Pathological mechanism of joint destruction in haemophilic arthropathy.

Haemophilic arthropathy (HA), caused by intra-articular haemorrhage, is one of the most common complications in patients with haemophilia. Factor replacement therapy provides missing coagulation factors to prevent children with haemophilia from joint bleeding and decreases their risk for HA. However, haemophilia patients in developing countries are still suffering from HA due to insufficient replacement therapy. Symptoms such as pain and activity limitations caused by HA seriously affect the functional abilities and quality of life of patients with HA, causing a high disability rate in the haemophilia cohort. The pathological mechanism of HA is complicated because the whole pathological mainly involves hypertrophic synovitis, osteopenia, cartilage and bone destruction, and these pathological changes occur in parallel and interact with each other. Inflammation plays an important role in the whole complex pathological process, and iron, cytokines, growth factors and other factors are involved. This review summarizes the pathological mechanism of HA to provide background for clinical and basic research.

Soft tissue knee injury with concomitant osteochondral fracture is associated with higher degree of acute joint inflammation.

BACKGROUND: Osteochondral fractures are often seen on magnetic resonance imaging (MRI) of acutely injured knees, but their existence has gained little interest because of a lack of knowledge of their relation to treatment options and outcome. It is not clear whether acute phase synovial fluid (SF) concentrations of cartilage and bone markers and proinflammatory cytokines are different between traumatically injured knees with or without osteochondral fracture. HYPOTHESIS: Acutely injured knees with an osteochondral fracture, particularly fractures with disrupted cortical bone, have higher concentrations of bone markers and cytokines than do knees without an osteochondral fracture. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Synovial fluid (hemarthrosis) was aspirated (median 1 day after injury) and 1.5-T MRI was performed (median 8 days after injury) in the acutely injured knee of 98 individuals (26% women; mean age, 23 years). As visualized on MRI, 39% knees had an osteochondral fracture with disrupted cortical bone, 30% had an osteochondral fracture with intact cortical bone, and 32% did not have an osteochondral fracture. Concentrations of sulfated glycosaminoglycan, ARGS aggrecan, cartilage oligomeric matrix protein, osteocalcin, secreted protein acidic and rich in cysteine (SPARC), osteopontin and proinflammatory cytokines (interleukin [IL]-1ß, IL-6, IL-8, and tumor necrosis factor [TNF]-α) were analyzed. RESULTS: After adjusting for days between injury and SF aspiration, age at injury, and sex, knees with any osteochondral fracture (with or without disrupted cortical bone) had significantly higher SF concentrations of TNF-α (median [interquartile range (IQR)] = 9 [7-12] pg/mL vs. 7 [5-14] pg/mL; P = .013), whereas knees with an osteochondral fracture with disrupted cortical bone had significantly higher SF concentrations (medians [IQRs]) of SPARC (492 [328-754] ng/mL vs. 407 [140-685] ng/mL; P = .030), IL-8 (278 [148-628] pg/mL vs. 138 [67-413] pg/mL; P = .028), and TNF-α (11 [7-15] pg/mL vs. 7 [5-14] pg/mL; P = .004) compared with knees without an osteochondral fracture. CONCLUSION: In acutely injured knees with hemarthrosis, a concomitant osteochondral fracture with disrupted cortical bone is associated with a higher degree of joint inflammation.

IL-4 alone and in combination with IL-10 protects against blood-induced cartilage damage.

OBJECTIVE: It has been reported that interleukin (IL)-10 limits blood-induced cartilage damage. Our aim was to study the effect of IL-4 alone and in combination with IL-10 on blood-induced cartilage damage. DESIGN: Healthy human full thickness cartilage explants were cultured for 4 days in the presence of 50% v/v blood. IL-4, IL-10, or a combination of both cytokines was added during blood exposure. Cartilage matrix turnover was determined after a recovery period; additionally cytokine production, chondrocyte apoptosis, and expression of the IL-4 and IL-10 receptors were analyzed directly after exposure. RESULTS: Blood-induced damage to the cartilage matrix was limited by IL-4 in a dose-dependent way (P<0.05). Also IL-10 limited this damage, although to a lesser extent (P<0.03). The effect of IL-4 plus IL-10 was more pronounced and protective than IL-10 alone (P<0.05). Production of IL-1ß and tumor necrosis factor (TNF)-α was limited by both IL-4 and IL-10 (P<0.05), but more strongly by IL-4. Blood-induced apoptosis of chondrocytes was limited by IL-4 and the combination, and not by IL-10 alone. No direct beneficial effect of IL-4 or IL-10 on cartilage was found, however, the chondrocyte receptor expression of both cytokine receptors was upregulated by exposure to blood. CONCLUSIONS: This study demonstrates that IL-4 alone and in combination with IL-10 prevents blood-induced cartilage damage. Expectedly, anti-inflammatory effects on monocytes in the blood fraction and protective effects on chondrocytes are both involved. IL-4 in combination with IL-10 might be used to prevent blood-induced joint damage as a result of trauma or surgery.

Interleukin-10 protects against blood-induced joint damage.

Despite prophylactic treatment, haemophilia patients suffer from spontaneous joint bleeds, which lead to severe joint damage. Also after joint trauma, an intra-articular haemorrhage can add to joint damage over time. This study evaluated interleukin 10 (IL-10) in the search for possible interventions to prevent or limit the damaging effects of joint bleeds. Human articular cartilage tissue explants were cultured in the presence or absence of 50% v/v blood (or its cellular components) for 4 d (the expected blood load in vivo after a joint haemorrhage), followed by a recovery period of 12 d. Pharmacological dosages of IL-10 reached during treatment (1 or 10 ng/ml) were added. Additionally, cartilage and synovial tissue obtained from joints with end-stage haemophilic arthropathy (HA) were cultured in the presence of IL-10 (10 ng/ml). IL-10 protected cartilage from the damaging effects of blood exposure, measured by its effects on proteoglycan turnover. In addition, IL-10 beneficially influenced cartilage from patients with HA and reduced the production of the inflammatory cytokines IL-1beta and tumour necrosis factor-alpha by haemophilic synovial tissue. Taken together, although effects were obtained in vitro, IL-10 protects against blood-induced joint damage and might be further evaluated as candidate in treatment of tissue damaging effects of joint haemorrhages.

Oxidant and anti-oxidant systems of synovial fluid from patients with knee post-traumatic arthritis.

It has been suggested that patients with knee post-traumatic arthritis (PA), associated or not to haemarthrosis (HA), display altered oxidant and anti-oxidant systems in their synovial fluid. This study aimed to establish whether this is really the case. Synovial fluid samples were obtained by transdermal arthrocentesis from 69 patients with PA (36 of them had HA) and 22 control subjects. The activities of synovial fluid zinc-copper superoxide dismutase (ZnCuSOD) and manganese superoxide dismutase (MnSOD) isoenzymes, catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR) and glutathione-S-transferase (GST) enzymes, and malondialdehyde (MDA) concentration and synovial fluid viscosity were measured in the study groups. Patients with PA had significantly increased activities of all antioxidant enzymes, except CAT, and MDA concentration than did the controls. However, synovial fluid viscosity was found to be decreased in the study group, mainly in the HA subgroup. Results suggest that excessive free radicals production may exist in synovial fluid of PA patients and may contribute to knee joint destruction.

Synovial fluid ferritin in traumatic hemarthrosis, rheumatoid arthritis and osteoarthritis.

Synovial fluid ferritin levels in patients with traumatic hemarthrosis (HA), rheumatoid arthritis (RA), and osteoarthritis (OA) were measured by double antibody radioimmunoassay. Synovial fluid ferritin levels were significantly higher in 60 patients with HA (mean +/- S.D., 536 +/- 536 ng/ml) and 39 patients with RA (614 +/- 486 ng/ml) than in 20 patients with OA (130 +/- 119 ng/ml) (p < 0.01). Individual levels, however, considerably varied. In HA patients, the synovial fluid ferritin level correlated well with the duration of hemarthrosis, but not with hemoglobin, hematocrit, or an inflammatory synovial fluid index such as the leukocyte count. In RA patients, there was no significant correlation between the synovial fluid ferritin levels and any inflammatory parameter, such as catalase activity, synovial leukocyte counts (including polymorphs and monocytes) or the duration of arthritis. Our results indicate that the synovial fluid ferritin level reflects primarily hemoglobin degradation and appears unrelated to inflammation in joint diseases.

Inflammation after blood injection into a synovial-like space is a result of the cellular component rather than the plasma.

The rat subcutaneous air pouch, a model for a synovial-like space, has been used to study the effect of blood as an inducer of inflammation. Six-day-old pouches were injected with autologous whole blood, with plasma or with blood cell pellets. We found significantly more inflammation and proliferation of pouch lining in pouches injected with whole blood or with the blood cell pellets than with the plasma. After the injection of blood or the cell component, large numbers of hemoglobin crystals and lipid droplets were found in the pouch fluid and were associated with erosions of the pouch membrane.

[Kallikrein-kinin system of the synovial fluid in closed injury to the knee joint]. / Kallikrein-kininovaia sistema sinovial'noi zhidkosti pri zakrytoi travme kolennogo sustava.

State of the kallikrein-kinin system components (activity of kallikrein and total esterase activity of trypsin-like enzymes) was studied in synovial fluid at the acute period of the knee joint closed injury. The kallikrein activity as well as the esterase activity of trypsin-like enzymes correlated completely with clinical manifestations of the reactive arthritis. These enzymes appear to have a definite importance in development of inflammation in the joint.

Synovial fluid lactate levels in septic and non-septic arthritides.

Lactate concentration was studied in 383 synovial fluid specimens from patients with various arthritides. The highest concentrations of lactate occurred in non-gonococcal septic synovial fluids. High values were recorded in seropositive rheumatoid arthritis and crystal-induced arthritides, medium values in synovial fluids from seronegative rheumatoid arthritis, seronegative spondylarthritides, gonococcal arthritis and haemarthrosis, and the lowest values in aspirates from osteoarthrotic joints. There was a positive correlation between synovial pH and lactic acid concentration. These data suggest that determination of lactate in synovial fluid can be valuable in the rapid exclusion of septic arthritis. Its value for differentiating between other inflammatory arthritides is discussed.

Electron probe x-ray analysis of siderosomes in the rabbit haemarthrotic synovial membrane.

Electron probe x-ray analysis of siderosomes produced in the rabbit synovial membrane by repeated injections of autologous blood revealed two kinds of siderosomes; (1) those containing a small amount of phosphorus and, (2) those in which no phosphorus was detectable. On the basis of these findings and past studies it is concluded that haemosiderin is an inorganic compound of iron, probably a hydrated ferric oxide and that a variable amount of organic material (proteins, lipids, phospholipids, etc.,) probably occurs in company with the haemosiderin in the siderosome, but these variable components which decrease in amount with the passage of time cannot be considered as an integral part of haemosiderin.