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The colloid osmotic pressure of synovial fluid from canine shoulders, elbows, wrists, hips, and knees varied significantly from one joint to the next with the lowest values regularly present in wrists. These differences imply a corresponding, regular variation in microvascular function which may contribute to the distribution patterns of specific rheumatic diseases.
Factor J (FJ) is a complement inhibitor that is able to regulate in vitro both the classical and alternative human complement pathways. In the search of its biological significance, we have analyzed FJ levels in synovial fluid from patients with different arthropathies, in which IL-6 levels had been previously measured. The pathologies included in this study were: rheumatoid arthritis (RA) (n = 21), crystal deposition diseases (CDD) (n = 6), osteoarthritis (OA) (n = 23), spondyloarthritis (SpA) (n = 3) and other inflammatory arthropathies (OIA) (n = 4). We found a good correlation between IL-6 and FJ levels (r = 0.33, p = 0.0132) in the 57 processed samples. Synovial fluids had high levels of IL-6 (median: 3000 pg/ml). Besides, we found that FJ levels were elevated (241 +/- 429 micrograms/ml) when compared with NHS (5.32 +/- 2.82 micrograms/ml). Considering OA patients as control group for non-inflammatory situation, we found that FJ levels were significantly elevated in inflammatory patients only if RA patients were excluded. Furthermore, there were also significant differences with CDD patients. In addition, we have examined the presence of this inhibitor in synovial fluid by Western blot after running gels at acid pH and electrophoretical transference at the same pH. In these experiments, we evidenced the presence of a cationic protein immunoreactive with polyclonal and monoclonal anti-FJ antibodies. In conclusion, FJ levels are elevated in pathological synovial fluids. FJ could be an acute phase reactant as other molecules present in the synovial fluid, or could be shed from extracellular matrix as a consequence of the high enzymatic activity present in the articular fluid or as a response to the inflammatory stimulus.
The T lymphocytes that reside in the synovium of the inflamed joints in patients with rheumatoid arthritis display severe hyporesponsiveness upon antigenic stimulation, which is probably due to their constant subjection to high levels of oxidative stress. Here we report that the synovial fluid T lymphocytes exert severely impaired phosphorylation of the adaptor protein linker for activation of T cells (LAT), a crucial component of the TCR-mediated signaling pathways. In healthy T lymphocytes, LAT is a membrane-bound protein and becomes phosphorylated by zeta-associated protein of 70 kDa (ZAP-70) upon TCR engagement. The molecular basis underlying the deficient phosphorylation of LAT and consequently the hyporesponsiveness of the synovial fluid T lymphocytes lies in the membrane displacement of LAT. We demonstrate that the subcellular localization of LAT is sensitive to changes in the intracellular levels of the antioxidant glutathione. The membrane anchorage of LAT, and consequently the phosphorylation of LAT and the cellular activation of the synovial fluid T lymphocytes upon TCR engagement, is restored in synovial fluid T lymphocytes after supplementation of the intracellular glutathione levels with N-acetyl-l -cysteine. These data suggest a role for the membrane displacement of LAT in the hyporesponsiveness of the synovial fluid T lymphocytes as a consequence of oxidative stress.
This study examined the serum and synovial fluid concentrations of cartilage oligomeric matrix protein (COMP) in relation to the evolution of joint cartilage damage and the requirement for surgery in 125 patients with rheumatoid arthritis (RA). We compared the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and matrix metalloproteinase-3 (MMP-3) levels with COMP levels determined by specific enzyme-linked immunosorbent assay (ELISA). Patients were divided into three groups: (1) patients with least erosive disease (LES); (2) patients with more erosive disease (MES); and (3) patients with mutilating disease (MUD). In addition, synovial fluid samples were collected from patients undergoing arthroscopic synovectomy of the knee joint (ASS) and total knee arthroplasty (TKA). Serum COMP levels correlated with the ESR (P < 0.0001, r = 0.374, n = 125) and the CRP level (P = 0.0014, r = 0.281, n = 125). COMP levels did not correlate with the MMP-3 level (P = 0.182, r = 0.114, n = 125). The COMP levels of the LES group were significantly lower than those of the MES or MUD groups. Lastly, synovial fluid COMP levels in the TKA group were higher than in the ASS group. Therefore, these findings suggest that serum and synovial fluid COMP levels in patients with RA may reflect cartilage destruction and are correlated with the ESR and the CRP level, which are indicators of the acute-phase response.
In order to why polymorphonuclear leukocytes (PMNs) are predominant and mononuclear leukocytes (MNLs) are few in rheumatoid synovial fluids, chemotactic factor(s) for PMNs and MNLs were studied in the synovial fluids of rheumatoid arthritis (RA-SF) and osteoarthritis (OA-SF) using both Boyden's and agarose methods. The RA-SF showed strong chemotactic activity for human peripheral blood PMNs compared with non-rheumatoid OA-SF. The chemotactic activity for PMNs was well correlated with the number of PMNs in RA-SF, suggesting that it was a natural mediator for PMN emigration into rheumatoid joint cavity. The major chemotactic factor for PMN in RA-SF was of apparent molecular weight of 14,000 and its activity was suppressed to less than 10 percent by anti-C5a antibody, but it failed to show any anaphylatoxin activity which was an attribute of C5a. It was, therefore, suggested to be C5a-like molecule but not C5a itself. The possibility that the factor may be a C5a des-Arg was discussed. On the contrary, the chemotactic activity for MNLs was not found neither in RA-SF nor OA-SF. These findings may explain the fact that PMNs are predominant in rheumatoid synovial fluids.
Synovial fluids from patients with rheumatoid arthritis and from patients with osteoarthritis degraded the matrix of living, but not killed, normal human cartilage as judged by loss of glycosaminoglycans. Normal human serum did not degrade living cartilage and neither, unexpectedly, did recombinant human cytokines.
Five sera and four synovial fluids from patients with rheumatoid arthritis were found to contain substances which consumed hemolytic C3 in normal human serum (NHS) and in normal guinea pig serum (NGPS). These fluids were then tested for ability to activate the alternative pathway by incubating them with NHS containing MgEGTA and C4 deficient GPS. All sera and two synovial fluids depleted C3 in these reagents, indicating direct activation by the alternative pathway. Density gradient ultracentrifugation demonstrated C3 fixing activity in some specimens in the greater than 19s regions. These substances may also activate complement similarly in vivo and participate in the development of inflammatory processes associated with this disease.
Synovial fluid (SF) of patients with rheumatoid arthritis (RA) has been noted to contain cholesterol crystals and increased amounts of cholesterol compared with normal SF. SF, plasma apolipoproteins (apos) A-I and B, and cholesterol in 12 untreated classic RA patients (inflammatory arthritis) and eight untreated degenerative joint disease ([DJD] noninflammatory arthritis) patients were analyzed. Results showed that mean apo A-I, apo B, and cholesterol levels of RA SF were significantly higher than those of DJD SF (apo A-I, P = .004; apo B, P = .0008; cholesterol, P = .0004). Regression analyses of plasma and SF apo A-I and apo B (r = .72, P = .008 and r = .63, P = .02, respectively) suggested an increased permeability for these lipoprotein constituents across RA synovial membrane that was not observed in DJD synovial membrane. These data suggest that RA synovium but not DJD synovium is more permeable to major apoproteins of low- and high-density lipoproteins (LDL and HDL). These apolipoproteins have been shown to influence the immune response and may therefore be involved in the pathogenesis of RA.
The response of peripheral blood and synovial fluid lymphocytes to three non-specific mitogens has been studied. The paired samples were taken from patients with a range of inflammatory arthritides. Unstimulated synovial fluid lymphocytes (SFL) tended to have a greater uptake of tritiated thymidine than had unstimulated peripheral blood lymphocytes (PBL). This background uptake of tritiated thymidine by SFL showed a positive correlation with the response these SFL then showed to the mitogens. A significant depression was observed in the SFL response to phytohaemagglutinin when compared with the paired PBL response; this was seen in both the rheumatoid arthritis and other inflammatory joint diseases groups. SFL responses to concanavalin A and pokeweed mitogen, although depressed in individual cases, failed to show a significant depression overall. Attempts to restore the SFL response to that of the paired PBL by removal of any possible blocking substance from the cell surface either by pre-incubation of SFL in tissue culture medium or by enzyme treatment were unsuccessful. This suggested that cell surface blockers were possibly not the reason for deficient SFL reponses and that other factors were involved.
To examine the involvement of cytokines in the mechanisms of N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine, MDP-Lys(L18)-induced arthritis, we analyzed interleukin-1 (IL-1), tumor necrosis factor (TNF), colony-stimulating factor (CSF), and neutrophil chemotactic factor (NCF) by bioassays in the rat macrophage-conditioned medium (Mluminal diameter-CM) stimulated by MDP-Lys(L18) in vitro and the synovial fluid from dogs treated subcutaneously with MDP-Lys(L18) for 14 days in vivo. The dog showed arthritis characterized by swelling of the knee joint, increased synovial fluid and thickened synovial membrane, and a single subcutaneous injection of MDP-Lys(L18) was previously shown to induced synovitis in rat tarsal joint. IL-1, TNF, CSF, and NCF activities in Mluminal diameter-CM were increased by MDP-Lys(L18), while only NCF activity was detected in the dog synovial fluid. Partial purification procedures revealed that NCF in Mluminal diameter-CM was not leukotriene B4 but a protein having heparin-affinity, and, in addition, immuno-reactive IL-8 was evident to be in Mluminal diameter-CM. The NCF activity in the dog synovial fluid was not inhibited by dialysis, showing that NCF is a protein substance, possibly a chemokine. These results suggest that MDP-Lys(L18) produces a chemokine, such as IL-8, which recruits neutrophils to the synovial membrane for subsequent development of synovitis in rats and dogs.
There is a major interest for using biochemical markers of bone metabolism as a non-invasive tool for diagnostic purposes in the field of bone and joint diseases. Based upon the fact that the pyridinium cross-links of collagen are markers of bone and cartilage degradation, this study was designed to assess the presence of pyridinoline in synovial fluid samples originating from various arthritic and non-arthritic knee joints. Using a sample pooling method, significant levels of pyridinoline could be measured in synovial fluid by high performance liquid chromatography. Pyridinoline levels ranged from 19.3 +/- 5.8 pmol mL-1 (mean +/- SD) in osteoarthritic knee joints up to 32.4 +/- 14.6 pmol mL-1 in rheumatoid arthritis joints. Pyridinoline levels in synovial fluid were not significantly correlated to disease duration and synovial fluid cell count, but were correlated to erythrocyte sedimentation rate in osteoarthritic patients (r = 0.99, P = 0.002). This study demonstrates that synovial fluid originating from knee effusion contains significant levels of pyridinoline which can be quantified by high performance liquid chromatography and could, therefore, be a tool to investigate the metabolism of a single joint.
A mycoplasma cultured from synovial fluid specimens from a patient with pneumonia and subsequent polyarthritis was identified initially as Mycoplasma pneumoniae. In retrospective studies, the culture was shown also to contain Mycoplasma genitalium. In this paper, the laboratory techniques employed in the identification and separation of the two species are presented, and evidence to implicate postinfectious autoimmunity is provided. An increasing number of reports of M. genitalium in human tissue sites and difficulties in isolation and identification of the organism in the clinical laboratory suggest the need for more extensive application of rapid and specific detection systems for both M. genitalium and M. pneumoniae in the clinical laboratory.
Synovial fluid from patients with the following diagnoses was investigated: - rheumatoid arthritis (RA) - rheumatoid arthritis with benign development (BRA) - osteoarthrosis (A) The sediment was isolated by ultracentrifugation, its C3 cleaving activity measured by 2-dimensional electrophoresis and its concentration if IgG, IgM, IgA, C3, C4 and C3-proactivator by immunoprecipitation. There is evidence that there is more C3 cleaving activity in RA than in osteoarthrosis. Activity levels of BRA were between those of osteoarthrosis and RA. Although there was no significant difference in the IgG-, IgM- or IgA-level of the 3 mentioned diagnoses after 21 minutes of centrifugation (133 000 g), it was possible to demonstrate more C3 breakdown products in RA than in osteoarthrosis and BRA. Very big molecules seem to be responsible for the generation of C3 cleaving products. These observations are not only of theoretical interest but seem also to be useful diagnostically.
The alkaline phosphatase enzyme in both serum and synovial fluid from 28 cases of rheumatoid arthritis and from the serum of 30 controls was measured. The enzyme was further studied by separating its isoenzymes to clarify their origin in both synovial fluid and serum of 10 patients with elevated level of the enzyme in their sera. The level of the enzyme in serum was elevated in 37% of patients confirming previous reports on that point. The most abundant isoenzyme in the synovial fluid (66.9%) was found to be bone in origin while in serum the most abundant isoenzyme was found to be hepatic (60.5%). This may be responsible for increased bone turn-over in rheumatoid joints whether in formation or resorption.
Synovial fluid (SF) contained by the knee joint from 102 patients (80 with rheumatoid arthritis, 12 with osteoarthrosis, 10 with posttraumatic arthritis) and controls was studied for cytosis, activity of acid phosphatase, N-acetyl-beta-D-glucosaminidase, and cAMP and cGMP content. In 18% of the cases, the local corticosteroid treatment of patients with RA produced no beneficial effect. To treat RA and OA patients, dimethylsulfoxide (DMSO, 5 ml of 20% solution) and polyvinylpyrrolidone (PVP, 5 ml of 15% solution) were administered intra-articularly. In OA patients, injection of DMSO and PVP provided a good therapeutic effect. In RA patients, injection of DMSO produced a beneficial antiinflammatory action but it appeared short-term. The use of PVP in RA patients with pronounced local process enhanced synovitis symptoms, entailed an increase of the SF amount and cytosis, did not reduce the activity of lysosomal enzymes, and produced a negligible effect on the level of cyclic nucleotides. A mixture of DMSO (1 ml of 100% solution) and PVP (5 ml of 15% solution) applied to the treatment of RA patients exerted a favourable action on the local process in the joint, namely reduced all the parameters mirroring the intensity of inflammation.
Polychrome-stained equine synovial fluid specimens from 34 normal joints and 129 joints with clinical abnormalities were examined cytologically. The smears from joints with abnormalities were categorized as within normal limits (4.7%), slight abnormality (27.9%), proliferative synovitis (21.7%), neutrophilic pattern (20.2%), elongated cell pattern (10.1%), other moderate to marked abnormality (11.6%) and unsatisfactory (3.9%). Cytologic abnormalities that were not restricted to a single category included spindle cells, crystals, stellate cells and cartilage fragments. Multinucleate cells and mononucleate cells with dense cytoplasm and a delicate periphery were seen in smears from cases with clinical diagnoses of osteochondrosis or fracture; interpretation of these cells as osteoclasts and their mononucleate precursors was supported by positive staining with tartrate-resistant acid phosphatase. Smears within the same cytologic category were not found to correspond with a single clinical diagnosis. The identification of several cytologic patterns in cases with the same clinical diagnosis suggests that multiple stages of disease were sampled. Except in cases with the cytologic neutrophilic pattern, there was not a consistent relationship between the histologic features in synovial biopsy specimens and the cytologic findings; the morphologic variation within synovial membrane sections and between sections from different locations was sometimes marked. When compared with air-dried, Wright-Giemsa-stained smears, the polychrome-stained smears were more sensitive in the detection of cytologic abnormalities and were less often falsely negative or unsatisfactory. Following surgery, cases with clinical diagnoses of osteochondrosis (29 cases) and fracture (25 cases) were analyzed according to clinical outcome and cytologic category. While 80% of the horses with proliferative synovitis in cytologic specimens were sound, only 67% of those with the elongated cell pattern, 50% of those with slight abnormality and 33% of those with other moderate to marked abnormality were sound. A statistically significant relationship (P less than .02) was found in cases with a diagnosis of osteochondrosis: animals with a proliferative synovitis pattern were almost three times as likely to be sound as compared to those with slight abnormality. These findings indicate that polychrome-stained equine synovial fluid smears (1) provide information that is different from that found in corresponding histologic sections and (2) are superior to air-dried, Wright-Giemsa-stained smears for cytologic examination. The polychrome-stained equine synovial fluid smears were found to provide information supportive of clinical, radiographic and prognostic data.
Synovial fluid (SF) from 74 asymptomatic knees of patients with gout was analyzed. These patients had never been treated with serum uric acid-lowering agents. SF samples were analyzed for the presence of crystals and for cell counts, using undiluted SF directly in a Niebauer cell counting chamber. Thirty-seven of the aspirated knees had previously been inflamed, and monosodium urate (MSU) crystals were seen in SF aspirates from 36 of them (97%). Of the 37 knees that had never been inflamed, only 8 contained MSU crystals (P less than 0.00001). After reaching the joint, MSU crystals will persist in the SF as long as the serum uric acid level has not been lowered by appropriate treatment. In this situation, analysis of SF is an excellent diagnostic test for the intercritical gout. The mean cell count in the 44 SF samples that contained MSU crystals was 449/mm3 (95% confidence interval 310-589); the mean cell count in the 30 SF without MSU crystals was 64/mm3 (95% confidence interval 34-95) (P less than 0.00002). The SF samples that contained MSU crystals also had a higher percentage of polymorphonuclear leukocytes than those without MSU crystals (P less than 0.002). These data suggest that there is a low-grade inflammation present in the knees of patients with MSU crystals, the consequences of which should be investigated.
Synovial fluid (SF) mononuclear cells (MNC) from 13 patients with rheumatoid arthritis (RA) and 12 patients with other arthritic diseases (OD) including osteoarthritis (OA), gout and spondyloarthritis (SA) were cultured in the presence of collagen types I and II or lipopolysaccharide (LPS) for 24 h. Interleukin-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-alpha) in the SF and culture supernatants were assayed using ELISA. The results showed that one-half of the RA patients with high SF monocyte count had high SF IL-6 levels that coincided with the high spontaneous release of IL-6 by SF MNC. In the other RA patients with lower SF monocyte count, type II collagen induced significantly higher IL-1 beta than the medium control levels by SF MNC (P < 0.01) or that of the other diseases (P < 0.01). Similarly, type II collagen-induced IL-6 and TNF-alpha production rose significantly (P < 0.01) from SF MNC of RA but less from OD (P < 0.05). In addition, type I collagen could also induce IL-1, IL-6 and TNF-alpha in these samples from RA and OD patients but was less potent than type II collagen. Our results indicate that collagen-induced cytokines may be important in the pathogenesis of the disease.