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Biomedical subjects

F P Lafeber

Publications and source records attributed to F P Lafeber.

At least 19 recordsLinked to original sources
PubMed2001

Accumulation of advanced glycation end products decreases collagen turnover by bovine chondrocytes.

The integrity of the collagen network is essential for articular cartilage to fulfill its function in load support and distribution. Damage to the collagen network is one of the first characteristics of osteoarthritis. Since extensive collagen damage is considered irreversible, it is crucial that chondrocytes maintain a functional collagen network. We investigated the effects of advanced glycation end products (AGEs) on the turnover of collagen by articular cartilage chondrocytes. Increased AGE levels (by culturing in the presence of ribose) resulted in decreased collagen synthesis (P < 0.05) and decreased MMP-mediated collagen degradation (P < 0.02). The latter could be attributed to increased resistance of the collagen network to MMPs (P < 0.05) as well as the decreased production of MMPs by chondrocytes (P < 0.02). Turnover of a protein is determined by its synthesis and degradation rates and therefore these data indicate that collagen turnover is decreased at enhanced AGE levels. Since AGE levels in human cartilage increase approximately 50 fold between age 20 and 80, cartilage collagen turnover likely decreases with increasing age. Impaired collagen turnover adversely affects the capacity of chondrocytes to remodel and/or repair its extracellular matrix. Consequently, age-related accumulation of AGE (via decreased collagen turnover) may contribute to the development of cartilage damage in osteoarthritis.

Animals↗
PubMed2001

Age-related decrease in susceptibility of human articular cartilage to matrix metalloproteinase-mediated degradation: the role of advanced glycation end products.

OBJECTIVE: Progressive destruction of articular cartilage is a hallmark of osteoarthritis (OA) and rheumatoid arthritis (RA). Age-related changes in cartilage may influence tissue destruction and thus progression of the disease. Therefore, the effect of age-related accumulation of advanced glycation end products (AGEs) on cartilage susceptibility to proteolytic degradation by matrix metalloproteinases (MMPs) present in synovial fluid (SF) of OA and RA patients was studied. METHODS: Cartilage was incubated with APMA-activated SF obtained from OA or RA patients, and tissue degradation was assessed by colorimetric measurement of glycosaminoglycan (GAG) release. Cartilage degradation was related to the level of AGEs in cartilage from donors of different ages (33-83 years) and in cartilage with in vitro-enhanced AGE levels (by incubation with ribose). MMP activity in SF was measured using a fluorogenic substrate. AGE levels were assessed by high-performance liquid chromatography measurement of the glycation product pentosidine. RESULTS: In cartilage from donors ages 33-83 years, a strong correlation was found between the age-related increase in pentosidine and the decrease in MMP-mediated tissue degradation (r = -0.74, P < 0.0005). Multiple regression analysis showed pentosidine to be the strongest predictor of the decreased GAG release (P < 0.0005); age did not contribute (P > 0.8). In addition, decreased MMP-mediated GAG release was proportional to increased pentosidine levels after in vitro enhancement of glycation (r = -0.27, P < 0.01). This was demonstrated for both OA and RA SF (for control versus glycated, P < 0.002 for all SF samples tested). CONCLUSION: Increased cartilage AGEs resulted in decreased cartilage degradation by MMPs from SF, indicating that aged cartilage is less sensitive than young cartilage to MMP-mediated cartilage degradation, such as occurs in OA and RA. Therefore, the level of cartilage glycation may influence the progression of these diseases.

Adult↗
PubMed2001

Age-related accumulation of the advanced glycation endproduct pentosidine in human articular cartilage aggrecan: the use of pentosidine levels as a quantitative measure of protein turnover.

During aging, non-enzymatic glycation results in the formation and accumulation of the advanced glycation endproduct pentosidine in long-lived proteins, such as articular cartilage collagen. In the present study, we investigated whether pentosidine accumulation also occurs in cartilage aggrecan. Furthermore, pentosidine levels in aggrecan subfractions of different residence time were used to explore pentosidine levels as a quantitative measure of aggrecan turnover. In order to compare protein turnover rates, protein residence time was measured as racemization of aspartic acid. As has previously been shown for collagen, pentosidine levels increase with age in cartilage aggrecan. Consistent with the faster turnover of aggrecan compared to collagen, the rate of pentosidine accumulation was threefold lower in aggrecan than in collagen. In the subfractions of aggrecan, pentosidine levels increased with protein residence time. These pentosidine levels were used to estimate the half-life of the globular hyaluronan-binding domain of aggrecan to be 19.5 years. This value is in good agreement with the half-life of 23.5 years that was estimated based on aspartic acid racemization. In aggrecan from osteoarthritic (OA) cartilage, decreased pentosidine levels were found compared with normal cartilage, which reflects increased aggrecan turnover during the OA disease process. In conclusion, we showed that pentosidine accumulates with age in aggrecan and that pentosidine levels can be used as a measure of turnover of long-lived proteins, both during normal aging and during disease.

Adolescent↗
PubMed2001

Ankle images digital analysis (AIDA): digital measurement of joint space width and subchondral sclerosis on standard radiographs.

OBJECTIVE: Reliable evaluation of joint space width and subchondral sclerosis of osteoarthritic joints is difficult. The present study describes a new digital method to analyse standard radiographs of the ankle. DESIGN: Standardized radiographs were taken of the ankle of 12 patients with severe osteoarthritis (OA) under full weight-bearing conditions, before treatment and 1 year after initiation of treatment. Treatment consisted of 3 months distraction of the tibio-talar joint, for which clinical benefit has been shown previously. The width of the joint space was measured on digitized images of the radiographs by means of the newly developed semi-automatic digital technique called AIDA (Ankle Images Digital Analysis) and by means of the most widely used conventional analogue measurements. In addition, AIDA was used to assess subchondral sclerosis by measuring the intensity of the radiograph at fixed positions at the bone-cartilage interface. RESULTS: AIDA appeared to be a reliable method for measuring small changes in joint space width and subchondral sclerosis because the intra- and interobserver variation was small. Mean JSW for two observers was 1.96 and 2.00 mm, with mean differences between two observations of 0.05 and -0.01, respectively. Mean subchondral sclerosis in the tibia was 1.52 and 1.61 with mean differences between two observations of, respectively, 0.00 and 0.03. In addition to conventional measurements, AIDA could demonstrate a decrease in subchondral sclerosis as a result of joint distraction of 71% and 69% after 1 year for talus and tibia, respectively. CONCLUSION: The use of AIDA is preferable to the conventional analogue method for evaluating the severity of ankle OA, because the method provides quantitative data not only for the joint space width but also for subchondral sclerosis.

Ankle Joint↗
PubMed2001

Accumulation of advanced glycation endproducts reduces chondrocyte-mediated extracellular matrix turnover in human articular cartilage.

OBJECTIVE: The prevalence of osteoarthritis (OAs) increases with age and coincides with the accumulation of advanced glycation endproducts (AGEs) in articular cartilage, suggesting that accumulation of glycation products may be involved in the development of OA. This study was designed to examine the effects of accumulation of AGEs on the turnover of the extracellular matrix of human articular cartilage. DESIGN: Chondrocyte mediated cartilage degradation (GAG release, colorimetric) was measured in human articular cartilage of donors aged 19-82 years (N=30, 4-day culture). In addition, to mimic the age-related increase in AGE levels in vitro, cartilage was cultured in the absence or presence of glucose, ribose or threose. Cartilage degradation and proteoglycan synthesis ((35)SO(2)(-4) incorporation) were measured and related to the degree of cartilage AGE levels (fluorescence at 360/460 nm). RESULTS: Chondrocyte-mediated degradation of articular cartilage (i.e. GAG release) decreased with increasing age of the cartilage donor (r=-0.43, P< 0.02). In vitro incubation of cartilage with glucose, ribose or threose resulted in a range of AGE levels that was highly correlated to the chondrocyte-mediated cartilage degradation (r=-0.77, P< 0.001, N=26). In addition, in these in vitro glycated cartilage samples, a decrease in proteoglycan synthesis was observed at increasing AGE levels (r=-0.54, P< 0.005, N=25). CONCLUSIONS: This study shows that an increase in AGE levels negatively affects the proteoglycan synthesis and degradation of articular cartilage. In combination, these two effects reduce the turnover of the cartilage and thereby the maintenance and repair capacity of the tissue. By this mechanism, the age-related increase in cartilage AGE levels may contribute to the development of OA.

Adult↗
PubMed2001

Experimentally challenged reactivity of the hypothalamic pituitary adrenal axis in patients with recently diagnosed rheumatoid arthritis.

OBJECTIVE: There is evidence that the hypothalamic pituitary adrenal (HPA) axis is subresponsive in patients with rheumatoid arthritis (RA). We assessed HPA axis responses to experimental stressors mimicking daily life challenges in patients with RA to determine whether HPA axis activity is associated with Th1 and Th2 activity. METHODS: ACTH and cortisol responses in reaction to the succession of a bicycle ergometer task, a cold pressor task, and a computerized Stroop Color-Word interference test, as well as basal Th1 and Th2 cell activity, were assessed in 29 patients (21 female, 8 male) with recently diagnosed RA (mean disease duration 29 wks, range 5-69), mean age 55.7 years, none receiving glucocorticoid treatment, and 30 (20 female, 10 male) healthy age and sex matched controls (mean age 54.1 yrs). RESULTS: Mean ACTH and cortisol levels did not differ between the groups (p > 0.10). Patients tended to have a less pronounced ACTH response (F2.50 = 2.7, p = 0.08) and had a significantly smaller cortisol response (P F2.50 = 6.1, p < 0.01) than healthy controls in reaction to the stressors. This difference in cortisol response was reduced, but remained significant when ACTH responsiveness was accounted for by entering it as a covariate (P F2.49 = 3.7, p = 0.03). ACTH and cortisol levels and responses were not associated (all p > 0.19) with basal interferon-gamma and interleukin 4 as reflections of Th1 and Th2 cell activity, respectively. HPA axis activity was not linked to current disease activity. CONCLUSION: Our findings show reduced HPA axis responsiveness in RA patients with recent diagnosis receiving longterm medication that is suggested to be located both at a hypothalamic/pituitary and at an adrenal level. It appears that common HPA axis activity accomplishes low amounts of cortisol release, which makes it difficult to determine an influence of endogenous cortisol changes on the Th1/Th2 balance.

Adrenocorticotropic Hormone↗
PubMed2001

Interleukin 10 (IL-10), not IL-4 or interferon-gamma production, correlates with progression of joint destruction in rheumatoid arthritis.

OBJECTIVE: Both interleukin 4 (IL-4) and IL-10, separately and in combination, and under in vitro and in vivo conditions in animals, have been reported to inhibit characteristics of rheumatoid arthritis (RA) and experimentally induced arthritis. We investigated if IL-10 and IL-4 production, as well as interferon-gamma (IFN-gamma) production, opposing IL-4, were related to RA disease variables. A method was chosen to exclude the influence of age and disease duration. METHODS: We selected RA patients with mild and severe disease. Inclusion criteria were erythrocyte sedimentation rate (ESR) < or = 28 mm/h and > or = 50, C-reactive protein (CRP) < or = 20 and > or = 30, Thompson joint score < or = 60 and > or = 100 and radiographic joint damage score, Sharp score < or = 30 and > or = 40. Age and disease duration were restricted: 30 to 70 years and 5 to 15 years, respectively. Peripheral blood mononuclear cells were isolated and the ex vivo 48 h production of T cell IL-10, IL-4, and IFN-gamma (after CD3-CD28 stimulation) was assessed and was correlated to clinical variables. RESULTS: Only IL-10 production differed significantly between the 2 groups of RA patients, being highest in the "mild" group. Taking all patients together, a strong negative correlation was found between IL-10 production and radiographic joint damage (r = -0.53, p < 0.001) as well as progression of joint damage (r = -0.56, p < 0.0001). Similar negative correlations, although less powerful, were found between IL-10 production and ESR, CRP, and Thompson joint score. No correlation was found for IFN-gamma, IL-4, or the ratio of the 2 with disease activity variables or joint damage. CONCLUSION: The findings suggest that the high IL-10 production found in patients with RA may be protective, especially against progression of joint destruction in RA.

Adolescent↗
PubMed2000

Effect of collagen turnover on the accumulation of advanced glycation end products.

Collagen molecules in articular cartilage have an exceptionally long lifetime, which makes them susceptible to the accumulation of advanced glycation end products (AGEs). In fact, in comparison to other collagen-rich tissues, articular cartilage contains relatively high amounts of the AGE pentosidine. To test the hypothesis that this higher AGE accumulation is primarily the result of the slow turnover of cartilage collagen, AGE levels in cartilage and skin collagen were compared with the degree of racemization of aspartic acid (% d-Asp, a measure of the residence time of a protein). AGE (N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, and pentosidine) and % d-Asp concentrations increased linearly with age in both cartilage and skin collagen (p < 0.0001). The rate of increase in AGEs was greater in cartilage collagen than in skin collagen (p < 0.0001). % d-Asp was also higher in cartilage collagen than in skin collagen (p < 0.0001), indicating that cartilage collagen has a longer residence time in the tissue, and thus a slower turnover, than skin collagen. In both types of collagen, AGE concentrations increased linearly with % d-Asp (p < 0.0005). Interestingly, the slopes of the curves of AGEs versus % d-Asp, i.e. the rates of accumulation of AGEs corrected for turnover, were identical for cartilage and skin collagen. The present study thus provides the first experimental evidence that protein turnover is a major determinant in AGE accumulation in different collagen types. From the age-related increases in % d-Asp the half-life of cartilage collagen was calculated to be 117 years and that of skin collagen 15 years, thereby providing the first reasonable estimates of the half-lives of these collagens.

Adolescent↗
PubMed2000

Age-related accumulation of Maillard reaction products in human articular cartilage collagen.

Non-enzymic modification of tissue proteins by reducing sugars, the so-called Maillard reaction, is a prominent feature of aging. In articular cartilage, relatively high levels of the advanced glycation end product (AGE) pentosidine accumulate with age. Higher pentosidine levels have been associated with a stiffer collagen network in cartilage. However, even in cartilage, pentosidine levels themselves represent <1 cross-link per 20 collagen molecules, and as such cannot be expected to contribute substantially to the increase in collagen network stiffness. In the present study, we investigated a broad range of Maillard reaction products in cartilage collagen in order to determine whether pentosidine serves as an adequate marker for AGE levels. Not only did the well-characterized AGEs pentosidine, N(epsilon)-(carboxymethyl)lysine, and N(epsilon)-(carboxyethyl)lysine increase with age in cartilage collagen (all P<0.0001), but also general measures of AGE cross-linking, such as browning and fluorescence (both P<0.0001), increased. The levels of these AGEs are all higher in cartilage collagen than in skin collagen. As a functional measure of glycation the digestibility of articular collagen by bacterial collagenase was investigated; digestibility decreased linearly with age, proportional to the extent of glycation. Furthermore, the arginine content and the sum of the hydroxylysine and lysine content of cartilage collagen decrease significantly with age (P<0.0001 and P<0. 01 respectively), possibly due to modification by the Maillard reaction. The observed relationship between glycation and amino acid modification has not been reported previously in vivo. Our present results indicate that extensive accumulation of a variety of Maillard reaction products occurs in cartilage collagen with age. Altogether our results support the hypothesis that glycation contributes to stiffer and more brittle cartilage with advancing age.

Adolescent↗
PubMed2000

Joint distraction in treatment of osteoarthritis (II): effects on cartilage in a canine model.

OBJECTIVE: From a clinical point of view, joint distraction as a treatment for osteoarthritis (OA) of hip and ankle has been demonstrated to be very promising. Pain, joint mobility and functional ability, the most important factors for a patient with severe OA, all improved. Although radiographic joint space enlargement in a significant number of patients suggested cartilage repair, actual cartilage repair remains difficult to evaluate. Therefore the present study was initiated to evaluate the actual effects of joint distraction on cartilage. METHODS: For this purpose a canine model for OA, anterior cruciate ligament transection (ACLT) was used. Sixteen weeks after ACLT articulating Ilizarov joint distraction of the knee was carried out. Absence of mechanical contact between articular surfaces and presence of intra-articular intermittent fluid pressure, characteristics of Ilizarov joint distraction, were confirmed. Twenty-five weeks after ACLT joint tissue of the dogs was analyzed. RESULTS: Biochemical analysis showed that after joint distraction the abnormal cartilage proteoglycan (PG) metabolism, characteristic for OA, had changed to a level found in control joints. Moreover, a mild degree of inflammation, present after ACLT, was reduced upon joint distraction. PG-content and histological cartilage degeneration had not (yet) improved within the time of treatment. DISCUSSION: Results suggest that the promising clinical results of Ilizarov joint distraction in patients with OA are accompanied by changes in cartilage metabolism. A change in proteoglycan turnover, indicating normalization of overall chondrocyte function, might in the long term, with normal joint use, lead to actual repair of cartilage.

Animals↗
PubMed2000

Articular cartilage is more susceptible to blood induced damage at young than at old age.

OBJECTIVE: It has been shown that cartilage is damaged upon intraarticular hemorrhage. We investigated differences in the susceptibility of cartilage from young adult and old animals to blood induced joint damage in a canine in vivo model. METHODS: Right knees of 6 young adult beagles (aged 2.2 +/- 0.1 yrs) and 6 old beagles (7.4 +/- 0.3 yrs) were intraarticularly injected twice in 4 days with autologous blood. Dogs were killed 4 or 16 days after the first injection and cartilage matrix proteoglycan content and synthesis and collagen damage were determined. RESULTS: Shortly after blood injection (Day 4), proteoglycan synthesis was inhibited and the proteoglycan content of the cartilage was decreased in both groups. However, the degree of the inhibition of proteoglycan synthesis was significantly greater in young adult animals than in old animals. On Day 16 proteoglycan synthesis was increased in both young adult and old cartilage, but more elevated in old cartilage. The proteoglycan content remained decreased in both young adult and old cartilage, but significantly more so in young adult cartilage than in old cartilage. CONCLUSION: Results suggest that intraarticular bleeding influences cartilage metabolism and repair, and that the cartilage of young adult animals is more susceptible to these influences than cartilage of old animals. Differences in the aging of chondrocytes and age related changes in matrix integrity may be involved. Prevention and appropriate treatment of joint bleeding is indicated and this is especially relevant for young adult cartilage.

Age Factors↗
PubMed1999

Age-related decrease in proteoglycan synthesis of human articular chondrocytes: the role of nonenzymatic glycation.

OBJECTIVE: To examine the effect of nonenzymatic glycation of cartilage extracellular matrix on the synthetic activity of chondrocytes. METHODS: The proteoglycan-synthesis rate (35SO4(2-) incorporation) and levels of advanced nonenzymatic glycation (determined by high-performance liquid chromatography measurement of pentosidine) were evaluated in human articular cartilage from 129 donors, varying in age from 25 to 88 years, and in cartilage with enhanced levels of advanced glycation end-products (AGEs) resulting from incubation with ribose. RESULTS: Cartilage showed a strong age-related increase in pentosidine levels (r = 0.97, P < 0.0005) and, concomitantly, a decrease in proteoglycan synthesis (r = -0.98, P < 0.0002). This decrease in proteoglycan synthesis correlated with the increase in pentosidine (r = -0.95, P < 0.02). Moreover, the elevation of pentosidine levels in the in vitro-ribosylated cartilage was proportional with the decrease in proteoglycan synthesis (r = -0.95, P < 0.005). CONCLUSION: In both aged and in vitro AGE-enriched cartilage, the rate of proteoglycan synthesis was negatively correlated with the degree of glycation. This suggests that the age-related increase in cartilage AGE levels may be responsible, at least in part, for the age-related decline in the synthetic capacity of cartilage.

Adult↗
PubMed1999

Blood-induced joint damage: a human in vitro study.

OBJECTIVE: To investigate mechanisms underlying cartilage damage caused by brief exposure of cartilage to blood, such as that occurring during intraarticular bleeding. METHODS: Human articular cartilage was cultured for 4 days in the presence of blood (components; 7.5-50% volume/volume). The synthesis of cartilage matrix, as determined by proteoglycan synthesis (incorporation of 35SO4(2-)), was measured directly after exposure and after a recovery period of 20 days, during which the cartilage was cultured in the absence of blood or blood components. The production of the cytokines interleukin-1 (IL-1) and tumor necrosis factor a (TNFalpha), which have a destructive effect on cartilage, was determined by enzyme-linked immunosorbent assay, and the viability of chondrocytes was determined by measuring lactate dehydrogenase release and with electron microscopy. The involvement of oxygen metabolites was evaluated by using N-acetylcysteine. RESULTS: Brief exposure to blood resulted in dose-dependent inhibition of proteoglycan synthesis. The combination of mononuclear cells and red blood cells was responsible for this effect. The effect was irreversible, independent of IL-1 and TNFalpha production, and was accompanied by chondrocyte death. These effects were partially prevented by N-acetylcysteine. CONCLUSION: Brief exposure of cartilage to blood, as occurs after a single episode or a limited number of bleeding episodes, results in lasting cartilage damage in vitro, in which cytotoxic oxygen metabolites play a role.

Aged↗
PubMed1999

Blood-induced joint damage: a canine in vivo study.

OBJECTIVE: To investigate the direct and indirect (via synovial inflammation) effects of intraarticular bleeding on cartilage in vivo. METHODS: Right knees of 14 beagle dogs were injected with autologous blood on days 0 and 2. Cartilage matrix proteoglycan turnover, collagen damage, and synovial inflammation of these knees, including the cartilage-destructive properties of the synovial tissue, were determined and compared with those of the left control knees on day 4 (short-term effects; n = 7) and day 16 (long-term effects; n = 7). RESULTS: Injected knees had a diminished content of proteoglycans in the cartilage matrix, and release of proteoglycans was enhanced (days 4 and 16). The synthesis of proteoglycans was significantly inhibited on day 4 but was enhanced on day 16. On day 4 more collagen was denatured in the injected joint than in the control joint; this effect was no longer detectable on day 16. Synovial tissue showed signs of inflammation on day 4 and day 16 but had cartilage-destructive properties only on day 16. CONCLUSION: In vivo exposure of articular cartilage to blood for a relatively short time results in lasting changes in chondrocyte activity and in cartilage matrix integrity, changes that may predict lasting joint damage over time. Interestingly, the direct effect of blood on cartilage precedes the indirect effect via synovial inflammation.

Animals↗
PubMed1999

[Pathology of synovitis and hemophilic arthropathy].

Hemophilia is an X chromosome linked disease characterized by an increased tendency to hemorrhage. Due to recurrent haemarthroses specific changes occur in synovium and cartilage. This process is called haemophilic arthropathy. The pathogenetic mechanisms involved are not precisely known. Current concepts, which are based on experimental in vitro studies and clinical experience, hold that the synovium becomes catabolically active because of the exposure to blood components and as a result induces cartilage destruction. A considerable amount of reports concerning blood induced joint damage suggest that synovial changes have a leading role in the development of the joint damage and therefore precede the changes in cartilage. However, there are also observations that question whether this is the only and the initiating mechanism of joint damage in hemophilia they hold that intra-articular blood has a direct harmful effect on cartilage before synovial changes and suggest that joint damage may occur before synovial inflammation is evident. Primarily there may be damage of articular cartilage with synovitis as a consequence. These studies show that synovitis is involved, but that it is not the only mechanism in the joint damage caused by intra-articular bleeding. These findings do not contradict the current concept of blood-induced cartilage damage in which synovial changes are thought to play an important role. Several pathological processes are possibly involved, some of them occurring in parallel and others sequentially. Possibly intra-articular blood first has an direct effect on cartilage, and then it affects the synovium. Thus, both processes occur in parallel, and while they influence each other they probably do not depend on each other. This concept resembles degenerative joint damage as found in osteoarthritis.

Cartilage, Articular↗
PubMed1999

Haemophilic arthropathy resembles degenerative rather than inflammatory joint disease.

AIMS: To investigate the pathogenetic mechanisms of haemophilic arthropathy (HA) by comparing end-stage arthropathy with osteoarthritis (OA; a degenerative joint disorder) and rheumatoid arthritis (RA; an inflammation-mediated joint disease). METHODS AND RESULTS: Cartilage and synovium from patients with HA (n=10), RA (n=8), OA (n=14) and normal control subjects (n=6) were examined morphologically, biochemically and histochemically. Cartilage in HA exhibited characteristics of degenerative joint disease (OA), as evidenced by morphological, histochemical (Safranin-O fast green-iron haematoxylin, Mankin grade) and biochemical (proteoglycan synthesis, glycosaminoglycan content and DNA content) changes, whereas synovium in HA showed characteristics of inflammation-mediated joint disease (RA), as evidenced by histochemical (inflammation, haematoxylin and eosin (H&E) and iron deposition, Perls' blue) and biochemical changes (interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)alpha and catabolic properties). CONCLUSION: Haemophilic arthropathy shows characteristics of both inflammatory and degenerative joint disease. On the basis of these results and published information, it appears that degenerative cartilage changes have a dominant role in HA and are augmented by relatively mild inflammation of the synovium.

Aged↗
PubMed1999

Lymphocyte stimulation by CD3-CD28 enables detection of low T cell interferon-gamma and interleukin-4 production in rheumatoid arthritis.

The analysis of cytokine production is increasingly important in defining the course of an immune response and in evaluating specific therapies of immune diseases. In rheumatoid arthritis (RA), a dysregulation in T1/T2 cell balance, as defined by the production of their specific cytokines, IFN-gamma and IL-4, respectively, is suggested. A predominance of T1-cell mediated macrophage activity in the joint plays a key role in the destruction of articular cartilage and subchondral bone, whereas local T2 cell activity, mitigating disease, fails. However, analysis of the cytokines defining both T cell subsets is difficult and spontaneous production is often below detection limits. Several stimuli are therefore used to increase cytokine production. In the present study we examined whether stimulation of peripheral blood T cells in the context of mononuclear cells (PB MNC) by CD3-CD28 is a reliable method for assessing IFN-gamma and IL-4 production and is representative for the spontaneous production of these cytokines. The production of IFN-gamma and IL-4 following CD3-CD28 stimulation of RA PB MNC correlated significantly in a ratio 1 : 1 with production following ionomycin-PMA stimulation. In samples with detectable spontaneous production of IFNgamma and IL-4, production following CD3-CD28 stimulation was significantly higher than in stimulated samples with undetectable spontaneous production. Moreover, in the case of spontaneous production there was a significant positive linear correlation between the CD3-CD28 stimulated and spontaneous IFNgamma and IL-4 production, although production of both cytokines was not equally enhanced. Serial sampling did not show significant daily or weekly variation in stimulated cytokine production. The results demonstrate that a pecific T-cell stimulation by CD3-CD28 is a reliable way to enhance IFN-gamma and IL-4 production above the detection limit and so measure the T1/T2 cell balance in RA.

Arthritis, Rheumatoid↗