Studies on YKL-40 in knee joints of patients with rheumatoid arthritis and osteoarthritis. Involvement of YKL-40 in the joint pathology.

OBJECTIVE: The presence of YKL-40 (human cartilage glycoprotein 39) in synovium, cartilage and synovial fluid (SF) from knee joints of patients with rheumatoid arthritis and osteoarthritis (OA) were related to histopathological changes in synovium and cartilage and to serum YKL-40 and other biochemical markers. METHODS: The localization of YKL-40 in synovium and cartilage was determined by immunohistochemistry. Synovial inflammation was estimated histologically and by magnetic resonance imaging (MRI). Biochemical markers of inflammation, neutrophil activation and cartilage metabolism were analysed. YKL-40 concentrations in serum and SF were determined by RIA and ELISA. RESULTS: In the synovium YKL-40 positive cells were found in lining and stromal cells (macrophages) and the number of YKL-40 positive cells was related to the degree of synovitis. In arthritic cartilage, YKL-40 was located to chondrocytes. YKL-40 levels in SF were higher in RA patients with moderate/severe or none/slight synovitis of the knee joint compared to OA patients with moderate/severe or none/slight synovitis. SF YKL-40 correlated with the synovial membrane and the joint effusion volumes determined by magnetic resonance imaging (MRI) and with other biochemical markers of intercellular matrix metabolism. SF YKL-40 was higher than serum YKL-40, and a relationship existed between the YKL-40 levels in SF and serum. Intraarticular glucocorticoid injection was followed by clinical remission and a decrease in serum YKL-40, which increased again at clinical relapse. CONCLUSIONS: YKL-40 in SF is derived from cells in the inflamed synovium, chondrocytes and SF neutrophils. Joint derived YKL-40 influences serum YKL-40. YKL-40 may be involved in the pathophysiology of the arthritic processes and reflect local disease activity.

Quantitative magnetic resonance imaging as marker of synovial membrane regeneration and recurrence of synovitis after arthroscopic knee joint synovectomy: a one year follow up study.

OBJECTIVES: By repeated magnetic resonance imaging (MRI) to study synovial membrane regeneration and recurrence of synovitis after arthroscopic knee joint synovectomy in patients with rheumatoid arthritis (RA) and other (non-RA) causes of persistent knee joint synovitis. METHODS: Contrast enhanced MRI was performed in 15 knees (nine RA, six non-RA) before and one day, seven days, two months, and 12 months after arthroscopic synovectomy. Synovial membrane volumes, joint effusion volumes, and cartilage and bone destruction were assessed on each MRI set. Baseline microscopic and macroscopic assessments of synovitis and baseline and follow up standard clinical and biochemical examinations were available. RESULTS: Synovial membrane and joint fluid volumes were significantly reduced two and 12 months after synovectomy. However, MRI signs of recurrent synovitis were already present in most knees at two months. No significant differences between volumes in RA and non-RA knees were seen. Synovial membrane volumes at two months were significantly inversely correlated with the duration of clinical remission, for all knees considered together (Spearman's correlation r(s)=-0.67; p<0.05), for RA knees (r(s)=-0.76; p<0.05), and for non-RA knees (r(s)=-0.83; p<0.05). Baseline volumes were not significantly correlated with clinical outcome. Only three knees (all RA) showed erosive progression. The rate of erosive progression was not correlated with MRI volumes or with clinical or biochemical parameters. CONCLUSION: The synovial membrane had regenerated two months after arthroscopic knee joint synovectomy and despite significant volume reductions compared with baseline it often showed signs of recurrent synovitis. MRI seems to be valuable as a marker of inflammation, destruction and, perhaps, as a predictor of therapeutic outcome in arthritis.

Two edged role of mannose binding lectin in rheumatoid arthritis: a cross sectional study.

OBJECTIVE: We investigated whether polymorphisms in the gene of mannose binding lectin (MBL) may be associated with onset of rheumatoid arthritis (RA), and whether MBL in conjunction with aggregated agalactosyl IgG (IgG-G0) may be associated with clinical and paraclinical variables. METHODS: MBL genotypes and serum concentrations were measured by polymerase chain reaction and ELISA in 189 patients with established RA. Binding of purified MBL to IgG-G0 in serum was assessed and clinical and paraclinical variables were recorded. RESULTS: The median age at onset of RA in the 3 genotypes (normal: A/A, hetero: A/0, and homozygous: 0/0 for variant alleles) was 54.1 (n = 108), 47.0 (n = 68), and 38.4 years (n = 13), respectively (p = 0.01). The frequency of variant alleles in patients with onset below the median age (50.8 yrs) was 0.32, but was 0.17 in patients with onset above 50.8 years (p = 0.003) and 0.20 in 250 controls (p = 0.001). Stratification according to erosion score (no, small, large) revealed an increasing tendency among the different groups in binding of MBL to IgG-G0, increased Health Assessment Questionnaire score, and acute phase reactants in A/A individuals, while no difference was seen among carriers of variant alleles. This effect was most pronounced in those with late onset RA. CONCLUSION: Presence of MBL variant alleles was associated with early onset of RA. MBL deficiency may, therefore, accelerate the disease. However, in patients with late onset and advanced disease our results indicate that the A/A type may be associated with additional inflammation different from that seen in carriers of variant alleles.

The distribution of YKL-40 in osteoarthritic and normal human articular cartilage.

YKL-40, also called human cartilage glycoprotein-39, is a major secretory protein of human chondrocytes in cell culture. YKL-40 mRNA is expressed by cartilage from patients with rheumatoid arthritis, but is not detectable in normal human cartilage. The aim was to investigate the distribution of YKL-40 in osteoarthritic (n=9) and macroscopically normal (n=5) human articular cartilage, collected from 12 pre-selected areas of the femoral head, to discover a potential role for YKL-40 in cartilage remodelling in osteoarthritis. Immunohistochemical analysis showed that YKL-40 staining was found in chondrocytes of osteoarthritic cartilage mainly in the superficial and middle zone of the cartilage rather than the deep zone. There was a tendency for high number of YKL-40 positive chondrocytes in areas of the femoral head with a considerable biomechanical load. The number of chondrocytes with a positive staining for YKL-40 was in general low in normal cartilage. The present findings, together with previous observations, suggests that YKL-40 may be of importance in cartilage remodelling/degradation of osteoarthritic joints.

Quantification of synovistis by MRI: correlation between dynamic and static gadolinium-enhanced magnetic resonance imaging and microscopic and macroscopic signs of synovial inflammation.

Dynamic and static gadolinium-diethylenetriaminepentaacetic acid(Gd-DTPA)-enhanced magnetic resonance imaging (MRI) were evaluated as measures of joint inflammation in arthritis, by a comparison with macroscopic and microscopic signs of synovitis. Furthermore, the importance of the size of the evaluated synovial areas was investigated, as was the optimal time for enhancement measurements. Seventeen rheumatoid arthritis knees and 25 osteoarthritis knees, scheduled for arthroscopy or arthrotomy, were included. Macroscopic and microscopic synovial inflammation as well as nine histologic tissue characteristics were graded at four preselected biopsy sites. Preoperative T1-weighted dynamic fast low angle shot and static spin-echo Gd-enhanced MRI were performed. The dynamic enhancement rate and the static enhancement were measured in the entire synovial membrane of a preselected slice as well as at the four biopsy sites, and compared to synovial pathology. The rate of early enhancement of the total synovial membrane of the preselected slice, determined by dynamic MRI, was highly correlated with microscopic evidence of active inflammation (Spearman p = 0.73; p < 10(-7). Dynamic MRI could distinguish knees with and without synovial inflammation with a high predictive value (0.81-0.90). Moderate and severe inflammation could not be differentiated. The early enhancement rate was correlated with histologic features of active inflammation, particularly vessel proliferation and mononuclear leucocyte infiltration. Dynamic evaluation of small synovial sections at the biopsy sites and static spin-echo MRI resulted in considerably weaker correlations to histologic inflammation than dynamic evaluation of the total synovium. The optimal time for enhancement measurements was one-half to one minute after Gd injection, as the highest correlation coefficients to histologic inflammation were observed in this interval. Dynamic MRI can be used to determine synovial inflammation. Evaluation of large synovial areas one-half to one minute after Gd injection best reflects joint inflammation.

YKL-40, a mammalian member of the chitinase family, is a matrix protein of specific granules in human neutrophils.

YKL-40, also called human cartilage glycoprotein-39 (HC gp-39), is a member of family 18 glycosyl hydrolases. YKL-40 is secreted by chondrocytes, synovial cells, and macrophages, and recently it has been reported that YKL-40 has a role as an autoantigen in rheumatoid arthritis (RA). The function of YKL-40 is unknown, but the pattern of its expression in normal and disease states suggests that it could function in remodeling or degradation of the extracellular matrix. High levels of YKL-40 are found in synovial fluid from patients with active RA. Neutrophils are abundant in synovial fluid of patients with RA, and the cells are assumed to play a role in joint destruction in that disorder. Therefore, we examined whether neutrophils are a source of YKL-40. YKL-40 was found to colocalize and comobilize with lactoferrin (the most abundant protein of specific granules) but not with gelatinase in subcellular fractionation studies on stimulated and unstimulated neutrophils. Double-labeling immunoelectron microscopy confirmed the colocalization of YKL-40 and lactoferrin in specific granules of neutrophils. Immunohistochemistry on bone marrow cells showed that neutrophil precursors begin to synthesize YKL-40 at the myelocyte-metamyelocyte stage, the stage of maturation at which other specific granule proteins are formed. Assuming that YKL-40 has a role as an autoantigen in RA by inducing T cell-mediated autoimmune response, YKL-40 released from neutrophils in the inflamed joint could be essential for this response. In RA and other inflammatory diseases, YKL-40 released from specific granules of neutrophils may be involved in tissue remodeling or degradation.

CC chemokine receptor 5 polymorphism in rheumatoid arthritis.

OBJECTIVE: Some chemokine receptors have been shown to be co-receptors for human immunodeficiency virus (HIV-1). A 32 base pair deletion allele in the CC chemokine receptor 5 gene (CCR5 delta32 allele) affects both transmission of HIV-1 and acquired immunodeficiency syndrome (AIDS)-free survival. Chemokines are suggested to be critical for establishment of inflammatory processes in autoimmune diseases such as rheumatoid arthritis (RA). We hypothesized that the defective allele may modulate the inflammatory process in RA. METHODS: Using polymerase chain reaction methods, we investigated the significance of the CCR5 delta32 allele in 163 Danish patients with RA and monitored clinical and paraclinical variables. RESULTS: The gene frequency of the CCR5 delta32 allele (0.10) did not deviate significantly from healthy controls and from that reported in healthy Caucasian populations, nor did the distribution deviate from the Hardy-Weinberg predictions (131 wild type, 30 heterozygous, 2 homozygous for the deletion allele; p = 0.85). However, a significantly increased proportion of those carrying the deletion allele were negative for IgM rheumatoid factor (RF) compared to those homozygous for the normal allele (29 vs 9%; p = 0.007). The proportion of CCR5 delta32 allele carriers with swollen joints was decreased compared to those homozygous for the normal allele (35 vs 58%, respectively; p = 0.03), as was the duration of morning stiffness (median 0 vs 60 min, respectively; p = 0.0002). CONCLUSION: The CCR5 delta32 allele seems to have some influence on RA variables including RF, which suggests that inhibition of chemokine receptors might be a potential target for disease modifying therapy in RA.

Magnetic resonance imaging-determined synovial membrane and joint effusion volumes in rheumatoid arthritis and osteoarthritis: comparison with the macroscopic and microscopic appearance of the synovium.

OBJECTIVE: To evaluate the relationship between synovial membrane and joint effusion volumes determined by magnetic resonance imaging (MRI) and macroscopic and microscopic synovial pathologic findings in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Synovial biopsies were performed, and macroscopic grades of synovitis assigned, at preselected knee sites during arthroscopy or arthrotomy in 17 knees with RA and 25 with OA. Synovial inflammation and 9 separate tissue characteristics were graded histologically. Synovial membrane and joint effusion volumes were determined by preoperative MRI, enhanced with intravenous gadopentetate dimeglumine. RESULTS: MRI-determined synovial membrane volumes were correlated with the overall histologic assessment of synovial inflammation (Spearman's sigma = 0.55, P < 0.001), with fibrin deposition, with subsynovial mononuclear and polymorphonuclear leukocyte infiltration (sigma = 0.51-0.59), and less significantly with macroscopic synovitis, vessel proliferation, and granulation tissue formation (sigma = 0.40-0.42). No correlation with synovial lining multiplication, perivascular edema, villous formation, or fibrosis was found (sigma < 0.30). CONCLUSION: MRI-determined synovial volumes are correlated with synovial inflammatory activity. Synovial volumes probably mainly reflect the mass of cell-infiltrated, vascularized subsynovial tissue, but may also be influenced by the cumulative synovial proliferative activity. MRI-determined synovial membrane and effusion volumes may be sensitive markers and/or predictors of disease activity and treatment outcome in RA.