
pressin-unresponsive von Willebrand disease and mild or moderate haemophilia Currently he is a PhD student in the Department of
A, Thromb. Haemost. 109 (2013) 248–254, http://dx.doi.org/10.1160/TH12-06- Experimental and Clinical Pharmacology at the Medical
0447. University of Warsaw. During his studies he received many
[136] C.V. Denis, K. Kwack, S. Saffaripour, S. Maganti, P. André, R.G. Schaub, et al., awards including the scholarship for outstanding achieve-
Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII ments from the Polish Ministry of Health. His research in-
in wild type and von Willebrand disease mouse models, Blood 97 (2001) 465–472, terests are concentrated on neurosurgery and im-
http://dx.doi.org/10.1182/blood.V97.2.465. munological aspects in the pathogenesis of musculoskeletal
[137] R.N. Wang, J. Green, Z. Wang, Y. Deng, M. Qiao, M. Peabody, Bone Morphogenetic and central nervous system diseases.
Protein (BMP) signaling in development and human diseases, Genes Dis. 1 (2014)
87–105, http://dx.doi.org/10.1016/j.gendis.2014.07.005.
[138] K.R. Garrison, I. Shemilt, S. Donell, J.J. Ryder, M. Mugford, I. Harvey, et al., Bone
morphogenetic protein (BMP) for fracture healing in adults, Cochrane Database
Syst. Rev. 6 (2010) CD006950, http://dx.doi.org/10.1002/14651858.CD006950.
Paweł Nauman is head of the Department of Neurosurgery
pub2.
at the Institute of Psychiatry and Neurology in Warsaw and
[139] J.M. Woods, G.K. Haines, M.R. Shah, G. Rayan, A.E. Koch, Low-level production of
former deputy head of the Department of Neurosurgery at
interleukin-13 in synovial fluid and tissue from patients with arthritis, Clin.
the Maria Skłodowska-Curie Memorial Cancer Center and
Immunol. Immunopathol. 85 (1997) 210–220, http://dx.doi.org/10.1006/clin.
Institute of Oncology in Warsaw. He received his PhD in the
1997.4441.
field of neurosurgery in 2001 from Mossakowski Medical
[140] T. Hanada, A. Yoshimura, Regulation of cytokine signaling and inflammation,
Research Centre of the Polish Academy of Sciences and did
Cytokine Growth Factor Rev. 13 (2002) 413–421, http://dx.doi.org/10.1016/
postdoctoral work at the Lund University and Memorial
S1359-6101(02)00026-6.
Sloan Kettering Cancer Center. His research interests are
[141] A. Tagliaferri, G.F. Rivolta, A. Iorio, E. Oliovecchio, M.E. Mancuso, M. Morfini,
concentrated on molecular oncology and brain tumor
et al., Mortality and causes of death in Italian persons with haemophilia,
biology.
1990–2007, Haemophilia 16 (2009) 437–446, http://dx.doi.org/10.1111/j.1365-
2516.2009.02188.x.
[142] E. Berntorp, A.D. Shapiro, Modern haemophilia care, Lancet 379 (2012)
1447–1456, http://dx.doi.org/10.1016/S0140-6736(11)61139-2.
[143] A.D. Shapiro, S. Akins, D.L. Cooper, Long-term outcomes from orthopaedic surgery Tomasz Mandat is a professor and deputy head of the
in haemophilia: are we measuring success and documenting and assessing com- Department of Neurosurgery at the Maria Skłodowska-
plications? Haemophilia 20 (2014) e367–371, http://dx.doi.org/10.1111/hae. Curie Memorial Cancer Center and Institute of Oncology in
12504. Warsaw and senior consultant in the Department of
[144] C. Négrier, J. Goudemand, T. Lambert, Haemophilic arthropathy from A to Z. Neurosurgery at the Institute of Psychiatry and Neurology
Introduction, Haemophilia 14 (Suppl. 4) (2008) 1–2, http://dx.doi.org/10.1111/j. in Warsaw. He received his PhD in the field of neurosurgery
1365-2516.2008.01731.x. in 2002 from Central Clinical Hospital of the Military
[145] E. Berntorp, J.J. Michiels, A healthy hemophilic patient without arthropathy: from Medical Academy in Warsaw (currently Military Institute of
concept to clinical reality, Semin. Thromb. Hemost. 29 (2003) 5–10, http://dx.doi. Medicine in Warsaw) and did postdoctoral work at the
org/10.1055/s-2003-37934. University of Paris-Est and University of British Columbia.
[146] D. Sen, A. Chapla, N. Walter, V. Daniel, A. Srivastava, G.R. Jayandharan, Nuclear His research interests are concentrated on stereotactic and
factor (NF)-(B and its associated pathways are major molecular regulators of functional neurosurgery, molecular oncology and brain
blood-induced joint damage in a murine model of hemophilia, J. Thromb. tumor therapy.
Haemost. 11 (2013) 293–306, http://dx.doi.org/10.1111/jth.12101.
[147] S.B. Jakowlew, Transforming growth factor-beta in cancer and metastasis, Cancer
Metastasis Rev. 25 (2006) 435–457, http://dx.doi.org/10.1007/s10555-006-
Agnieszka Paradowska-Gorycka is head of the
9006-2.
Department of Biochemistry and Molecular Biology at the
[148] J.D. Milner, T. Orekov, J.M. Ward, L. Cheng, F. Torres-Velez, I. Junttila, et al.,
Eleonora Reicher National Institute of Geriatrics,
Sustained IL-4 exposure leads to a novel pathway for hemophagocytosis, in-
Rheumatology and Rehabilitation in Warsaw. She received
flammation, and tissue macrophage accumulation, Blood 116 (2010) 2476–2483,
her PhD in the field of medical biology in 2010 from
http://dx.doi.org/10.1182/blood-2009-11-255174.
Medical University of Warsaw. Her research interests are
[149] C.A. Haskell, M.D. Cleary, I.F. Charo, Molecular uncoupling of fractalkine-medi-
concentrated on immunogenetics of rheumatic diseases.
ated cell adhesion and signal transduction. Rapid flow arrest of CX3CR1-expres-
sing cells is independent of G-protein activation, J. Biol. Chem. 274 (1999)
10053–10058, http://dx.doi.org/10.1074/jbc.274.15.10053.
[150] J.K. Harrison, Y. Jiang, E.A. Wees, M.N. Salafranca, H.X. Liang, L. Feng,
L. Belardinelli, Inflammatory agents regulate in vivo expression of fractalkine in
endothelial cells of the rat heart, J. Leukoc. Biol. 66 (1999) 937–944.

Piotr Wojdasiewicz was graduated and obtained his MD

Katarzyna Romanowska-Próchnicka is senior consultant
from the Medical University of Warsaw in 2010. He re-
in the Department of Systemic Connective Tissue Diseases
ceived his PhD in the field of pathology and orthopaedics in
at the Eleonora Reicher National Institute of Geriatrics,
2017 from Medical University of Warsaw. Currently he is
Rheumatology and Rehabilitation in Warsaw and assistant
assistant in the Department of General and Experimental
in the Department of General and Experimental Pathology
Pathology at the Medical University of Warsaw. His re-
at the Medical University of Warsaw. She received her PhD
search interests are concentrated on neurotraumatology,
in the field of pathology and rheumatology in 2014 from
immunological aspects in the pathogenesis of arthritis-as-
Medical University of Warsaw. Her research interests are
sociated diseases and spine surgery in patients with rheu-
concentrated on immunogenetics of rheumatic diseases and
matoid and degenerative diseases.
their specific treatment including its all practical and the-
oretical aspects.

90
P. Wojdasiewicz et al.
Dariusz Szukiewicz is a professor and head of the
Department of General and Experimental Pathology at the
Medical University of Warsaw. He received his PhD in the
field of pathology in 1997 from Medical University of
Warsaw and did postdoctoral work at the New York State
Institute for Basic Research in Developmental Disabilities
and Erasmus University Rotterdam. His research interests
are concentrated on interactions within the cytokine net-
work and immunopathological mechanisms underlying
pathophysiology of various diseases including rheumatoid,
neurological, endocrine and placental diseases.
Andrzej Kotela is resident in orthopaedic and trauma-
tology in the Department of Orthopaedics and
Traumatology at the Medical University of Warsaw. He
received his PhD in the field of orthopaedics and trauma-
tology in 2013 from Central Clinical Hospital of the
Ministry of the Interior and Administration in Warsaw. His
research interests are concentrated on joint replacement
surgery and orthopaedic treatment of patients with mus-
culoskeletal complications of hemophilia and other in-
herited bleeding disorders.
nating diseases of the central nervous system, neurodegenerative diseases and epilepsy.
Łukasz Kubaszewski is head of the Department of
Spondyloorthopaedics and Biomechanics of the Spine and
senior consultant in the Department of Orthopaedics and
Traumatology at the Poznań University of Medical Sciences.
He received his PhD in the field of orthopaedics and trau-
matology in 2006 from Poznań University of Medical
Sciences. His research interests are concentrated on spine
surgery including complex degenerative, deformity, trau-
matic and oncologic pathology.
91
Cytokine and Growth Factor Reviews 39 (2018) 71–91
Ireneusz Kotela is a professor and head of the Department
of Orthopaedics and Traumatology at the Central Clinical
Hospital of the Ministry of the Interior and Administration
in Warsaw. He received his PhD in the field of orthopaedics
and traumatology in 1993 from Medical University of
Warsaw. His research interests are concentrated on appli-
cation of biomaterials and its biomechanics in the man-
agement of joint diseases and orthopaedic treatment of
patients with musculoskeletal complications of hemophilia
and other inherited bleeding disorders.
Iwona Kurkowska-Jastrzębska is a professor and head of
the 2nd Department of Neurology at the Institute of
Psychiatry and Neurology in Warsaw. She has worked for
more than 10 years in the Department of Experimental and
Clinical Pharmacology at the Medical University of
Warsaw, where she was involved in basic research of neu-
rodegenerative processes and the role of neuroin-
flammatory reaction, and of the interactions between the
nervous and immune systems. She spent few short post-
doctoral internships in the Department of Neuropathology
and in the Department of Neuroimmunology of Max Planck
Institute of Psychiatry in Martisried. Her research interest
are currently concentrated on neuroimmunology, demyeli-
Robert Gasik is a professor and head of the Department of
Neuroorthopaedics and Neurology and former head of the
Department of Rheumaorthopaedics at the Eleonora
Reicher National Institute of Geriatrics, Rheumatology and
Rehabilitation in Warsaw. He received his PhD in the field
of rheumatology in 2002 from Eleonora Reicher Institute of
Rheumatology in Warsaw (currently Eleonora Reicher
National Institute of Geriatrics, Rheumatology and
Rehabilitation in Warsaw). His research interests are con-
centrated on spine surgery in patients with rheumatoid
diseases including specialized care for sacroiliac pain and
immunological aspects in the pathogenesis of musculoske-
letal system diseases.