Golovach I.Yu., Egudina E.D.
Feofaniya Clinical
Hospital, Kyiv, Ukraine,
Dnepropetrovsk Medical Academy of Health
Ministry of Ukraine, Dnipro, Ukraine
POSTTRAUMATIC OSTEOARTHRITIS: CONTEMPORARY VIEWS OF DEVELOPMENT, PROGRESSION AND THERAPEUTIC APPROACHES
Osteoarthrosis and osteoarthritis
Rheumatologists and radiologists have
differentiated two main forms of chronic arthritis at the turn of the century:
(1) atrophic arthritis with synovial inflammation, with formation of erosions
and/or atrophy of cartilage and a bone (for example, rheumatoid arthritis), and
(2) hypertrophic arthritis, which is characterized by focal loss of cartilage,
without formation of a typical inflammatory cascade, and growth (hypertrophy)
of an adjacent bone and soft tissues [3]. The last group has become the synonym
of osteoarthrosis. This term accentuated the absence of clear inflammation and
even was used as the surrogate for normal tissue of joints. Osteoarthrosis was
considered as a non-inflammatory disease of moving joints which is
characterized by worsening properties of articular joint and formation of a new
bone on the surface of joints and borders. The basis of the disease, as was
believed, was slowing restorative processes in an injured cartilage. During
animal experiments, this opinion was confirmed by absent blood circulation in
cartilaginous tissue, by low metabolism of chondrocytes and their inability to
restore an injured cartilage. Changes in dynamic balance between the synthesis
and degradation of matrix by chondrocytes were considered as a main mechanism
in development of degeneration of articular cartilage leading to
osteoarthrosis. Therefore, osteoarthrosis was determined as a primary
non-inflammatory articular disease in persons at the age more than 45-50, with
pain of mechanic type as the main clinical sign, and with some diagnostic sings
of a lesion of joints during imaging examinations [3].
However it has been proved recently that
this opinion is incorrect, and the term osteoarthritis (OA) is more appropriate – a pathologic remodeling of
articular tissues, which is corrected by various pro-inflammatory factors,
which are produced by synovial and subchondral bone tissue [3]. Chronic
inflammation is a common sign of OA with a pathologic process involving all
components of articular tissue: a cartilage, synovial membrane, joint capsule,
ligaments and subchondral bone [15]. In the etiopathogenesis of OA, the main
biomechanical factors are pathologic changes in articular cartilage determined
by abnormal load [16]. Therefore, trauma-induced injuries to structure of
articular cartilage cause the long term inflammatory process [12].
Posttraumatic osteoarthritis
Posttraumatic OA (PTOA) is a type of OA,
with trauma as a confirmed etiological factor [24]. The main traumatic injuries
leading to PTOA are ruptures and significant injuries to menisci and/or ligamentous
apparatus, cartilaginous tissue, intraarticular fractures, especially
accompanied by hemarthrosis. A traumatic injury to the joint, relating to
disordered biomechanics, significantly increases the risk of PTOA [8].
Emergence of PTOA is common mainly for young patients and is characterized by
quite fast progression [10].
In contrast to age-dependent and/or
metabolic OA, PTOA can be estimated and understood in terms of pathogenetic
mechanisms after joint injury, considering the known time of a traumatic accident.
One should note that the disorder of
functioning and articular instability appear both after an injury and after
surgical interventions for restabilization of the joint. According to
literature data, surgical operations for joint stabilization are the factors
associating with progressing degeneration of joints [12]. It was noted that
tibiofemoral or patellofemoral OA developed in almost ¾ of patients 20 years
after surgery on average [38]. It was found that such patients demonstrated the
high levels of pro-inflammatory markers (IL-6 and TNF-a)
in synovial fluid over the long period of time. It allowed offering that these
values promoted the development of PTOA and progression of OA [26].
It was found that meniscectomy worsen the further injury to the
articular cartilage. According to the literature data, meniscectomy-induced
osteoarthritis develops after arthroscopic meniscectomy due to laceration of
meniscus. Partial meniscectomy four times increases the risk of OA that was
estimated 16 years after surgery. During comparison of cartilage recovery
degree, it was found that it was more efficient and faster in case of
degeneration lesion of meniscus as compared to its absence. It can be explained
by a secondary injury to joint tissues [29].
The most common causes of PTOA are intraarticular fractures, and
injuries to meniscus, ligamentous apparatus and cartilaginous tissue [30]. As
for joints, the knee and ankle joints are the most often injured. A general
feature of joint injuries leading to PTOA is a sudden application of mechanic
force (strike) to articular surface. A mechanical injury degree depends on
strike intensity. The studies show that stronger energetic influence causes
higher local injury to tissues which could be estimated experimentally with the
proportion of cells realizing the active oxygen forms, with death of
chondrocytes and destruction of matrix [10, 11]. Various levels of applied impact
energy causes the different types of joint injuries with various feedbacks to
recovery and with different potential of healing: (1) an injury to calls and/or
matrix without macroscopic destruction of structure of a cartilage or a bone;
(2) an injury to cells and/or matrix along with macroscopic destruction of
cartilage structure without a displaced fracture of a bone (these injuries can
be related to microdestructions of a calcified cartilage and of the subchondral
or trabecular bone in some cases; (3) fractures with displacement of articular
surface, with impaction of a cartilage and a bone [12, 13]. Low-energy
injuries, including joint contusions, dislocation and tendon injuries, usually
cause the first two types of articular surface injury, whereas injuries with
higher energy of impaction cause the intraarticular displaced fractures [8, 9].
There are enough evidences that a laceration of the anterior cruciate
ligament (ACL) and a rupture of meniscus are two main risk factors of PTOA in
the knee joint [10]. ACL injuries often appear in young patients, especially in
sportsmen, resulting in pain, functional disorders and decreasing physical
activity in so-called young patients with old knees.
Injuries cause the accumulation of blood in the joint cavity (hemarthrosis
formation). Moreover, the changes appear at the cellular level: chondrocyte and
osteoblast apoptosis, release of high amount of pro-inflammatory mediators. The
studies of the acute posttraumatic stage showed higher expression of molecules
participating in both catabolic and anabolic processes [7, 37].
Abnormal changes in pro-inflammatory cytokines in synovial capsule of the joint
Some studies of synovial fluid (SF) in relatively young patients with
traumatic injuries to ACL showed the high levels of IL-1 β,
IL-6, IL-8 and TNF-a,
mainly by means of IL-8 and TNF-a
[44]. Primarily, IL-1 decreases in SF, but IL-6 and TNF-a
remain at high level within prolonged period (about 6 months after an injury)
[11].
The higher levels of IL-10 and IL-1Ra in SF were high within several
weeks after ACL rupture, with subsequent decrease within 3-6 weeks [36]. After
6 months, persistence of high levels of IL-1 β was found in SF. Moreover, a degree of elevation was
directly correlated with a degree of cartilage injuries [36]. The animal models
of PTOA showed that IL-10 and IL-4 protected the articular cartilage from
subsequent pro-inflammatory response and prevented the subsequences of
inflammation activation in response to hemarthrosis. Therefore, one may make a
conclusion on a possible chondroprotective action of these cytokines [47].
IL-1Ra can neutralize the negative effects of IL-1 in an injured joint [23].
Three phases are observed during the first two weeks after trauma: the
early phase, which is characterized by cellular death and inflammatory events;
the subacute phase with preservation of inflammation, but with lower intensity;
the late phase with increasing degradation of articular matrix [40]. It is
supposed that activation of additional proteolytic cascade and toll-like
receptors (TLR), such as TLR-2 and TLR-4, happens simultaneously with
cytokines/chemokines as the first line of protection of inborn immunity [15].
Along with activation of posttraumatic pro-inflammatory response, one
can observe the decrease in lubricin in SF, resulting in increasing risk of faster
development of destructive changes in the joint as result of disorder of viscoelastic
properties of SF. The posttraumatic level of lubricin is low within quite long
period (about 12 months) [48]. The decrease in lubricin level is associated
with high level of TNF-a.
It was found that inhibition of TNF-a
causes the increase in proteoglycan-4 [11]. Moreover, the high levels of pro-inflammatory
cytokines, such as TNF-a,
IL-1β and thrombocyte growth factor-β (TGF-β) decelerate and suppress the formation of
other articular lubricants – hyaluronic acid, general proteoglycans, oligomeric
matrix protein of cartilage [4].
Acute synovial inflammation, related to
joint injury, is closely related to cellular filtration and is correlated with
severity and degree of an injury. The animal studies confirm the role of
infiltrating macrophages and T-lymphocytes in progression of posttraumatic
disease. By the example of cases with cattle, synovial inflammation also causes
the oxidative injury to chondrocytes of articular cartilage and matrix through
high secretion of reactive oxygen species (ROS) and decreasing antioxidant
protection [44, 49]. In addition to direct injury to vital chondrocyte, ROS
make the synergetic influence on pro-inflammatory cytokines and nitrogen oxide
for stimulation of expression of catabolic genes through extracellular
signal-regulated kinase-1/2 (ERK) and c-Jun N-terminal kinase (JNK) [49].
Abnormal changes in matrix enzymes in synovial membrane of the joint
Within the first hours post-injury in the
acute period, the levels of matrix enzymes, which destruct the articular
cartilage, increase rapidly: tissue inhibitor of metalloproteinase, matrix
metalloproteinase-3, stromelysin-1, disintegrin, metalloproteinase with thrombospondin
5 (ADAMTS-5) [20]. All above-mentioned enzymes determine the posttraumatic
destruction of extracellular matrix of articular cartilage. In comparison of
activity of matrix enzymes, ADAMTS-5 causes less intense changes in the
subchondral bone and articular cartilage. HTRA1 protein, which regulates the
activity of insulin-like growth factors, also participates in destruction of
extracellular matrix. It was found that expression of this protein increased
significantly after trauma [39]. Moreover, excessive release of type 2 collagen
happens in the posttraumatic period, resulting in destruction of proteoglycans
[33]. Collagen molecules influence on the receptor domain (Ddr2) through ras/raf/MEK/ERK
and p28 signal pathways and cause the high release and formation of MMP-13,
formation of mitogen-activated protein kinase p38 (MAPK p38) and nuclear factor
kappa B (NF-kB) [20]. There are some findings that type 2 collagen induces the
expression of MMP-1, -2, -13, -14 and pro-inflammatory cytokines (IL-1 β,
IL-6 and IL-8).
Tenascin-C is a relatively new marker of local activation of
inflammatory cascade after joint injuries [33]. Tenascin-C is a glycoprotein of
extracellular matrix, which interacts with other matrix molecules and plays the
main role in adhesion, migration of proliferation of cells. Considering the low
level of Tenascin-C in the normal articular cartilage of adults, it was noted
that its evident release in SF after injury is a product of high expression of tenascin
by chondrocytes and synoviocytes. Therefore, it is considered as the marker of
local activation of inflammation pathways. Particularly, tenascin-C, being an
endogenic activator of inborn immune receptor TLR-4, fulfils the criteria of
molecular patterns relating to an injury [16]. This glycoprotein is highly
expressed in SF of an injured joint, where PTOA develops [48].
Formation of PTOA
The ratio of anti- and pro-inflammatory cytokines towards dominance of
the latter ones causes the chronic course of inflammation and, finally, PTOA
[29]. The levels of pro-inflammatory cytokines remain high in subacute and
chronic phase (from 2 months to 1 year).
In the chronic phase, the main role in PTOA formation is given to
progression of loss of glycosaminoglycans, and the cartilage injury promotes
the release and disintegration of many other proteins such as MMP and type 2
collagen [17]. Many extracellular proteins originate from pericellular matrix
and can be the result of it injury. As result, post-injury, SF contains a lot
of matrix proteins; the levels of fragments of oligomeric proteins of collagen
and cartilage, which are generated by various aggrecanases, are also high.
Since these fragments remain within years after injury, they can promote the
development of PTOA [43]. A lower level of lubricants (hyaluronic acid and
lubricin) in SF as result of proteolysis, which is induced by neutrophilic
enzymes, and accumulation of inflammatory mediators, causes the disorder of
lubricating function. The chronic phase is characterized by progression of
metabolic and destructive changes in joints, resulting in clinically
symptomless period with pain and disordered function of joints.
The articular cartilage injury initiates the expression of vascular endothelial
growth factor (VEGF) [20]. The increase in VEGF level causes the decrease in
expression of chondromodulin-1 and anti-angiogenic factor which actively
participate in supporting the function and trophics of articular cartilage
[19].
Abnormal changes in articular cartilage and the bone in formation of PTOA
The intensity of abnormal changes, which appear in PTOA, depends on a
degree of traumatic factor.
In the acute period, the main factors promoting the development of PTOA
are plasma extravasation into SF with decreasing levels of lubricin and
hyaluronic acid, decreasing synthesis of proteoglycans, overexpression of
matrix metal proteinases and pro-inflammatory mediators by functioning cells
[27].
In the acute posttraumatic stage, an injury to joint tissues happens,
with initiation of apoptosis of chondrocytes and osteoblasts [45]. The
disordered biomechanics and physicochemical properties of tissue lead to
significant changes in chondrocytes, with alternation of their ability to
express the proteins participating in metabolic pathways, and resulting in cell
death. Since chondrocytes are responsible for supporting the functions of
articular cartilage, their death through apoptotic mechanisms takes one of the
leading places in formation of PTOA [41]. It is confirmed by the fact that
higher percentage of apoptotic cells was found in the cartilages in patients
with intraarticular fractures as compared to patients with OA and RA without
injuries [32]. In vitro and in vivo studies identified a relationship between
cellular death and such factors as impact energy, closeness to articular
surface, and a presence of a fracture [1]. The table summarizes the main links
of PTOA pathogenesis.
Table. Pathogenesis of posttraumatic degradation of cartilage in formation of posttraumatic osteoarthritis over time
Immediate (seconds) |
Acute (months) |
Chronic (years) |
Cellular necrosis |
Apoptosis |
Articular tissue remodelling |
Collagen laceration |
Infiltration with leukocytes and inflammatory mediators |
Inflammation |
Glycosaminoglycan loss |
Extracellular matrix dehydratation |
|
|
Deficiency of lubricants |
|
|
Arthrofibrosis |
|
In vivo and in vitro models
The last decade is associated with multiple scientific works of
experimental models of PTOA in animals and human tissues that show the
actuality of this problem. Most possible, it is related to the fact that more
detailed research of molecular and cellular processes, which cause the
cartilage degradation, especially in the acute posttraumatic phase, opens the
new perspectives for early pharmacological interventions and prevention of
PTOA.
Multiple mechanic and biochemical processes are involved in initiation
of PTOA. Therefore, it is difficult to conduct precise reproduction of tissue
injuries in vitro and to activate the specific cellular pathways. Most studies
review the role of trauma in models of human cartilage with investigation of
cell survival, expression of genes and inflammatory mediators. The cartilaginous
explants are exposed to specific impact load or to recurrent injuries by means
of various devices for estimation of additive effect of cytokines, inhibitors
and drugs on the trauma-induced inflammatory process [34].
The animal models are critical for understanding the development of PTOA
and estimation of new possible treatment techniques [13]. Experimental PTOA is
usually induced by means of surgical intervention or direct physical damage of
the joint. In the first case, the patellar ligament is dissected, and the
medial lateral menisci are removed by microsurgical technique, with the
articular cartilage undamaged. Surgical destabilization of medial meniscus
(DMM) is the most popular procedure for formation of PTOA model [14]. DMM leads
to degenerative injuries to the articular cartilage of the tibia within 10-12
weeks after the procedure, with subchondral bone sclerosis and moderate
synovitis. In a mice model of DDM, the signs of inflammation appeared very
early, with big infiltrates of inflammatory monocytes and activated macrophages
in 7-10 days after surgery [21].
The mice model with the intraarticular fracture of the tibia showed the
high levels of IL-1β, IL-6, IL-8
and MCP-1 on the third day post-surgery, with persistence up to 16th week [35].
After 7 days, significant erosive changes appear in the cartilage in the
fracture site, bone mass loss and acute synovitis within 7 days [9].
Some
recent animal studies showed that specific genetic mutations, which influence
on synthesis of various molecules, can act as predictive biomarkers in
development of chronic posttraumatic arthritis and PTOA. Particularly,
modifications in the genes participating in cartilaginous matrix degradation,
inflammation, differentiation and apoptosis of chondrocytes promote the
initiation of PTOA [30].
The
studies of epigenetic phenomena in the human identified some pathogenetic
mechanisms in development of PTOA. So, progression of the disease is promoted
by the decrease in CpG methylation of PH domain leucine-rich repeat protein
phosphatase-1 (PHLPP1), resulting in increasing expression of PHLPP1. PHLPP1 presents Ser/Thr phosphatase, which
decreases the activity of some kinases, which stimulate the anabolic function
of the cartilage. Moreover, it was shown that deficiency of PHLPP1 in mice with surgical
destabilization through dissection of the medial meniscal ligament protect from
initiation of PTOA by means of increasing cellular contents and thickness of
the articular cartilage [6].
Treatment and prevention
For development of efficient therapeutic strategies, deeper
understanding of molecular, mechanic, biological and cellular events of PTOA
pathogenesis is required. It can open some interesting perspectives in relation
to new therapeutic possibilities and, therefore, to offer safer and more
efficient treatment techniques in the acute posttraumatic phase and in the
period of symptomless course of PTOA.
There are not any confirmed treatment methods of acute posttraumatic
arthritis (APTA) and prevention of chronic course of PTOA. The main objectives
of treatment of patients with APTA are minimization of symptoms, loss of
function, and pain decrease. Currently, treatment of APTA includes the
anti-inflammatory drugs (non-steroidal anti-inflammatory or intraarticular injections
of glucocorticoids), physical exercises with low intensity, and change in life
style, for example, body weigh decrease if necessary. However such treatment is
not efficient for all patients. Surgical techniques are often used:
arthroplasty and endoprosthetics. Possibly, efficient therapeutic interventions
prevent the surgical interventions at early stages after trauma.
It is considered that preventive measures present the most efficient
strategy for limitation of a degree of acute injury to joints and possible
development of PTOA. Therefore, ideal therapy should include early therapeutic
interventions and consider several abnormal ways at the first stages after
trauma.
The preclinical studies gave the attention to the molecules –potential
targets for treatment, including inhibitors of MMP, caspases and growth
factors, antioxidants and even mesenchimal stem cells, which demonstrated the
efficiency as potentially modulating drugs in animal models with PTOA [18, 31].
Since it is considered that activation of inflammatory cascades have the
first-priority significance for development of a chronic disease,
anti-inflammatory therapy presents the best available possibility for
intervention at the early stage of the posttraumatic period. A study by J.S. Lewis
et al. confirms this hypothesis in the animal model [29]. Particularly, anti-cytokine
therapy showed the evident efficiency as a preventive measure of long term
initiation of PTOA.
Inhibition of IL-1, mainly by means of an intraarticular injection,
which influences on IL-1β, or adenoviral
transfer of IL-1Ra and retroviral transduction to overexpression of IL-1Ra, is
an efficient therapeutic method in the animal models of surgically induced PTOA
[14]. The blocking of TNF-α promotes the increase in release of glycosaminoglycans,
resulting in chondroprotective effect in the rat models with APTA and PTOA
[11]. The use of RNA interference with use of lentiviral vector for inhibition
of IL-1β and TNF- β in treatment
of PTOA in rabbits demonstrated the decrease in intensity of an injury and
velocity of degeneration of the cartilage [46]. However both cytokines play the
role in acute phase of posttraumatic process. Some studies of mice models show
that intraarticular inhibition of IL-1, not TNF-α, can decrease the development of the
chronic process, PTOA namely [23].
Although the use of all these agents proved the efficiency in decreasing
progression of the chronic posttraumatic inflammatory response in animal models,
only single randomized pilot clinical study was carried out. Currently, IL-1Ra
is a single agent, which was used as the anti-cytokine approach in patients
with APTA. This study showed that intraarticular administration of IL-1Ra
within 30 days post-injury (n = 6) decreased the pain and improved the function
in two weeks as compared to placebo (n = 5). IL-1Ra also showed the strong anti-fibrous
action [25]. Although this strategy showed the efficiency at the early
posttraumatic phase, the results were not confirmed in larger studies.
IL-10, the anti-inflammatory cytokine, makes the chondroprotective
action with stimulation of type II collagen and expression of proteoglycans,
inhibits the MMP and pro-inflammatory cytokines and prevents the chondrocyte
apoptosis. IL-10 also showed the therapeutic efficiency in the experimental
animal model of early PTOA [49].
The high concentrations of glucosamine and similar aminosugars have the
anabolic and pro-inflammatory effects on chondrocytes and other cells in joint
tissue. Its high concentration in joints is possibly can be achieved after
peroral administration, and intraarticular injections can present the efficient
approach in treatment of PTOA. Among other aminosugars, which were tested, N- acetylglucosamine
has the fine range of activity in vitro [42]. Intraarticular injection of N- acetylglucosamine
was efficient in animal models of PTOA [42].
The hyaluronic acid and lubricin are the important lubricants for
cartilaginous surfaces. The use of lubricin in SF decreases in patients with
PTOA because of degradation of enzymes and suppression of synthesis by
inflammatory cytokines [22]. In the animal models of PTOA, intraarticular
injections of recombinant lubricines resulted in modification of the disease
and chondroprotection [11]. Like lubricine, hyaluronic acid influences on
inflamed joints. There are some multiple reports on its chondroprotective
activity in the experimental models of PTOA [5].
CONCLUSION
Therefore, the injury is the ethiological factor of PTOA which develops
subsequently. However even with surgical intervention, the risk of PTOA exists
in each second patient after trauma and consists more that 50 % [24]. The acute
posttraumatic period is the most dangerous, when maximal abnormal changes
appear in SF, the articular cartilage and the subchondral bone which persist
within a year. The treatment of PTOA is a complex task. Currently, there are
not any biomechanical markers, which predict and correlate with progression of
the disease. The treatment is limited by recovery and stabilization of the
joint. Anti-inflammatory therapy, particularly intraarticular inhibition of
cytokines, can provide the efficient approach for decrease or prevention of
PTOA. The ideal therapy should be various and include the positive effects on
metabolism of chondrocytes and on stimulation of internal recovery, with
simultaneous suppression of catabolic pathways, which cause the death of
chondrocytes and loss of matrix. Some molecular targets were identified, as
well as possible drugs, which showed the efficiency in animal models of joint
injuries and PTOA.
However further studies are required. They will determine the specific
markers for early identification of disease progression and research of
innovative possibilities for prevention of future chronic disease.
Information on financing and conflict of interests
The study was conducted without sponsorship.
The authors declare the absence of any clear or potential risk factors
relating to publication of this article.
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