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ID PMID Title PublicationDate abstract
10374419 Primary Sjögren's syndrome and its lymphoid malignancy: a report of four cases. 1998 Mar OBJECTIVE: To evaluate the incidence and spectrum of malignancy of primary Sjögren's syndrome (pSS). METHODS: 250 pSS who were followed-up in Peking Union Medical College (PUMC) Hospital were analyzed. RESULTS: Four of them were diagnosed with histopathological findings of 2 non-Hodgkin Lymphoma, 1 AILD, 1 multiple myeloma. Two died of secondary infection while receiving chemotherapy for lymphoma, 2 remained remitted. CONCLUSIONS: The risk factors were persistent enlargement of major salivary glands, appearance of monoclonal serum lg, and disappearance of auto antibodies.
9503450 A comparison of intraoral Candida carriage in Sjögren's syndrome patients with healthy xe 1998 Feb OBJECTIVE: Determination of the incidence of Candida carriage in patients with Sjögren's syndrome (SS) and xerostomic controls to assess the influence of immunologic disturbances in SS on carriage. STUDY DESIGN: A total of 16 primary SS patients, 12 secondary SS patients, and 14 xerostomic controls were included in the study. Sampling was performed using an oral rinse method. Aliquots (100 microliters) were spread onto CHROMagar* and incubated for 48 hours. Species identification was confirmed by the germ tube test and API ID32C. Total colony-forming units per milliliter (CFU/ml) were counted and statistical analyses performed by the Kruskal-Wallis test. RESULTS: Candida carriage in primary SS, secondary SS, and xerostomic patients was 81.25%, 66.7%, and 71.4%, respectively. There were no statistically significant differences in total CFU/ml. A wide range of species was isolated in each group. CONCLUSION: The immunologic disturbances seen in SS do not significantly influence the intraoral Candida carriage in patients with a dry mouth.
9274404 Long-term course of tear gland function in patients with keratoconjunctivitis sicca and Sj 1997 Jun AIMS: To assess the course of tear gland function of patients with keratoconjunctivitis sicca (KCS) associated with primary (KCS-PSS) or secondary Sjögren's syndrome (KCS-SSS), and of patients with KCS not related to Sjögren's syndrome (KCS-NS). METHODS: In 106 patients with dry eye an ophthalmic diagnosis of KCS was made. Subsequent evaluations revealed a diagnosis of KCS-PSS in 31, KCS-SS in 19, and KCS-NS in 56 patients. Follow up assessments have been performed 10-12 years after initial diagnosis. RESULTS: At baseline and at follow up tear gland function tests were worse in patients with KCS-PSS compared with the other forms of KCS. At follow up in the KCS-SSS patient group the tear gland function variables returned to marginal normal limits. In contrast with expectation, a marked improvement of the tear gland function variables in the KCS-NS patient group was noted. CONCLUSIONS: In KCS-PSS patients tear gland function is characterised by a steady state situation. In KCS-SSS patients the normalisation of tear gland function variables most probably reflects a remission of the underlying disease. In view of the overall improvement in KCS-NS patients the term age related KCS should be avoided.
11140467 Involvement of apoptotic protease cascade for tissue destruction in Sjögren's syndrome. 2000 Sjögren syndrome (SS) is an autoimmune disease characterized by diffuse lymphoid cell infiltrates in the salivary and lacrimal glands, resulting in symptoms of dry mouth and eyes due to insufficient secretion. Although it has been assumed that a combination of immunologic, genetic and environmental factors may play a key role in the development of autoimmune lesions in the salivary and lacrimal glands, little is known about the disease pathogenesis of SS in humans. We have identified the 120 kDa alpha-fodrin as an important autoantigen in the development of SS in both an animal model and SS patients, but the mechanism of alpha-fodrin cleavage leading to tissue destruction in SS remains unclear. Tissue-infiltrating CD4+ T cells purified from the salivary glands of a mouse model for SS bear a large proportion of Fas ligand and the salivary gland duct cells possess apoptotic receptor Fas. Anti-Fas antibody-induced apoptotic salivary gland cells result in specific alpha-fodrin cleavage to the 120 kDa fragment in vitro. Preincubation with a combination of calpain and caspase inhibitor peptides could be responsible for inhibition of the 120 kDa alpha-fodrin cleavage. Thus, an increase in apoptotic protease activities including calpain and caspases may be involved in the progression of alpha-fodrin proteolysis and tissue destruction in the development of SS.
9421226 Oral manifestations of collagen vascular disease. 1997 Dec Lupus erythematosus is a multisystem disorder. One of its defining features is oral ulceration. In addition to oral ulcers, cheilitis may occur. Sjögren's syndrome is an autoimmune disorder of exocrine glands that causes a decrease in salivary gland function. This results in symptoms of xerostomia, which can be complicated by caries. Scleroderma has rare oral manifestations, which include a decrease in the maximal oral aperture and mat-like telangiectasias.
11235211 [Analysis of infiltrating T cells in the affected autoimmune lesions of HTLV-I transgenic 2001 Jan Human T-cell leukemia virus type I(HTLV-I) is known to be associated with a number of disorders, inducing adult T cell leukemia, myelopathy, arthropathy, uveitis, and probably Sjögren's syndrome, T cell alveolitis, polymyositis, and infective dermatitis. To investigate the pathogenetic role of HTLV-I in these clinical disorders, we established a transgenic rat model carrying the env-pX gene of HTLV-I(env-pX rat), which develops arthritis, myocarditis, dermatitis, necrotizing arteritis, myositis and sialoadenitis. Several autoantibodies, such as anti-nuclear and anti-cardiolipin antibodies and rheumatoid factor, were detected in the sera. Peripheral T lymphocytes of env-pX rats expressed co-stimulatory molecules and showed hyper-immune reactivity to various stimulation in vitro. In this study, to characterize major pathogenic autoantigens in the affected lesions, the author examined the clonalities of T cells in the spleen and of infiltrating T cells in the skin lesions as well as affected joints of env-pX rats by single strand conformation polymorphism (SSCP) of polymerase chain reaction-amplified cDNA fragments of T cell receptor (TCR) V beta. No specific expansion of particular T cell clones was evident in the spleen of env-pX rats. Oligoclonal T cell expansions were observed in both infiltrating T cells of the affected joints and skin lesions, but no specific T cell clones common in the two lesions expanded in env-pX rats. Also, no specific amino acid motif in the complementarity determining region 3 of TCR V beta was evident in the affected joints. Those results suggest that the locally expanded T cell clones against various autoantigens of the joint or skin induced by the transgene may play major pathogenetic roles in development of autoimmune diseases in env-pX rats. On the other hand, env-pX rats easily developed arthritis by immunization of type II collagen and the SSCP patterns of accumulated T cell clonotypes in the arthritis were similar to those of arthritis developed in env-pX rats without immunization. The evidence suggests that the type II collagen-immunization may be a trigger to develop the inherent arthritis of env-pX rats.
11312114 Control of osteoclastogenesis and bone resorption by members of the TNF family of receptor 2001 Mar Skeletal mass is maintained by a balance between cells which resorb bone (osteoclasts) and cells which form bone (osteoblasts). Bone development and growth is an on-going, life-long process. Bone is formed during embryonic life, grows rapidly through childhood, and peaks around 20 years of age (formation exceeds resorption). For humans the skeleton then enters a long period, approximately 40 years, when bone mass remains relatively stable. Skeletal turnover continues but the net effect of resorption and formation on bone mass is zero. For women this ends when they enter menopause and similar bone loss occurs for men, but later in life. These opposite functions are coupled, resorption precedes formation, and osteoblasts, or their precursors, stromal cells, regulate osteoclast formation and activity. Until recently, the molecular nature of this regulation, was poorly understood. However, recent observations have identified members of the TNF family of ligands and receptors as critical regulators of osteoclastogenesis. Osteoprotegerin (OPG) a decoy receptor was first identified. Its ligand, receptor activator of nuclear factor-kappaB ligand (RANKL), was quickly found, and shown to be expressed on stromal cells and osteoblasts. Its cognate receptor, RANK, was found to be expressed in high levels on osteoclast precursors. The interaction between RANKL and RANK was shown to be required for osteoclast formation. These observations have provided a molecular understanding of the coupling between osteoclastic bone resorption and osteoblastic bone formation. Moreover, they provide a framework on which to base a clear understanding of normal (e.g. postmenopausal osteoporosis and age associated bone loss) and pathologic skeletal changes (e.g. osteopetrosis, glucocorticoid-induced osteoporosis, periodontal disease, bone metastases, Paget's disease, hyperparathyroidism, and rheumatoid arthritis).
10555891 Immunological analysis of pulmonary hypertension in connective tissue diseases. 1999 Nov OBJECTIVE: To analyze the immunological characteristics of the sera of patients with inflammatory connective tissue diseases complicated by pulmonary hypertension (PH). METHODS: Sera of 24 patients with mixed connective tissue disease complicated by PH (MCTD-PH), sera of 11 patients with other connective tissue diseases complicated by PH (Other-PH; 6 systemic sclerosis, 3 systemic lupus erythematosus, 2 rheumatoid arthritis), and sera of 15 patients with MCTD not complicated by PH (MCTD-non-PH) were tested for IgG antibodies against U1RNP proteins, U1RNP-70K protein, U1RNP-A protein, and U1RNP-C protein, and for IgG and IgM antibodies to beta2-glycoprotein I dependent cardiolipin (CL) and human umbilical vein endothelial cells. We also measured the serum levels of von Willebrand factor related antigens and interleukin 6 (IL-6). RESULTS: (1) The titers of the anti-U1RNP, anti-U1RNP-70K, anti-U1RNP-A, and anti-U1RNP-C antibodies were significantly higher in the MCTD-PH and MCTD-non-PH groups than in the Other-PH group. However, there were no statistically significant differences in the titers of these 4 antibodies between the MCTD-PH and MCTD-non-PH groups. (2) The titers of the IgG aCL and the serum IL-6 levels were significantly higher in the MCTD-PH group than in the MCTD-non-PH group. (3) Statistically significant correlations between the anti-U1RNP and IgG anti-CL antibody titers, and between the IgG anti-endothelial cell and IgG anti-CL antibody titers were observed within the MCTD-PH and Other-PH groups, but not within the MCTD-non-PH group. CONCLUSION: The occurrence of anti-U1RNP, anti-endothelial cell, and anti-CL antibodies is associated with PH in certain patients with connective tissue disease.
9433865 The cost-effectiveness of misoprostol in preventing serious gastrointestinal events associ 1998 Jan OBJECTIVE: To reexamine the cost-effectiveness of misoprostol, using data from a recently published placebo-controlled trial of misoprostol in > 8,000 patients with rheumatoid arthritis (RA) taking nonsteroidal antiinflammatory drugs (the Misoprostol Ulcer Complications Outcome Safety Assessment [MUCOSA] study). METHODS: Actual clinical events and the rates of endoscopies and upper gastrointestinal (GI) radiographic series, hospitalizations, and surgery for these events were derived from the MUCOSA study and used in a decision analysis. Estimates of costs for the management of these events were derived from the Ontario Case Cost Project database and published economic evaluations; costs were adjusted to 1994 Canadian dollars. Incremental cost-effectiveness (from the viewpoint of the provincial health care plan in Canada) was calculated for the original trial population (risk of a serious GI complication 1%) and for the subsets of patients with medium (3%) and high (6%) risk. RESULTS: For the original study population, averting 1 serious GI complication by prescribing misoprostol would cost an additional $94,766 (Canadian; range $60,286-137,146). For patients with previous peptic ulcer disease (medium risk), the cost would be $14,943 (range $10,912-32,157), and for patients with previous peptic ulcer disease and age > 75 (high risk), the cost would be $4,101 (range $-220 to $18,146). CONCLUSION: Prescribing misoprostol for all patients with RA who are > or =52 years old costs $94,766 for each additional GI event averted. However, when patients at higher risk are specifically selected, the cost per averted GI complication is markedly reduced. These results, based on actual serious event rates and actual data on endoscopies and upper GI series, hospitalizations, and surgeries, provide a better estimate of the true cost-effectiveness of misoprostol than previous analyses based on endoscopic data and modeling of all resource utilizations.
9229361 The effect of OM-89 (Subreum) on the murine model of systemic lupus erythematosus MRL-lpr/ 1997 OM-89 (Subreum), an E. coli extract, is used clinically in the treatment of rheumatoid arthritis. In this study, the authors examined the effect of OM-89 on some aspects of SLE in the murine model MRL-lpr/lpr. Animals were given OM-89 orally at a dose of 400 mg/kg weight (40 mg active substance) 5 d a week from six weeks old. It was found that mice receiving the drug reached the point of 55% (6/11) survival at the age of 33 weeks compared with 27 weeks for the control group (54%; 7/13). There was a significant increase in the delay before developing alopecia in the treated group (P < 0.01). The increase in proteinuria in the control group was significantly higher than in the treated group (P < 0.03). In a second set of experiments sacrificing the animals at week 22, a significant decrease in anti-dsDNA auto-antibodies was also found in the treated group (P < 0.05), histopathologically a less severe tubular destruction in the kidney was observed in the treated group. It can be concluded that the oral treatment of OM-89 can significantly reduce the severity of SLE in this strain of mice. It can be postulated that the administration of the bacterial extract could modulate the immune response, modifying the Th1 and Th2 balance and inducing oral tolerance.
11469471 Pigmented villonodular synovitis. Review of 20 cases. 2001 Jul OBJECTIVE: Pigmented villonodular synovitis (PVS) is a rare aggressive lesion. Inclusion of this disease in the differential diagnosis of rheumatoid arthritis can lead to early diagnosis and treatment. In this retrospective study we evaluated diagnostic procedures, therapies, and outcomes of PVS. METHODS: Twenty surgically treated cases of PVS were evaluated: joint, 16; tenosynovial, 3; and bursa, one. The 20 patients had undergone the following surgeries: 4 total synovectomies, 2 subtotal synovectomies, eight arthroscopically assisted resections, 4 resections of extraarticular lesions, and 2 arthroplasties. The mean followup was 17.5 mo (1-54). RESULTS: At diagnosis, pain was present in 19 of 20 cases. Joint swelling or a tumor was found in 11 cases, and 12 patients complained of repeated joint effusions. The mean duration of symptoms was 23.8 mo (range 1-144). Half the cases had a nodular pattern and the other half a diffuse pattern. The most common location of PVS was the knee (14 patients). Surgical treatment before admission did not always lead to an accurate diagnosis. For example, in 2 patients, arthroscopy did not reveal PVS. In 2 patients a soft tissue sarcoma was suggested. In 3 patients, the diagnosis was made incidentally with arthroscopy or arthroplasty. On radiographs, bone lesions were seen in 8 cases; in 13 of 17 cases the diagnosis was by magnetic resonance imaging (MRI). After surgery 17 patients stayed free of recurrence, 14 without symptoms. One patient who had an incidental diagnosis of PVS has a synovectomy planned as a second procedure. One patient awaits a second dorsal procedure after a ventral knee synovectomy. One patient shows recurrent disease 33 mo after resection of a nodular knee lesion. CONCLUSION: PVS should be included in the differential diagnosis of any arthritis. MRI is the most effective diagnostic tool in identifying PVS. The treatment of PVS consists of surgical excision in sound tissue. A total synovectomy should be the treatment of choice in diffuse disease. From the literature, nonsurgical therapies, such as steroid injections, 90Y synoviorthesis, or external beam radiation, seem to be of benefit in selected patients.
10451077 Pregnancy alters gene expression in normal synovium: influence of age and parity. 1999 Aug OBJECTIVE: To determine whether pregnancy leads to changes in mRNA levels for molecules in normal synovium in an experimental model. METHODS: Total RNA was isolated from synovium of primigravida adolescent and skeletally mature rabbits, multiparous adult rabbits, and age matched controls. mRNA levels for cytokines, COX-2, iNOS, growth factors, proteinases and inhibitors, and matrix molecules were assessed by semiquantitative reverse transcription polymerase chain reaction. RESULTS: Pregnancy led to significant alterations in mRNA levels for 14/17, 6/17, and 5/17 genes in the 3 pregnant groups, respectively, compared to their controls. The only mRNA levels significantly depressed in all 3 groups were for collagen I and III, a finding consistent with a role for relaxin in the observed changes. CONCLUSION: Pregnancy can affect the molecular biology of the normal synovium and thus pregnancy associated hormones such as relaxin may also affect the inflamed synovium. The effect of relaxin in models of rheumatoid arthritis should be evaluated.
9686606 Covalent cross-linking of immune complexes by oxygen radicals and nitrite. 1998 Aug 1 We have shown that polymorphonuclear neutrophils mediate the covalent cross-linking of immune complexes (ICs) using H2O2 and myeloperoxidase (MPO). Moreover, activated superficial chondrocytes produce large amounts of nitric oxide (NO), suggesting that high concentrations of these radicals may interact at the cartilage surface in rheumatoid arthritis. We describe the effects of the interaction of NO and its decay product, NO2, with H2O2 and MPO on IC cross-linking. Cross-linking was measured by resistance to the guanidine extraction of plastic-bound ICs. The combination of H2O2, MPO, and NO in the absence of O2 did not alter the magnitude of cross-linking. The addition of O2 resulted in a significant enhancement of cross-linking (p < 0.004), suggesting that nitrite was responsible for the increase observed. Indeed, NaNO2 greatly increased H2O2-dependent cross-linking (control: 29.2+/-3.8; 1 mM NaNO2: 58.4+/-9.9; 10 mM: 60.4+/-4.2% cross-linking,p < 0.0002). Sodium azide, which is an inhibitor of MPO, completely inhibited cross-linking. These results indicated that the product of interaction of H2O2 and NO2 mediated by MPO may be responsible for the increase in cross-linking. The generation of nitrotyrosine was demonstrated when NO2 was added to the cross-linking system. Cross-linking was also shown with an O2--generating system and NO. Peroxynitrite alone mediated cross-linking (100 microM ONOO-: 40.3+/-1.9% cross-linking; p < 0.002), and the addition of MPO significantly enhanced this effect (100 microM: 57.7+/-6.0%; p < 0.0002 with respect to no nitrite control). Oxygen radicals and NO are likely to interact at the cartilage surface in inflammatory arthritis, resulting in an increase in oxidative damage within the joint cavity.
9624450 Vascular volume determination of articular tissues in normal and anterior cruciate ligamen 1998 Jun The vasculature of diarthroidal joints has been well documented; however, the volume of vessels supplying different articular tissues is unknown. Angiogenesis, the formation of new vessels from preexisting ones, is difficult to quantify in joints due to the unavailability of a suitable technique. Although angiogenesis is known to occur in rheumatoid arthritis, the development of new vessels following joint injury has not been ascertained. A vascular casting technique was developed using carmine red dye to measure the vascular volume of the medial collateral ligament (MCL), lateral collateral ligament (LCL), menisci, medial capsule, and infrapatellar fat pad of the rabbit knee joint. Vascular volume determinations were repeated at 4 weeks in a group of anterior cruciate ligament (ACL)-transected animals and in a sham-operated control group. The volume of vessels supplying the MCL was estimated to be 0.22 +/- 0.07 microliter (mean +/- S.E.M.), the LCL volume was 0.25 +/- 0.05 microliter, the medial meniscus volume was 0.19 +/- 0.03 microliter, the lateral meniscus volume was 0.40 +/- 0.08 microliter, the medial capsule volume was 0.14 +/- 0.05 microliter, and the infrapatellar fat pad volume was 1.90 +/- 0.62 microliters. Following ACL transection, angiogenesis was found to occur in the MCL only. All other tissue vascularities were not significantly different from sham-operated controls. A quantifiable method for measuring vascular volume of knee joint tissues has been described. Joint instability stimulates angiogenesis in the ipsilateral MCL; however, the absence of angiogenic activity in other articular tissues might help explain the lack of posttraumatic healing associated with these joints.
11028754 Cyclooxygenase-2: its rich diversity of roles and possible application of its selective in 2000 Aug In addition to housekeeping cyclooxygenase (COX)-1, which is constitutively expressed in many body cells, an inducible COX-2 has been described and cloned. Induction or presence of COX-2 has been reported not only in isolated cells, but also in cells in various tissues, as well as in both physiological and pathophysiological states, including acute exudative inflammation, proliferative inflammation, animal arthritis, rheumatoid arthritis, angiogenesis, bone absorption, gastric ulcer, colon cancer, hyperalgesia, Alzheimer's disease and certain states of the kidney, brain and female reproductive organs. This review article introduces results from recent works in these fields. COX-1- or COX-2-knockout mice may provide many clues on the roles of COX-2, but may simultaneously cause unnecessary confusion in the recognition of the roles of COX-2, and this is discussed. Recently the roles of COX-2 in exudative inflammation and the anti-inflammatory effects of selective COX-2 inhibitors have been questioned. This is discussed in the text. Prostanoids mediate signals to adjacent cells to provide fine regulation of cellular function. Because of the short duration of the expression of COX-2 gene and protein, COX-2 must play some roles different from those of COX-1 gene and protein in vivo. It is not yet possible to identify all the roles of COX-2, but in some tissues, such as the kidney, the brain and others, COX-2 may be expressed constitutively, whereas the prostaglandin generation by COX-2 may replace that by COX-1 in some states (or vice-versa). Precise analyses of the expression of COX-2 may disclose fine modulation of cellular and organ functions by PGs. Several selective or preferential COX-2 inhibitors have been developed and were shown to be effective in clinical trials. Most were reported to be free of adverse gastrointestinal effects, but it should be noted that in the healing process of gastric ulcers and in sodium-restricted states, adverse effects of selective COX-2 inhibitors could be expected. Soon, with more detailed knowledge of the delicate roles of COX-2 in vivo, effective and safe application of COX-2 inhibitors should be realized.
10943867 SR proteins are autoantigens in patients with systemic lupus erythematosus. Importance of 2000 Aug OBJECTIVE: To determine whether members of the highly phosphorylated SR protein family are autoantigens and, if so, to determine the frequency and molecular basis of antigen recognition. METHODS: Native human SR proteins were purified to homogeneity from HeLa cells, and an enzyme-linked immunosorbent assay (ELISA) was developed. Further studies employed immunoblotting of both phosphorylated and dephosphorylated SR proteins. RESULTS: Anti-SR protein reactivity was frequently detected in the sera of patients with systemic lupus erythematosus (SLE). Sera from 52% of the SLE patients in a group of patients with a variety of autoimmune and other disorders (n = 137) and from 50% of the SLE patients in a separate group (n = 102) were positive in an ELISA. In contrast, sera from patients with other disorders, such as rheumatoid arthritis and primary antiphospholipid syndrome, reacted infrequently. Reactivity with double-stranded DNA (dsDNA), used in the diagnosis of SLE, did not correlate with SR protein reactivity. Anti-SR autoantisera did not bind highly charged unphosphorylated peptides related to the SR domain, which is rich in arginine and phosphoserine residues. Surprisingly, many of the epitopes were influenced by the presence or absence of SR protein phosphorylation. In immunoblots, some patient sera lost reactivity upon SR protein dephosphorylation, while others significantly gained reactivity. CONCLUSION: We have identified a novel set of autoantigens in SLE, the SR protein family of non-small nuclear RNP pre-messenger RNA splicing factors. Anti-SR autoantibodies are distinct from those which bind dsDNA. The identification of this new set of autoantigens and the observation that the auto-epitope(s) involves posttranslational modification offer new possibilities for understanding autoimmunity and its development.
9291340 The effect of tenidap on cytokines, acute-phase proteins, and virus load in human immunode 1997 Sep Proinflammatory cytokines may be important in the pathogenesis of human immunodeficiency virus type 1 (HIV-1) disease. Tenidap decreases interleukin (IL)-6, IL-1, and tumor necrosis factor (TNF) production by peripheral blood mononuclear cells and decreases IL-6 plasma levels in rheumatoid arthritis patients. In this randomized double-blind study, 43 HIV-1-infected patients received tenidap (120 mg) or placebo daily for 6 weeks and then crossed over to the alternative therapy for an additional 6 weeks. Mean entry CD4 cell count was 140/microL. Analyses were performed on cytokines, acute-phase proteins, virus load, and CD4 cell counts. With the exception of small differences in plasma TNF levels, tenidap had no significant effect on these indices. Significant correlations of plasma IL-6 and TNF levels with HIV-1 RNA were noted. Six patients discontinued tenidap due to rash. The effects of tenidap in HIV-1 infection contrast to results in arthritis patients, in whom tenidap decreased plasma levels of IL-6 and acute-phase proteins.
11518285 The effects of static and intermittent compression on nitric oxide production in articular 2001 Jul Nitric oxide (NO) production and NO synthase (NOS) expression are increased in osteoarthritis and rheumatoid arthritis, suggesting that NO may play a role in the destruction of articular cartilage. To test the hypothesis that mechanical stress may increase NO production by chondrocytes, we measured the effects of physiological levels of static and intermittent compression on NOS activity, NO production, and NOS antigen expression by porcine articular cartilage explants. Static compression significantly increased NO production at 0.1 MPa stress for 24 h (P < 0.05). Intermittent compression at 0.5 Hz for 6 h followed by 18 h recovery also increased NO production and NOS activity at 1.0 MPa stress (P < 0.05). Intermittent compression at 0.5 Hz for 24 h at a magnitude of 0.1 or 0.5 MPa caused an increase in NO production and NOS activity (P < 0.05). Immunoblot analysis showed stress-induced upregulation of NOS2, but not NOS1 or NOS3. There was no loss in cell viability following any of the loading regimens. Addition of 2 mM 1400 W (a specific NOS2 inhibitor) reduced NO production by 51% with no loss of cell viability. These findings indicate that NO production by chondrocytes is influenced by mechanical compression in vitro and suggest that biomechanical factors may in part regulate NO production in vivo.
11037874 Acidic fibroblast growth factor in synovial cells. 2000 Oct OBJECTIVE: To characterize the production and regulation of acidic fibroblast growth factor (aFGF) in type B (fibroblast-like) synoviocytes cultured from both inflammatory and noninflammatory synovial lesions. METHODS: Immunohistochemistry, Western blotting, and reverse transcriptase-polymerase chain reaction were used to examine the expression of aFGF by synovial cells in vitro. Incorporation of 3H-thymidine by NIH3T3 cells in the presence or absence of neutralizing antibody to aFGF was used to measure bioactive aFGF levels in culture media. RESULTS: Acidic FGF was detected in all synovial cell lines during growth in vitro; however, synoviocytes from rheumatoid arthritis (RA) patients sustained more abundant production of cytoplasmic and nuclear aFGF. Acidic FGF production persisted after multiple passages and did not depend on the presence of serum. Both RA and noninflammatory synovial cells were competent to release aFGF into the media, even though aFGF lacks a signal peptide. Tumor necrosis factor alpha, interleukin-6, and epidermal growth factor did not increase aFGF expression in vitro; in contrast, transforming growth factor beta1 (TGFbeta1) was found to markedly increase aFGF production by cultured synovial cells. CONCLUSION: Acidic FGF synthesis and release is a component of synovial cell growth that is markedly increased in RA. TGFbeta1, and not proinflammatory cytokines, is a potent inducer of aFGF production by synoviocytes in vitro. These findings suggest that in RA, interactions between TGFbeta1 and aFGF may contribute to angiogenesis and fibroblast proliferation, potentially independently of inflammatory mediators.
11014343 The antiinflammatory drug sulfasalazine inhibits tumor necrosis factor alpha expression in 2000 Sep OBJECTIVE: Sulfasalazine (SSZ) is a commonly used drug in the treatment of inflammatory diseases such as rheumatoid arthritis and Crohn's disease. In both diseases, the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) plays a prominent role. In these studies, we investigated the mechanism by which SSZ inhibits TNFalpha expression in macrophages and macrophage-like cell lines. METHODS: Monocyte-derived macrophages and several macrophage-like cell lines were exposed to SSZ in vitro, and the effect on TNFalpha expression was monitored by reverse transcriptase-polymerase chain reaction and Western blot analysis. In addition, the effects of SSZ in vivo were examined by intraperitoneally injecting mice with SSZ, after which peritoneal cells were harvested and examined using various staining methods. RESULTS: Preincubation of macrophages with SSZ, but not with methotrexate, inhibited lipopolysaccharide (LPS)-induced TNFalpha expression. Inhibition of TNFalpha expression by SSZ coincided with the induction of apoptosis, as judged by the appearance of morphologic changes typical of apoptosis, such as nuclear condensation and fragmentation. Induction of apoptosis by SSZ was confirmed by TUNEL analysis and by the detection of cleaved U1-70K, a substrate of caspase 3. Intraperitoneal injections of SSZ in mice resulted in the induction of apoptosis of peritoneal cells within a few hours. SSZ-induced cleavage of the U1-70K protein was inhibited by Zn2+ and by specific inhibitors of caspases 3 and 8, but not caspases 1 and 9. Interestingly, the reduced expression of LPS-induced TNFalpha in the presence of SSZ was restored by inhibition of caspase 8. CONCLUSION: Inhibition of TNFalpha expression in macrophages by SSZ is due to the induction of apoptosis and involves the activation of caspase 8.