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Abstract and Figures

Rheumatic and joint diseases, as exemplified by osteoarthritis and rheumatoid arthritis, are among the most widespread painful and disabling pathologies across the globe. Given the continuing rise in life expectancy, their prevalence is destined to grow. Osteoarthritis, a degenerative joint disease, is, in particular, on its way to becoming the fourth leading cause of disability worldwide by 2020, with the rising incidence of obesity in addition to age being important factors. It is estimated that 25% of osteoarthritic individuals are unable to perform daily activities. Accompanying osteoarthritis is rheumatoid arthritis, which is a chronic systemic disease that often causes pain and deformity. At least 50% of those affected are unable to remain gainfully employed within 10 years of disease onset. A growing body of evidence now points to inflammation, locally and more systemically, as a promoter of damage to joints and bones, as well as joint-related functional deficits. The pathogenesis underlying joint diseases remains unclear; however, it is currently believed that crosstalk between cartilage and subchondral bone—and loss of balance between these 2 structures in joint diseases—is a critical element. This view is amplified by the presence of mast cells, whose dysregulation is associated with alterations of junction structures (cartilage, bone, synovia, matrix, nerve endings, and blood vessels). In addition, persistent activation of mast cells facilitates the development of spinal neuroinflammation mediated through their interaction with microglia. Unfortunately, current treatment strategies for rheumatic and articular disease are symptomatic and do little to limit disease progression. Research now should be directed at therapeutic modalities that target osteoarticular structural elements and thereby delay disease progression and joint replacement. This article is protected by copyright. All rights reserved.
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REVIEW ARTICLE
Degenerative Joint Diseases and
Neuroinflammation
Mariella Fusco, PhD*; Stephen D. Skaper, PhD
; Stefano Coaccioli, MD, PhD
;
Giustino Varrassi, MD, PhD, FIPP
,
** ; Antonella Paladini, MD, PhD
§
*Scientific Information and Documentation Center, Epitech Group;
Department of
Pharmaceutical and Pharmacological Sciences, University of Padua, Padua;
Department of
Internal Medicine and Rheumatology, Santa Maria Hospital, University of Perugia, Terni;
Department of Anesthesiology and Pain Medicine, School of Dentistry, LUdeS University, La
Valletta, Malta; **Paolo Procacci Foundation and European League Against Pain, Rome;
§
Department MESVA, University of L’Aquila, L’Aquila, Italy
&Abstract: Rheumatic and joint diseases, as exemplified
by osteoarthritis and rheumatoid arthritis, are among the
most widespread painful and disabling pathologies across
the globe. Given the continuing rise in life expectancy, their
prevalence is destined to grow. Osteoarthritis, a degenera-
tive joint disease, is, in particular, on its way to becoming the
fourth leading cause of disability worldwide by 2020, with
the rising incidence of obesity in addition to age being
important factors. It is estimated that 25% of osteoarthritic
individuals are unable to perform daily activities. Accompa-
nying osteoarthritis is rheumatoid arthritis, which is a
chronic systemic disease that often causes pain and defor-
mity. At least 50% of those affected are unable to remain
gainfully employed within 10 years of disease onset. A
growing body of evidence now points to inflammation,
locally and more systemically, as a promoter of damage to
joints and bones, as well as joint-related functional deficits.
The pathogenesis underlying joint diseases remains unclear;
however, it is currently believed that cross-talk between
cartilage and subchondral boneand loss of balance
between these two structures in joint diseasesis a critical
element. This view is amplified by the presence of mast cells,
whose dysregulation is associated with alterations of junc-
tion structures (cartilage, bone, synovia, matrix, nerve end-
ings, and blood vessels). In addition, persistent activation of
mast cells facilitates the development of spinal neuroinflam-
mation mediated through their interaction with microglia.
Unfortunately, current treatment strategies for rheumatic
and articular disease are symptomatic and do little to limit
disease progression. Research now should be directed at
therapeutic modalities that target osteoarticular structural
elements and thereby delaying disease progression and joint
replacement. &
Key Words: joint diseases, joint pain, neuroinflammation,
mast cells, palmitoylethanolamide
INTRODUCTION
Rheumatic or musculoskeletal conditions comprise over
150 diseases and progressive syndromes, which are
associated with pain. Among those with the greatest
impact on society are osteoarthritis and rheumatoid
arthritis.
1,2
Osteoarthritis, also known as arthritis, is
considered a degenerative joint disease that affects all
articular joints and is associated with degeneration of
the joint cartilage and menisci, subchondral sclerosis,
and inflammation of the synovial membrane. The
Address correspondence and reprint requests to: Giustino Varrassi,
MD, PhD, FIPP, c/o Fondazione Paolo Procacci, Via Tacito 6, 00193 Rome,
Italy. E-mail: giuvarr@gmail.com.
Submitted: October 24, 2016; Revised December 17, 2016;
Revision accepted: December 17, 2016
DOI. 10.1111/papr.12551
©2016 World Institute of Pain, 1530-7085/17/$15.00
Pain Practice, Volume 17, Issue 4, 2017 522–532
disease negatively impacts on limb use as cartilage,
which has been worn away, results in bones rubbing
against each other. This creates friction and causes pain,
trauma, and ligament damage. The disease is related to
aging and generally affects the joints that are subject to
stress, such as the knees, hips, small joints of the hands,
and the cervical and lumbar spine.
Rheumatoid arthritis is a chronic systemic disease
that affects the joints, connective tissue, muscles,
tendons, and fibrous tissue. It occurs in adults during
their most productive years, between 20 and 40 years of
age, and is a chronic disabling condition that often
causes pain and deformity. Its prevalence ranges from
0.3% to 1% of the general population, being higher in
women and in industrialized countries. In the latter, at
least 50% of those affected are unable to maintain a full-
time job within 10 years of disease onset
3,4
(http://www.
who.int/chp/topics/rheumatic/en/).
These diseases, in particular osteoarthritis, can no
longer be simply labeled as “degenerative” diseases.
Growing evidence supports a role of inflammation, not
only locally, in promoting damage to joints and bones,
as well as joint-related functional deficits. In this review,
we will consider key observations, which highlight the
contribution of mast cells and microglia in the develop-
ment of tissue damage and joint-related pain, and the
prospects of innovative treatment to slow progression of
these diseases by controlling neuroinflammation.
CROSS-TALK BETWEEN ARTICULAR CARTILAGE
AND SUBCHONDRAL BONE IS THE BACKBONE OF
JOINT DISEASES
Joint cartilage has long been considered the hub of
rheumatic and musculoskeletal diseases. However,
recent studies now show that other articular joint
structures may contribute to disease symptoms and
pathogenesis and symptoms affecting the joints. Among
these, the subchondral bone seems to play a significant
role.
5
The involvement of bone in articular disorders
was once thought to be secondary to cartilage damage
and, in essence, caused by the need of the junction to
adapt. Recent investigations based on magnetic reso-
nance imaging now show that subchondral bone
changes such as thickening, reduced flexibility, and
density of the trabeculae (often found in the early phase
of arthritis) may be significant in the development of
osteoporosis and microcrystalline arthropathies. In
some cases, changes in the subchondral bone may
precede cartilage injury.
6
A recent systematic review, based on the use of
nonconventional radiographic techniques, examined the
association between disorders of the subchondral bone
and joint transplants, pain, or structural progression of
osteoarthritis of the knee, hip, hand, ankle, and foot.
This analysis confirmed that bone lesions, osteophytes,
and changes in bone morphology are associated, inde-
pendently from each other, with structural progression
and joint replacement. Bone lesions and changes in bone
morphology were also associated with pain in cases of
osteoarthrosis involving the knee, hands, and hip.
5
This
meta-analysis points to the existence of a robust cross-
talk between subchondral bone and articular cartilage
underlying joint diseases.
5
Shared features in patients
with rheumatoid arthritis and osteoarthritis include not
only subchondral bone resorption but also microarchi-
tecture and periarticular bone remodeling, including the
subchondral bone.
7
Cytokines and trophic factors released during ele-
vated subchondral bone turnover interact with articular
cartilage to create a positive feedback loop between the
bone healing process and cartilage damage. On the other
hand, chondrocytes, in response to stimuli such as
inappropriate loads or the presence of subchondral bone
catabolic factors, undergo a change in phenotype and
begin producing cytokines and chemokines, which act in
a paracrine fashion to initiate a vicious cycle leading to
degradation of the cartilage itself. Moreover, tissue
damage triggers an inflammatory reaction that involves
the synovia: Articular mast cells are rapidly activated to
drive the inflammatory response and promote restora-
tion of intertissue equilibrium. The close interaction
between joint structures shows also how protection or
damage to a joint structure can impact other structures.
For example, administration of osteoprotegerin prevents
not only the loss of trabecular bone but also the cartilage
degradation. On the other hand, at the cellular level
osteoblasts from patients with osteoarthritis induce a
change in chondrocyte phenotype in favor of hyper-
trophic differentiation and matrix mineralization.
811
ARTICULAR MAST CELLS
Mast Cells as Coordinators of Cross-Talk Between
Articular Cartilage and Subchondral Bone,
Neuroinflammation, and Pain
Cytokines and growth factors are the principal media-
tors of cross-talk between subchondral bone, cartilage,
and synovia. Not only are mast cells the main source of
Joint Diseases and Neuroinflammation 523
these agents, but they also orchestrate neuroinflamma-
tory processes, both low-grade and frank inflammation.
At the articular level, mast cells are located mainly in the
synovial membrane and joint capsule,
1217
and else-
where mostly along blood vessels and nerve endings of
the joint.
18
Mast cell density increases in the early stages
of joint disease, especially in synovial membranes.
Hyperplasia and hyperactivation of mast cells correlate
with the appearance of osteoarthritic pathogenic hall-
marks (eg, cartilage erosion, and flogistic and painful
pouss
ees).
14,1923
Mast cells contribute to all stages of
the inflammatory process and to disease pathogenesis in
the chronic-evolutive phases.
2426
Mediators released by
joint tissue mast cells have specific actions in joint
inflammation and degenerativedestructive pro-
cesses.
27,28
For example, histamine stimulates synovial
fibroblast proliferation, the production of metallopro-
teinases like matrix metalloproteinase-1 (MMP-1), and
the upregulation of histamine H
1
receptors.
29,30
Mast
cell tryptase, by inhibiting fibroblast apoptosis, favors
their proliferation.
31
Synovial tissue from patients with
rheumatoid arthritis or osteoarthritis exhibits marked
increases (sixfold to 25-fold) in tryptase type b,
32
which
is capable of degrading aggrecan (chondroitin sulfate
proteoglycan 1), a principal component of the cartilage
matrix. The tetrameric form of tryptase bactivates the
latent forms of MMP-3 and pro-MMP-13, which are
constitutively produced by B synoviocytes, chondro-
cytes, and other cell types in arthritic cartilage. Aggrecan
can be degraded by activated MMPs and its fragments
released in the synovial fluid, which, unlike the parent
molecule, are unable to bind hyaluronic acid.
33
The activity of these mast cell mediators contributes
to the marked reduction in viscoelasticity of synovial
fluid, due to a reduced concentration and average
molecular weight of hyaluronic acid.
3440
Mast cell
derived b-D-hexosaminidase can also degrade hyaluro-
nic acid during these inflammatory and degenerative
processes.
41,42
This enzyme, together with hyaluroni-
dase, plays an important role in the altered catabolism of
hyaluronic acid seen in the joint diseases. In particular,
b-D-hexosaminidase expression is significantly higher
in joint tissues of patients with rheumatoid arthritis
and osteoarthritis. These enzymes represent the main
glycosidases found in the knee, are able to degrade
even hyaline cartilage, and are present both in syn-
ovial fibroblasts and mast cells, two types of cells that
interact closely during joint inflammatory processes and
degeneration.
28,43,44
Mast cells also can influence indi-
rectly the degradation of hyaluronic acid through
proinflammatory mediators such as histamine, prosta-
glandin D2, cytokines, and chemokines, which are able
to interact with fibroblasts, synoviocytes, and chondro-
cytes, thereby influencing hyaluronic acid production by
way of its biosynthetic enzymes hyaluronan synthase-1
and synthase-2, as well as degradation mediated by
catabolic enzymes.
4547
In addition, the proinflamma-
tory milieu elaborated by mast cells promotes the
formation of reactive oxygen intermediates that con-
tribute to the degradation of hyaluronic acid.
24,25,48,49
Synovial mast cells interact with blood vessels and
nerve endings, and dysregulation can affect their func-
tionality and phenotype.
50
In particular, the rapid
release of mast cell histamine can cause tissue edema
and consequent destruction of the stromal matrix via
activation of endothelial cell H
1
receptors. Moreover,
mast cells are a source of numerous growth factors, such
as vascular endothelial growth factor, nerve growth
factor (NGF), and angiogenin,
51
whose release could
contribute to the development of angiogenic processes
typical of joint diseases.
25,52,53
The levels of these
factors are usually altered in joint tissues of chronic
pathologies. NGF, for example, is elevated in synovial
membranes and fluid of patients with arthritis; this
increase is correlated with mast cell density.
5458
The
proangiogenic effect of mast cell tryptase is favored by
its degrading of the extracellular matrix to promote
invasion of new vessels. This excessive release of mast
cell mediators, along with their proangiogenic, oxida-
tive, and inflammatory effects, sets the stage for the
classic manifestations of joint inflammation.
5961
Exper-
imental models of osteoarthritis show increased vessel
density in calcified cartilage, which is especially pro-
nounced in older animals (+100%) compared to young
adults (+50%). Angiogenesis is associated with a thick-
ening of subchondral bone, the area from which
angiogenesis originates.
11
Mast cellderived NGF, other
than its proangiogenic effect, plays an important role in
the development of joint pain and plasticity of sympa-
thetic and somatosensory fibers typical of osteoarthritic
joints of patients with bone metastatic pathology.
53,62,63
NGF, interacting with its receptors on sensory nerve
endings, triggers a series of processes that profoundly
alter cellular activity to amplify pain. In molecular
terms, NGF binding to the high-affinity receptor
tropomyosin receptor kinase A (TrkA) stimulates syn-
thesis of neuropeptides such as substance P and calci-
tonin gene-related peptide, together with TrkA itself and
transient receptor potential channels. The action of
NGF is complemented by participation of the so-called
524 FUSCO ET AL.
low-affinity neurotrophin p75 receptor, which facilitates
release of these neuropeptides.
64
Antidromic release of
such neuropeptides causes tissue neurogenic inflamma-
tion,
65,66
an event that, on the one hand, amplifies the
ongoing inflammatory process in the joint areas (eg,
caused by the attraction, proliferation, and activation of
new mast cells) and, on the other hand, feeds the joint
neurogenic pain.
6770
Over the course of osteoarthritis,
the direct correlation between synovial neuropeptide
concentration, severity of synovitis, and extent of joint
pain confirms the intimate inter-relationship between
sensory nerve activation and inflammation.
71
In these
conditions, and unlike what occurs physiologically, one
sees not a single electrical pulse (spike), but rather a
series of pulses. Consequently, the threshold of neuronal
activation is lowered and the neuron now becomes
receptive to stimuli not normally painful (allodynia), an
indication of peripheral sensitization.
7
High levels of NGF contribute to phenotypic changes
in dorsal root ganglion neurons and their endings that
innervate the joint. The ectopic sprouting of sensory and
sympathetic nerve terminals observed in a model of
arthritic pain was reduced by administration of
anti-NGF antibodies.
63
This plasticity of sensory and
sympathetic nerve fibers innervating the knee joint
(sprouting) is preserved in the elderly.
53
Besides NGF, many other mast cell mediators
(tryptase, bradykinin, adenosine triphosphate, and
prostaglandin E2) may activate their cognate recep-
tors on sensory endings, thereby contributing to
development of peripheral sensitization through mech-
anisms such as phosphorylation of the transient
receptor potential vanilloid 1 receptor.
64,72,73
In the
case of joint diseases, persistent peripheral sensitiza-
tion may also result from an abnormal mechanical
stress-irritative nerve fiber joint caused by stretching/
compression induced by osteochondrophytes, bone
microfractures, and bone marrow hypertension, which
can induce chronic pain as, for example, in
osteoarthritis. Persistent sensitization of peripheral
neurons is the first phase of central sensitization. In
fact, neuronal hyperexcitability is followed by exces-
sive release of neurotransmitters not only from
peripheral terminals but also from those that connect
to the dorsal horn of the spinal cord. This results in a
“transfer” of hyperexcitability to second-order neu-
rons and activation of immune cells in the spinal
cord, the microglia. The main evidence supporting the
role of mast cells in the onset and progression of joint
diseases is reported in Table 1.
Mast Cells as Interlocutors of Microglia and Promoters
of Central Sensitization
The mast cellmicroglia axis supports central and
peripheral nervous system inflammation and the
aberrant processes of chronic pain in joint diseases.
Peripheral mast cells interact with spinal and suprasp-
inal ganglionic microglia directly through chemical
mediators and indirectly through somatosensory
neurons.
66,76,77
A growing body of literature supports the existence of
spinal and supraspinal neuroinflammation in articular
diseases.
7888
For example, at the spinal level microglia
pass from the quiescent to the activated state, astrocytes
increase in number, and the production of proinflam-
matory cytokines such as interleukin-1b(IL-1b), IL-6,
and tumor necrosis factor alpha (TNF-a) rises, suggest-
ing that changes in glia are both morphological as well
as functional.
89,90
In a model of osteoarthritis, spinal
levels of IL-1bincrease, while its inhibition reduces pain.
Moreover, induction of abnormal IL-1bexpression in
the spinal cord induces a condition similar to arthritis.
These results confirm the existence of cross-talk between
the spinal cord and articulation and demonstrate that
both peripheral signals can cause changes at the spinal
level and central immune alteration can modify periph-
eral processes.
91
Central sensitization has also been
observed in patients with osteoarthritis, where pain
thresholds to pressure and prick stimuli are lower than
in healthy subjects,
78,92
and is unrelated to radiological
findings, suggesting that central sensitization is the
factor that contributes most to osteoarticular pain.
78
The main evidence supporting the existence of spinal
and supraspinal neuroinflammation in joint diseases is
reported in Table 2.
In short, joint pain is not a single typology but rather
is associated with different mechanisms primarily of a
nociceptive/inflammatory and neuropathic nature.
93–97
Development of the neuropathic component can be
facilitated by an abnormal mechanical-irritative stress
acting on the joint’s nerve fibers, resulting, for example,
from stretching/compression due to osteochon-
drophytes, bone microfractures, bone marrow hyper-
tension due to variations in blood flow to trabecular
bone, and muscle spasms. The persistence of these
factors can lead to neuropathic pain, especially in the
elderly, a situation in which mechanical-irritative stress
can occur alongside age-dependent degeneration of
proprioceptive sensory innervation.
98,99
Mast cells
appear also to be directly involved in neuropathic
Joint Diseases and Neuroinflammation 525
pain.
100,101
In fact, direct nerve fiber damagewhether
of a traumatic, degenerative, or compressive nature
triggers, via release of neuropeptides
95
, mast cell
degranulation. Massive release of mast cell mediators,
such as histamine and NGF, enhances and supports
electrophysiological alterations of nerve fibers, leading
to their sensitization (Figure 1).
POTENTIAL NEW TARGETS FOR THE TREATMENT
OF DEGENERATIVE JOINT DISEASES
Current treatment options for rheumatic and articular
disease, such as nonsteroidal anti-inflammatory drugs,
are mainly symptomatic and have limited efficacy on
disease progression, apart from nervous sensitization,
when used precociously. New treatment options that
target osteoarticular structural elements can delay dis-
ease progression and joint replacement. Some new drugs
have been shown effective in reducing pain and in
preserving joint structures; however, clinical develop-
ment of most has stopped, mainly because of adverse
effects. Thus, treatment options for osteoarthritis
remain very limited.
102
The ideal treatment should preserve joint structure,
improve patient quality of life, and possess a good safety
profile. Real hope for new therapeutic solutions for
articular diseases is now focused on the so-called
“disease-modifying drugs”.
86,87,103
At the cellular level,
mast cells and microglia represent very attractive
targets, as their modulation allows one not only to
attack peripheral and central neuroinflammation and
reduce pain but also to promote restoration of tissue
Table 1. Main Evidence Supporting the Role of Mast Cells in the Onset and Progression of Joint Diseases
Condition/Articular Tissue Main Results References
Normal human
synovial tissue
Tissue MCs represent nearly 3% of cellular population of the synovia 12
Normal rat
synovial tissue
MCs are present just beneath the lining cells and in the subsynovial and periarticular connective
tissues and around the arteriole
18
RA/cartilagepannus
junction
MCs have been identified at sites of cartilage erosion 13
RA and other rheumatic
diseases/synovia
More synovial MCs/vessels are present in patients with RA and other rheumatic diseases vs. those
without joint disease
14, 15, 31, 45
MCs are not functionally different from pulmonary or intestinal mucosal MCs
Mice lacking their tryptase/heparin complexes have attenuated arthritic responses
MC tryptase secretion into RA synovial fluid is higher than OA synovial fluid
Tryptase has a strong anti-apoptotic effect on RA synovial fibroblasts
OA synovia In OA, MCs constitute 0.8% of all the cell profiles present in the synovia 16, 22, 54
In the subsynovial layer of patients with OA, MCs were higher than those in patients
suffering from RA
NGF increases in the synovia of patients affected by arthritis as well as in animal models
OA cartilage Immunopositive staining for histamine receptors H1 and H2 and for the enzyme
histidine decarboxylase
in human articular chondrocytes in OA cartilage was higher than in controls
30, 33, 41, 47
Tryptase enhances release of vascular endothelial growth factor from OA chondrocytes
Tetramer-forming tryptases are MMP convertases that mediate cartilage damage
and the proteolytic
loss of aggrecan proteoglycans in arthritis
Inhibition of hexosaminidase activity in cultured articular chondrocytes and
chondrosarcoma cells results
in accumulation of hyaluronic acid
SpA, RA, OA, synovial
fluid, and tissue
MCs were elevated in the synovial fluid of OA patients as compared to RA patients 17, 27, 58, 61, 74, 75
MCs are the major IL-17expressing cell population in the SpA synovium
In dogs with chronic lameness, the level of NGF in synovial fluid was found to
be significantly higher
than that found in healthy dogs
Multiple factors in synovial fluid act as MC chemoattractants, 2 of which are SCF and TGF-b
The synovitis score is significantly correlated with the number of MCs
Tendinosis/patellar
tendinosis tissue
Increase of MCs in tendinosis tissue vs. control; number of MCs correlated with the
vessel area fraction
and with symptom duration
21
OA serum NGF concentrations were significantly higher in children with juvenile chronic arthritis
than in controls
56
NGF-induced arthritis Intra-articular NGF injection induces an increase of MCs in the synovium 55
MC knockout mouse Depletion of MCs during the preclinical phase results in a significant reduction of arthritis 74
MCs, mast cells; RA, rheumatoid arthritis; OA, osteoarthritis; MMP, matrix metalloproteinase; SpA, spondylarthritis; NGF, nerve growth factor; SCF, stem cell factor; TGF-b,
transforming growth factor-b.
526 FUSCO ET AL.
homeostasis, thereby limiting disease progression.
Among disease-modifying drugs targeting the mast cell
microglia axis are the N-acylethanolamines,
55,104
such
as N-palmitoylethanolamine (palmitoylethanolamide or
PEA). PEA is an endogenous fatty acid amide-signaling
molecule and a congener of the endocannabinoid anan-
damide.
In synovial fluid, PEA is normally present in elevated
amounts (1,500 pmol/mL), which are drastically
reduced in patients with osteoarthritis or rheumatoid
arthritis,
73
suggesting a protective role in these condi-
tions. In experimental models of joint disease, changes in
PEA levels were also detected in the spinal cord.
80
These
results point to a dysregulation in PEA metabolism in
articular diseases and suggest that PEA supplementation
may prove beneficial in these situations. In support of
this hypothesis, administration of PEA or inhibition
of endocannabinoid degradation ameliorates
Table 2. Main Evidence Supporting the Existence of Spinal
and Supraspinal Neuroinflammation in Joint Diseases
Conditions Main Results References
Human OA Negative correlations between pain intensity
and PPT were found (more pain, more
sensitization)
78, 85, 88
Temporal summation to repeated pressure
stimulation and conditioning pain
modulation, representing central pain
mechanisms, are present in patients with
painful knee OA
Specific serologic biomarkers are associated
with pain sensitization mechanisms in
patients with different degrees of knee pain
MIA-OA [3H]PK11195 binding in the ipsilateral
(injured) lumbar spinal cord was increased by
approximately 25% in MIA-OA
81, 90, 93
Dorsal horn neuron activation and microglial
activation but not reactive astrocytes are
present 2 weeks after intra-articular MIA
injection
At day 28, microglia activation was
significantly correlated with distal allodynia
Adjuvant-OA Higher numbers of IL-1b, IL-6, and TNF-a
mRNA-expressing cells are present in
adjuvant-OA rats vs. control rats
89
The number and immunostaining intensity of
microglia and astrocytes increase in the spinal
cord
CIA Mechanical hypersensitivity in the early phase
of CIA is associated with central sensitization
that is dependent upon microglial-mediated
release of IL-1bin the spinal cord
94, 95
CIA-induced mechanical hypersensitivity was
paralleled by significant microglial and
astrocytic activation, alongside T-cell
infiltration, in the spinal cord
Central changes in the dorsal horn of the
spinal cord are readily detectable, including
significant microgliosis and enhanced release
of the pronociceptive peptide CGRP from
nociceptor central terminals
CGRP release evoked by dorsal root
stimulation was higher in the dorsal horn on
day 18 in rats with CIA compared to control
rats. Prolonged intrathecal administration of
CGRP(8-37) attenuated established
mechanical hypersensitivity and reduced
spinal microgliosis
Microglial inhibitors attenuated mechanical
hypersensitivity and spinal microglial
response in rats with CIA
CGRP receptor antagonist to the lumbar spinal
cord attenuates both mechanical allodynia
and spinal microgliosis
CAIA Following the induction of CAIA, spinal
astrocytes and microglia displayed time-
dependent signs of activation, and inhibition
of glial activity reversed CAIA-induced
mechanical hypersensitivity
96
OA, osteoarthritis; PPT, pressure pain thresholds; MIA-OA, monosodium iodoacetate in
the knee joint; IL, interleukin; TNF-a, tumor necrosis factor-a; mRNA, messenger RNA;
CIA, collagen-induced arthritis; CGRP, calcitonin gene-related peptide; CAIA, collagen
antibody-induced arthritis.
Figure 1. Schematic representation of the contribution of mast
cells and microglia to degenerative joint diseases and neuroin-
flammation. At the articular level, mast cells are located mainly in
the synovial membrane and joint capsule, and elsewhere mostly
along blood vessels and nerve endings of the joint. Peripheral
and central mast cells are likely play a crucial role in the shift of
acute to chronic pain by interacting with other immune cells and
somatosensory nerve terminals. In the periphery, persistent mast
cell activation promotes the recruitment of other immune cells
such as lymphocytes at the lesion site, amplifying inflammatory
processes and causing a sensitization of peripheral nociceptors
and spinal somatosensory neurons. In the CNS, mast cells amplify
neuroinflammatory processes by promoting glial cell activation,
which coordinates inflammation at the spinal level and central
sensitization of central somatosensory neurons.
Joint Diseases and Neuroinflammation 527
collagen-induced arthritis in mice.
105,106
Moreover, PEA
administration exerts anti-inflammatory and analgesic
effects in different conditions of chronic inflamma-
tion,
107,108
modulates mast cell degranulation,
109
and
reduces activation of spinal cord microglia.
110113
Clini-
cally, PEA reduces chronic and neuropathic pain associated
with numerous pathological conditions
103,114
and reduces
pain and improves function in patients with temporo-
mandibular disorders.
115,116
Importantly, PEA possesses an
optimum tolerability profile, conditions fundamental for
chronic treatment of the elderly.
86,87,117,118
Both membrane and nuclear receptors appear to be
important targets for controlling disease progression.
Among membrane receptors, endocannabinoids may be
of particular interest, as they play a key role in bone
formation, resorption, and growth. Both cannabinoid
receptors CB1 and CB2 are present in the skeleton, with
CB1 being expressed on nerve endings and CB2 on
osteoblasts, osteocytes, and osteoclasts.
119,120
Both
cannabinoid receptors are expressed on hypertrophic
chrondrocytes.
121
The CB2 receptor is also expressed by
synovial tissue fibroblasts of patients with rheumatoid
arthritis
122,123
and on immune system cells like mast cells.
CB1 and CB2 receptor agonists have a protective role
in joint diseases, with CB1 intervening in bone remod-
eling and age-dependent bone loss. The CB2 receptor
also protects against bone loss, such as that linked to
menopause, and its presence on immune cells endows it
with immunomodulatory and anti-inflammatory activ-
ities as well. Therefore, molecules that activate the CB2
receptor, either directly or indirectly, such as PEA, are
good candidates for the treatment of rheumatic diseases.
Among nuclear receptors, peroxisome proliferator-
activated receptors alpha and gamma (PPARa, PPARc)
have been proposed as potential targets for joint diseases.
Interestingly, PEA has agonist activity toward PPARa.
Diverse studies suggest that PPARcagonists also reduce
the synthesis of inflammatory and catabolic agents to
prevent cartilage lesions. Mice genetically modified to
lack PPARcdevelop, in adulthood, a form of osteoarthri-
tis characterized by increased degradation of cartilage,
hypocellularity, fibrosis, synovial inflammation, and an
increased expression of catabolic factors including
MMP-13 and other MMPs. Activity of the latter leads
to a reduced expression of collagen type II and aggrecan
and a high number of apoptotic chondrocytes.
124
PPARc
protects cartilage by inhibiting mammalian target of
rapamycin (mTOR), a serine/threonine kinase and neg-
ative regulator of autophagy.
125
Inhibition of mTOR and
intracellular kinases that promote cellular metabolism,
growth, energy consumption, and differentiation pre-
vents development of osteoarthritis by reducing chon-
drocyte apoptosis and increasing autophagy.
126
Autophagy is a key mechanism in maintaining
cellular homeostasis and for removing dysfunctional
cellular organelles and macromolecules. Autophagy is
prolonged in cases of catabolic or nutritional stress. It
should be noted that articular chondrocytes, which live
isolated in gaps, are not removed by specialized cells of
the hematopoietic system such as macrophages. For this
reason, autophagic processes are critical for maintaining
chondrocyte integrity and cartilage homeostasis.
CONCLUSIONS
Rheumatic and joint diseases remain among the most
common and widespread painful and disabling pathologies
worldwide, whose prevalence is expected to grow mainly
due to the rise in life expectancy. Pain associated with joint
disease stems from both inflammatory and neuropathic
components, the latter appearing to contribute substan-
tially to the intensity and quality of the algic events. While
the pathogenesis of joint diseases is still not completely
clear, general consensus favors an underlying cross-talk
between cartilage and subchondral bone. Loss of balance
between these two structures in joint diseases is amplified by
thepresenceofmastcells,whose dysregulation is associated
with alterations of all junction structures (cartilage, bone,
synovium, matrix, nerve endings, and blood vessels). In
addition, persistent activation of mast cells facilitates the
development of spinal neuroinflammation mediated by
their interaction with microglia. At present, these diseases
lack a satisfactory therapeutic solution. Drugs that are
disease-modifying, that is, those capable of counteracting
disease progression, represent the future direction of
research. Molecules targeting cannabinoid receptors and
PPARsareamongthepotentialtherapeutic avenues for
these new therapies.
ACKNOWLEDGEMENTS
This study was supported in part by MIUR, PON
“Ricerca e Competitivit
a 20072013” project PON01_
02512.
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... 3,10 Lastly, the role of neuroinflammation and central sensitization mechanisms as underlying causes of pain chronicity has been characterized. 14,15 This evidence has led to a renewed definition of OA, which is now intended as a complex multifactorial joint pathology caused by inflammatory and metabolic factors underlying joint damage. 1,3,6,10 This new perspective directly impacts the definition of the correct therapeutic approach to OA. ...
... Bidirectional interactions between the immune and nervous systems are increasingly understood to play a pathogenic role in OA chronic pain. 14,15 Communication between the two systems can occur at different levels: in the affected synovium, where nociceptors and macrophages interact, in the dorsal root ganglion, which can become infiltrated by macrophages in response to peripheral inflammation, and in the spinal cord dorsal horn, where microglia can modify synapses between nociceptors and second-order neurons. 15 People with OA are more sensitive to experimental noxious stimuli at body sites distant from their affected joints than unaffected people, suggesting the presence of central sensitization. ...
... This leads to hyperexcitability of second-order neurons and activation of microglia. 14 ...
Preprint
Understanding the basis of osteoarthritis (OA) has seen some interesting advancements in recent years. It has been observed that cartilage degeneration is preceded by subchondral bone lesions, suggesting a key role of this mechanism within the pathogenesis and progression of OA, including the formation of ectopic bone and osteophytes. Moreover, low-grade, chronic inflammation of the synovial lining has gained a central role in the definition of OA pathophysiology, and central immunological mechanisms, innate but also adaptive, are now considered crucial in driving inflammation and tissue destruction. In addition, the role of neuroinflammation and central sensitization mechanisms has been characterized as underlying causes of pain chronicity. This has led to a renewed definition of OA, which is now intended as a complex multifactorial joint pathology caused by inflammatory and metabolic factors underlying joint damage. Since this evidence can directly affect the definition of the correct therapeutic approach to OA, an improved understanding of these pathophysiological mechanisms is fundamental. This review provides an overview of the most updated evidence on OA pathogenesis; it presents the most recent insight on the pathophysiology of OA, describing the interplay between immunological and biochemical mechanisms proposed to drive inflammation and tissue destruction, as well as central sensitization mechanisms. Moreover, although the therapeutic implications consequent to the renewed definition of OA are beyond this review scope, some suggestions for intervention have been addressed.
... [1,2,4] Bu yapılar arasındaki dengeleşim (homeostasis) ve iletişim büyüme faktörleri ve sitokinler aracılığıyla gerçekleştirilir. [5] Yapılar içi ve arasındaki yapım-yıkım dengesi eklem homeostazını sağlarken, bu dengenin bozulması eklem hastalıklarıyla sonuçlanır. [3,6,7] Modern tıpla eklemin yapısındaki en küçük düzensizlikleri tespit etmek ve yeni tedavi yöntemleri geliştirmek mümkün olmuştur. ...
... During the inflammatory response to nerve injury, various inflammatory mediators such as cytokines and chemokines are released by damaged cells and immune cells in the microenvironment of the lesion, which in turn induces painful neuropathy [48]. TNF-α, a proinflammatory cytokine, has been suggested to be involved in the pathogenesis of neuroinflammation, and elevated TNF-α levels have been found locally and systemically in patients with neuropathic pain [49][50][51]. TNF-α signals through ligand binding to two receptors, TNFR1 and TNFR2. Binding of TNF-α to TNFR1 activates apoptosis via intracellular death domain proteins [52]. ...
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The entrapment of peripheral nerves is associated with chronic neuroinflammation and neuropathic pain, and perineural injection therapy with glucose is emerging as an effective treatment for peripheral entrapment neuropathy. However, the mechanism underlying the pharmacological effect of glucose on nerves remains unclear. One of the hypothesized mechanisms is that glucose reduces neurogenic inflammation. Therefore, we investigated the effects of high glucose concentrations on cytokine-induced neuroinflammation in vitro. Human SH-SY5Y neuronal cells were challenged with 10 ng/mL TNF-α for 16 h and subsequently treated with different glucose concentrations (0–25 mM) for 24 h. Cell viability was evaluated using the diphenyltetrazolium bromide assay, and proinflammatory cytokine levels were assessed using ELISA and quantitative PCR. In addition, mRNA levels of NF-κB and cyclooxygenase-2 were analyzed using quantitative PCR. Exposure to 10 ng/mL TNF-α resulted in decreased viability of SH-SY5Y cells and significant upregulation of IL-6, IL-1β, NF-κB, and cyclooxygenase-2. Subsequent exposure to high glucose levels (25 mM) markedly reduced the upregulation of IL-6, IL-1β, cyclooxygenase-2, and NF-κB, and restored the functional metabolism of SH-SY5Y cells, compared with that of the normal glucose control. Our findings suggest that high glucose concentrations can mitigate TNF-α-induced NF-κB activation, upregulation of proinflammatory cytokines, and metabolic dysfunction
... The effect may be uncontrolled and lead to toxicity and brain damage, widespread inflammation and further infiltration of leucocytes through the BBB, a process called chronic neuroinflammation (Mayer et al., 2013). It is a vicious cycle, contributing to the development and maintenance of neurodegenerative diseases including PD (Fusco et al., 2017;Yong, 2010;Kempuraj et al., 2016). Neuroinflammation is prevalent in PD and contributes to PD progression throughout all stages. ...
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Parkinson’s disease (PD) is the second most common age-associated neurodegenerative disorder and is characterized by progressive loss of dopamine neurons in the substantia nigra. Peripheral immune cell infiltration and activation of microglia and astrocytes are observed in PD, a process called neuroinflammation. Neuroinflammation is a fundamental response to protect the brain but, when chronic, it triggers neuronal damage. In the last decade, central and peripheral inflammation were suggested to occur at the prodromal stage of PD, sustained throughout disease progression, and may play a significant role in the pathology. Understanding the pathological mechanisms of PD has been a high priority in research, primarily to find effective treatments once symptoms are present. Evidence indicates that early life exposure to neuroinflammation as a consequence of life events, environmental or behaviour factors such as exposure to infections, pollution or a high fat diet increase the risk of developing PD. Many studies show healthy habits and products that decrease neuroinflammation also reduce the risk of PD. Here, we aim to stimulate discussion about the role of neuroinflammation in PD onset and progression. We highlight that reducing neuroinflammation throughout the lifespan is critical for preventing idiopathic PD, and present epidemiological studies that detail risk and protective factors. It is possible that introducing lifestyle changes that reduce neuroinflammation at the time of PD diagnosis may slow symptom progression. Finally, we discuss compounds and therapeutics to treat the neuroinflammation associated with PD.
... Symptoms of the disease can be reduced after sympathetic tone decreases in RA patients [9]. In addition, both excessive and insufficient production of neuropeptides may be harmful to joint cartilage [10]. The treatment carried out for neuropeptides also showed good results in arthritis experiments in mice [11]. ...
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Objectives: Synovial fibroblasts (SFs) play an important role in the development and progression of rheumatoid arthritis (RA). However, the pathogenic mechanism of SFs remains unclear. The objective of this study was to investigate how neuropeptides and N6-methyladenosine (m6A) played an important role in the underlying pathogenic processes of SFs that contribute to the development of RA. Methods: Single-cell RNA sequencing data were examined using single-cell analysis and machine learning. SF subgroups were identified based on the clustering and annotation results of the single-cell analysis. Moreover, cell-cell communication was used to analyse neuropeptide-related receptor and ligand pairs on the surface of SF cell membranes. Machine learning was used to explore the m6A factors acting on these neuropeptide genes. Results: NPR3, GHR, BDKRB2, and CALCRL, four neuropeptide genes, were shown to be differently expressed among SF subgroups. Further investigation of receptor-ligand interactions found that NPR3 (in conjunction with NPPC, OSTN, NPPB, and NPPA) and GHR (in conjunction with GH1 and GH2) may have a role in SF interactions. As predicted by machine learning, IGFBP2 and METTL3 were identified as key factors regulating m6A of NPR3 and GHR. The expression levels and enrichment pathways of METTL3 and IGFBP2 were different among SF subgroups. Conclusions: Single-cell analysis and machine learning efficiently identified neuropeptide genes and m6A factors that perform important regulatory functions in RA. Our strategy may provide a basis for future studies to identify pathogenic cell subpopulations and molecular mechanisms in RA and other diseases.
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Knee osteoarthritis is a common cause of pain and disability in old subjects. Pain may 13 predispose to the development of frailty. Studies on mechanisms underlying pain in osteoarthritis 14 models during aging are lacking. In this work we use the monosodium-iodoacetate-model of oste-15 oarthritis in adult (11-week-old) and old (20-month-old) C57BL/6J mice to compare hypersensitivity, 16 locomotion, neuroinflammation and the effect of morphine treatment. After osteoarthritis induction 17 in adult and old mice, spontaneous pain, mechanical allodynia and thermal hyperalgesia similarly 18 develop, while locomotion and frailty are more affected in old than in adult animals. When behav-19 ioral deficits are present, animals are treated for 7 days with morphine. The opioid counteracts be-20 havioral alterations and the frailty index worsening in adult and old mice. To address the mecha-21 nisms that underlie pain, we evaluated neuroinflammatory markers and proinflammatory cyto-22 kines expression in the sciatic nerve, DRG and spinal cord. An overexpression of cytokines and glia 23 markers are present in osteoarthritis adult and old mice, but the activation is qualitatively and quan-24 titatively more evident in aged mice. Morphine is able to counteract neuroinflammation in both age 25 groups. We demonstrate that old mice are more vulnerable to pain detrimental effects, however a 26 prompt treatment is successful in mitigating them. 27
Article
Objective To review current knowledge surrounding the role of mast cells in joint inflammation and arthritis. Method Narrative review. Results Mast cells (MCs) are commonly observed in the synovium of the joint, particularly surrounding blood vessels and nerve endings. Some studies have reported increased MC number and degranulation in patients with osteoarthritis (OA). In two studies, MCs were the only immune cell type found in higher concentrations in synovium of OA patients compared to rheumatoid arthritis patients. Activation of MCs in OA includes signaling pathways such as immunoglobulin E/Fc epsilon Receptor 1 (IgE/FcεR1), immunoglobulin G/Fc gamma receptor (IgG/Fc γ R), complement, and toll-like cell surface receptor-mediated signaling, resulting in context-dependent release of either pro-inflammatory and/or anti-inflammatory mediators within the joint. Conclusions Recent literature suggests MCs may play a role in mediating synovial inflammation and OA progression. Activation of MCs results in the release of pro-inflammatory mediators that ultimately contribute to inflammation of the synovium, bone remodeling, and cartilage damage. However, some studies have proposed that MCs can also exhibit anti-inflammatory effects by secreting mediators that inactivate pro-inflammatory cytokines such as interleukin 6 (IL-6). Thus, the mechanisms governing MC activation, the downstream pro- and/or anti-inflammatory effects, and their impact on osteoarthritis pathogenesis remains to be elucidated and requires extensive further study. Furthermore, it is important to establish the pathways of MC activation in OA to determine whether MCs exhibit varying phenotypes as a function of disease stage. Ultimately, such research is needed before understanding whether MCs could be targeted in OA treatments.
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Osteoarthritis has become the fourth cause of disability in the world and its occurrence and development are caused by apoptosis and extracellular matrix (ECM) degradation of chondrocytes. Asiaticoside (ASI) is a triterpene saponin compound obtained from Centella Asiatica and has anti-inflammatory and anti-apoptotic effects in various diseases. However, its effects on OA are not clear. In this study, we reported that ASI has a protective effect on the occurrence and progression of OA in vivo and in vitro, and demonstrated its potential molecular mechanism. In vitro, ASI treatment inhibited the release of pro-apoptotic factors induced by TBHP and promoted the release of the anti-apoptotic proteins. In addition, ASI promotes the expression of Aggrecan and Collagen II, while inhibiting the expression of thrombospondin motifs 5 (ADAMTS5) and matrix metalloproteinase-13 (MMP-13), which causes extracellular matrix (ECM) degradation. Mechanistically, ASI exerts its anti-apoptotic effect by activating the Nrf2/HO-1 pathway and preventing p65 from binding to DNA. Similarly, in vivo, ASI has been shown to have a protective effect in a mouse OA model. The conclusion is that our research shows that ASI can be used as a potential drug for the treatment of OA.
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Severe pain and, as a result, limitation of function are the main disabling factors in knee osteoarthritis. In such cases, percutaneous denervation (cryo- and chemoneurolysis, radiofrequency ablation) is used as one of the methods to reduce the intensity of pain and improve the patient's quality of life. Unfortunately, the relative 6-month effectiveness of this minimally invasive manipulation varies greatly and, according to the literature, ranges from 10 to 63%. The article discusses the scope of the most obvious interrelated factors that can negatively affect the effectiveness of denervation. Thanks to the fundamental works of recent years the anatomical location of the target sensory nerves of the knee joint in relation to bone and soft tissue landmarks have become more clear. This revised anatomy can significantly increase the effectiveness of percutaneous denervation of this joint and needs to be validated in clinical trials.
Article
Objective Inflammation plays a central role in the pathophysiology of rheumatic diseases as well as in osteoarthritis. Temperature, which can be quantified using infrared thermography, provides information about the inflammatory component of joint diseases. This systematic review aims at assessing infrared thermography potential and limitations in these pathologies. Design A systematic review was performed on 3 major databases: PubMed, Cochrane library, and Web of Science, on clinical reports of any level of evidence in English language, published from 1990 to May 2021, with infrared thermography used for diagnosis of osteoarthritis and rheumatic diseases, monitoring disease progression, or response to treatment. Relevant data were extracted, collected in a database, and analyzed for the purpose of this systematic review. Results Of 718 screened articles 32 were found to be eligible for inclusion, for a total of 2094 patients. Nine studies reported the application to osteoarthritis, 21 to rheumatic diseases, 2 on both. The publication trend showed an increasing interest in the last decade. Seven studies investigated the correlation of temperature changes with osteoarthritis, 16 with rheumatic diseases, and 2 with both, whereas 2 focused on the pre-post evaluation to investigate treatment results in patients with osteoarthritis and 5 in patients with rheumatic diseases. A correlation was shown between thermal findings and disease presence and stage, as well as the clinical assessment of disease activity and response to treatment, supporting infrared thermography role in the study and management of rheumatic diseases and osteoarthritis. Conclusions The systematic literature review showed an increasing interest in this technology, with several applications in different joints affected by inflammatory and degenerative pathologies. Infrared thermography proved to be a simple, accurate, noninvasive, and radiation-free method, which could be used in addition to the currently available tools for screening, diagnosis, monitoring of disease progression, and response to medical treatment.
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Palmitoylethanolamide (PEA) is a natural fatty acid amide found in a variety of foods, which was initially identified in egg yolk. MicroPEA of defined particle size (0.5-10 μm) was evaluated for mutagenicity in Salmonella typhimurium, for clastogenicity/aneuploidy in cultured human lymphocytes, and for acute and subchronic rodent toxicity in the rat, following standard OECD test protocols, in accordance with Good Laboratory Practice (GLP). PEA did not induce mutations in the bacterial assay using strains TA1535, TA97a, TA98, TA100, and TA102, with or without metabolic activation, in either the plate incorporation or liquid preincubation methods. Similarly, PEA did not induce genotoxic effects in human cells treated for 3 or 24 h without metabolic activation, or for 3 h with metabolic activation. PEA was found to have an LD50 greater than the limit dose of 2000 mg/kg body weight (bw), using the OECD Acute Oral Up and Down Procedure. Doses for the 90-day rat oral toxicity study were based on results from the preliminary 14-day study, that is, 250, 500, and 1000 mg/kg bw/day. The No Effect Level (NOEL) in both subchronic studies was the highest dose tested.
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Background Rheumatoid arthritis (RA) is a multifactorial autoimmune disease, which is characterized by inflammation of synovial joints leading to the destruction of cartilage and bone. Infiltrating mast cells can be found within the inflamed synovial tissue, however their role in disease pathogenesis is unclear. Therefore we have studied the role of mast cells during different phases of experimental arthritis. Methods We induced collagen-induced arthritis (CIA), the most frequently used animal model of arthritis, in an inducible mast cell knock-out mouse and determined the effect of mast cell depletion on the development and severity of arthritis. ResultsDepletion of mast cells in established arthritis did not affect clinical outcome. However, depletion of mast cells during the preclinical phase resulted in a significant reduction in arthritis. This reduction coincided with a decrease in circulating CD4+ T cells and inflammatory monocytes but not in the collagen-specific antibody levels. Mast cell depletion resulted in reduced levels of IL-6 and IL-17 in serum. Furthermore, stimulation of splenocytes from mast cell-depleted mice with collagen type II resulted in reduced levels of IL-17 and enhanced production of IL-10. Conclusions Here we show that mast cells contribute to the preclinical phase of CIA. Depletion of mast cells before disease onset resulted in an altered collagen-specific T cell and cytokine response. These data may suggest that mast cells play a role in the regulation of the adaptive immune response during the development of arthritis.
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Background: Rheumatoid arthritis (RA) patients frequently show weak correlations between the magnitude of pain and inflammation suggesting that mechanisms other than overt peripheral inflammation contribute to pain in RA. We assessed changes in microglial reactivity and spinal excitability and their contribution to pain-like behaviour in the early stages of collagen-induced arthritis (CIA) model. Methods: Mechanically evoked hypersensitivity, spinal nociceptive withdrawal reflexes (NWRs) and hind paw swelling were evaluated in female Lewis rats before and until 13 days following collagen immunization. In the spinal dorsal horn, microgliosis was assayed using immunohistochemistry (Iba-1/p-p38) and cyto(chemo)kine levels in the cerebrospinal fluid (CSF). Intrathecal administration of microglia-targeting drugs A-438079 (P2X7 antagonist) and LHVS (cathepsin S inhibitor) were examined upon hypersensitivity, NWRs, microgliosis and cyto(chemo)kine levels in the early phase of CIA. Results: The early phase of CIA was associated with mechanical allodynia and exaggerated mechanically evoked spinal NWRs, evident before hind paw swelling, and exacerbated with the development of swelling. Concomitant with the development of hypersensitivity was the presence of reactive spinal microgliosis and an increase of IL-1β levels in CSF (just detectable in plasma). Prolonged intrathecal administration of microglial inhibitors attenuated the development of mechanical allodynia, reduced microgliosis and attenuated IL-1β increments. Acute spinal application of either microglial inhibitor significantly diminished the sensitization of the spinal NWRs. Conclusions: Mechanical hypersensitivity in the early phase of CIA is associated with central sensitization that is dependent upon microglial-mediated release of IL-1β in the spinal cord. Blockade of these spinal events may provide pain relief in RA patients.
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Background: A growing body of evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of mast cells and glial cells, and production of inflammatory mediators in the peripheral and central nervous systems, has an important role in the induction and maintenance of chronic pain. These findings support the notion that new therapeutic opportunities for chronic pain might be based on anti-inflammatory and pro-resolving mediators that act on immune cells, in particular mast cells and glia, to mitigate or abolish neuroinflammation. Among anti-inflammatory and pro-resolving lipid mediators, palmitoylethanolamide (PEA) has been reported to down-modulate mast cell activation and to control glial cell behaviors. Objective: The aim of this study was to perform a pooled meta-analysis to evaluate the efficacy and safety of micronized and ultra-micronized palmitoylethanolamide (PEA) on pain intensity in patients suffering from chronic and/or neuropathic pain. Study design: Pooled data analysis consisting of double-blind, controlled, and open-label clinical trials. Methods: Double-blind, controlled, and open-label clinical trials were selected consulting the PubMed, Google Scholar, and Cochrane databases, and proceedings of neuroscience meetings. The terms chronic pain, neuropathic pain, and micronized and ultra-micronized PEA were used for the search. Selection criteria included availability of raw data and comparability between tools used to diagnose and assess pain intensity. Raw data obtained by authors were pooled in one database and analyzed by the Generalized Linear Mixed Model. The changes in pain over time, measured by comparable tools, were also assessed by linear regression post-hoc analysis and the Kaplan-Meier estimate. Twelve studies were included in the pooled meta-analysis, 3 of which were double-blind trials comparing active comparators vs placebo, 2 were open-label trials vs standard therapies, and 7 were open-label trials without comparators. Results: Results showed that PEA elicits a progressive reduction of pain intensity significantly higher than control. The magnitude of reduction equals 1.04 points every 2 weeks with a 35% response variance explained by the linear model. In contrast, in the control group pain, reduction intensity equals 0.20 points every 2 weeks with only 1% of the total variance explained by the regression. The Kaplan-Meier estimator showed a pain score = 3 in 81% of PEA treated patients compared to only 40.9% in control patients by day 60 of treatment. PEA effects were independent of patient age or gender, and not related to the type of chronic pain. Limitations: Noteworthy, serious adverse events related to PEA were not registered and/or reported in any of the studies. Conclusion: These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.
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Objective: To investigate the presence of mast cells in the osteoarthritic (OA) synovium and their association with clinical parameters in comparison with rheumatoid arthritis (RA) samples. Method: Synovial tissues of 56 symptomatic OA and 49 RA patients were obtained. Two to three paraffin slides were used to quantify inflammation using haematoxylin and eosin staining (synovitis score 0-9), and numbers of mast cells (per 10 high-power fields) using double immunofluorescence for CD117 and tryptase. Average scores per patient were used for analysis. Knee radiographs of OA patients were scored according to the Kellgren and Lawrence (KL) system and pain was determined in OA patients at baseline by visual analogue scale. Results: Median (range) of mast cells was significantly higher in OA samples 45 (1-168) compared to RA samples 4 (1-47) (p-value < 0.001), despite a lower median (range) synovitis score in OA (2.5 (0-6.0)) compared to 4.6 (0-8.0) in RA samples. The synovitis score was significantly correlated with the number of mast cells (in OA Spearman's rho (p-value) 0.3 (0.023) and RA 0.5 (p-value < 0.001)). Interestingly, we observed a trend towards an association between the number of mast cells and an increased KL-grade (p-value 0.05) in OA patients, independently of synovitis. No associations were found with self-reported pain. Conclusion: Prevalence of mast cells in OA synovial tissue is relatively high and associates with structural damage in OA patients, suggesting a role of mast cells in this disease.
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Introduction: The endocannabinoid system modulates function of immune cells and mesenchymal cells such as fibroblasts, which contribute to cartilage destruction in rheumatoid arthritis (RA). The aim of the study was to determine the influence of N-acylethanolamines anandamide (AEA), palmitoylethanolamine (PEA) and oleylethanolamine (OEA) on several features of arthritic inflammation in vitro (human material) and in vivo (a mouse model). Methods: Immunofluorescence and western blotting were used to detect cannabinoid receptors and related enzymes. Cytokines and MMP-3 were measured by ELISA. Intracellular signaling proteins were detected by proteome profiling. Proliferation was quantified by CTB reagent. Adhesion was assessed by the xCELLigence system. After onset of collagen type II arthritis, mice were treated daily with the FAAH inhibitor JNJ1661010 (20 mg/kg) or vehicle. Results: IL-6, IL-8 and MMP-3 (determined only in synovial fibroblasts (SFs)) were downregulated in primary synoviocytes and SFs of RA and OA after AEA, PEA and OEA treatment. In SFs, this was due to activation of TRPV1 and TRPA1 in a COX-2-dependent fashion. FAAH inhibition increased the efficacy of AEA in primary synoviocytes but not in SFs. The effects of OEA and PEA on SFs were diminished by FAAH inhibition. Adhesion to fibronectin was increased in a CB1-dependent manner by AEA in OASFs. Furthermore, elevation of endocannabinoids ameliorated collagen-induced arthritis in mice. Conclusions: N-acylethanolamines exert anti-inflammatory effects in SFs. A dual FAAH/COX-2 inhibitor, increasing N-acylethanolamine levels with concomitant TRP channel desensitization, might be a good candidate to inhibit the production of proinflammatory mediators of synovial cells and to reduce erosions.
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Introduction: Osteoarthritis (OA) is a common joint disease with multiple pathophysiological processes, affecting the whole joint. Current therapeutic options such as NSAIDs can provide a palliative effect on symptoms but have limited effect on disease progression. New drugs targeting OA structures may retard disease progression at an earlier stage and delay the need for joint replacement. Areas covered: Some drugs have entered into clinical trials and a few, such as strontium ranelate, do have improvements in both pain and structure changes. However, most of them have failed in clinical trials largely due to increased side effects or the failure to identify the right OA phenotype for the right drug in clinical design. This review describes various investigational drugs developed for the treatment of OA covering those at stages from preclinical experiments to early phase clinical trials. They include drugs for slowing cartilage degradation, regulating cartilage metabolism, targeting subchondral bone, controlling inflammation and relieving pain. Expert opinion: Treatment options for OA remain limited. However, with the emergence of sensitive tools to detect early disease progression and identification of different OA phenotypes, disease-modifying anti-OA drugs with increased benefit and reduced risks will become available for OA treatment in the near future.
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Background: Elderly patients in general exhibit a higher incidence of chronic and neuropathic pain conditions. This group poses a particular clinical challenge due to age-related pharmacokinetic and pharmacodynamic issues, comorbid conditions, and polypharmacy, as well as frailty and cognitive decline. Poor control of pain has consistently been identified as an issue for older people. The identification of safe and efficacious treatments for chronic pain remains a critical public health concern, especially considering the progressive increase of the world's elderly population.
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Bone is an integral part of the osteoarthritis (OA) process. We conducted a systematic literature review in order to understand the relationship between non-conventional radiographic imaging of subchondral bone, pain, structural pathology and joint replacement in peripheral joint OA. A search of the Medline, EMBASE and Cochrane library databases was performed for original articles reporting association between non-conventional radiographic imaging-assessed subchondral bone pathologies and joint replacement, pain or structural progression in knee, hip, hand, ankle and foot OA. Each association was qualitatively characterised by a synthesis of the data from each analysis based upon study design, adequacy of covariate adjustment and quality scoring. In total 2456 abstracts were screened and 139 papers were included (70 cross-sectional, 71 longitudinal analyses; 116 knee, 15 hip, six hand, two ankle and involved 113 MRI, eight DXA, four CT, eight scintigraphic and eight 2D shape analyses). BMLs, osteophytes and bone shape were independently associated with structural progression or joint replacement. BMLs and bone shape were independently associated with longitudinal change in pain and incident frequent knee pain respectively. Subchondral bone features have independent associations with structural progression, pain and joint replacement in peripheral OA in the hip and hand but especially in the knee. For peripheral OA sites other than the knee, there are fewer associations and independent associations of bone pathologies with these important OA outcomes which may reflect fewer studies; for example the foot and ankle were poorly studied. Subchondral OA bone appears to be a relevant therapeutic target. PROSPERO registration number: CRD 42013005009.