POSTTRAUMATIC OSTEOARTHRITIS: CONTEMPORARY VIEWS OF DEVELOPMENT, PROGRESSION AND THERAPEUTIC APPROACHES Golovach I.Yu., Egudina E.D

Feofaniya Clinical Hospital, Kyiv, Ukraine,

Dnepropetrovsk Medical Academy of Health Ministry of Ukraine, Dnipro, Ukraine

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	Апоптоз 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.