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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To summarise the key points: The ability to mount an angiogenic response is probably present in all tissues, and stimulation of endothelial cells by any one of a wide variety of factors initiates a cascade of events leading to angiogenesis. In most tissues the overall lack of angiogenesis in normal situations probably results from the interaction of a complex series of multifactorial systems, each of which maintained in a state of balance between stimulation and inhibition. An imbalance in any one of these systems, for example by an increase in the concentration of a growth factor, may lead to angiogenesis. Inhibition of angiogenic stimuli is unlikely to be effective as an approach to new angiostatic drugs, given the multiple stimulatory pathways available. Tumour cells for example may induce angiogenesis via release of numerous growth factors, prostaglandins etc, and by their attraction of inflammatory cells which in turn release multiple angiogenic stimuli. Inhibitory modulation of many of the individual steps of capillary growth which occur following an angiogenic stimulus can block the angiogenic response. This leads to the expectation that an effective inhibitor of a single key step in this cascade would be able to completely suppress angiogenesis. Inappropriate angiogenesis is an important factor in many diseases including cancer and arthritis. In particular angiogenesis is an absolute requirement for neoplastic growth of solid tumours, and the establishment of secondary growths. There is also a strong link between induction of angiogenesis by a tumour and its ability to metastasise. Several drugs with proven clinical effects in diseases involving angiogenesis have recently been found to be angiogenesis inhibitors, and this may be their primary mechanism of action. In particular the activities of methotrexate and gold compounds in arthritis, and alpha-interferon and medroxyprogesterone in cancer therapy may be due to inhibition of angiogenesis. In animal models, treatment with angiogenesis inhibitors has proven anti-tumour effects in vivo, and can both reduce metastases and lead to regression of the primary growth by necrosis following capillary retraction. In man the success of alpha-interferon and TNF alpha in AIDS related Kaposi's sarcoma may be due to inhibition of angiogenesis. Interferon has also been successfully used to treat pulmonary hemangiomatosis, in which angiogenesis in the lung may be the pathogenic basis of the disease.
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PMID:Angiogenesis and its inhibition: potential new therapies in oncology and non-neoplastic diseases. 172 22

Using immunoaffinity-purified polyclonal anti-human recombinant tumor necrosis factor alpha (TNF alpha) F(ab')2 fragments and immunohistochemical techniques, the cells that make TNF alpha were localized in the inflamed synovial tissue of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Anti-TNF alpha antibody-stained cells were demonstrated in 9 of 11 RA and 2 of 4 OA but none of 5 normal synovial membranes examined. In RA, 26-64% of the lining layer cells were positive for TNF alpha. In the interaggregate area, 10-30% of the cells contained TNF alpha, often in a perivascular distribution, and up to 19% of the cells in lymphoid aggregates stained for TNF alpha. Some endothelial cells also stained with these antibodies. In OA tissues, the TNF alpha-containing cells were found predominantly in the deeper layer. Cells containing TNF alpha were also found at the cartilage-pannus junction in all 4 RA specimens examined. Double immunofluorescence analysis demonstrated that most TNF alpha-secreting cells in the RA synovial membrane expressed the monocyte/macrophage marker antigens CD11b and CD14, and a few expressed the T cell marker CD3. Our findings provide histologic evidence that TNF alpha is locally produced in the lining and deeper layers of the synovium by cells of the monocyte/macrophage lineage, supporting its role in inflammation. Further, our findings demonstrate that TNF alpha is produced by cells at the cartilage-pannus junction, which could affect chondrocyte metabolism, leading to the cartilage degradation in RA.
Arthritis Rheum 1991 Sep
PMID:Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. 193 Mar 31

Because Haemophilus influenzae type b (Hib) is the principal cause of suppurative arthritis in young children and its lipooligosaccharide (LOS) is thought to be the main virulence factor, Hib endotoxin was evaluated for its ability to induce synovial inflammation in rabbits. Also, the role of the cytokines tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta (IL-1 beta) in mediating the synovial inflammatory process was studied. Intraarticular inoculation of 2 pg to 20 ng of Hib LOS produced a dose-dependent increase in concentrations of leukocytes and protein in synovial lavage fluid that was significantly modulated by concomitant administration of rabbit TNF alpha- and rabbit IL-1 beta-specific antibodies. Inoculation of joints with either 10(4) IU of rabbit TNF alpha or 10 ng recombinant rabbit IL-beta induced synovial inflammatory changes similar to those observed after LOS intraarticular challenge. These data provide evidence for the role of Hib LOS in inducing suppurative arthritis and for the critical participation of TNF alpha and IL-1 beta in the initial events of the synovial inflammatory response.
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PMID:Induction of suppurative arthritis in rabbits by Haemophilus endotoxin, tumor necrosis factor-alpha, and interleukin-1 beta. 203 91

Recent evidence suggests that reactive oxygen intermediates may play a role in the etiology of cartilage matrix degradation in arthritis. We have previously established that normal articular chondrocytes can functionally act as macrophages. These functions include expression of class II MHC Ag, presentation of Ag and induction of mixed and autologous lymphocyte stimulation. Inasmuch as the production of reactive oxygen intermediates is a hallmark of macrophage activity during inflammatory response, we were interested in examining the ability of normal articular chondrocytes to produce reactive oxygen intermediates. Using the trapped indicator 2',7'-dichlorofluorescin diacetate (DCFH-DA), we measured the levels of intracellular hydrogen peroxide within normal rabbit articular chondrocytes. We found that Concanavalin A induces chondrocytes to rapidly oxidize 2',7'-dichlorofluorescin diacetate to a highly fluorescent dichlorofluorescin in a dose- and time-dependent manner. Fluorescent dichlorofluorescin oxidation by chondrocytes was inhibited by the addition of catalase, an enzyme that detoxifies hydrogen peroxide. Exposure of rabbit chondrocytes to either IFN-gamma or TNF primed the chondrocytes to produce significantly greater amounts of hydrogen peroxide with or without further stimulation. Using scopoletin oxidation as a measure of the release of hydrogen peroxide, we confirmed that chondrocytes released this reactive oxygen intermediate after adherence to serum coated culture plates. Rabbit articular chondrocytes produced and released greater amounts of hydrogen peroxide than pulmonary alveolar macrophages, a well characterized macrophage cell type. These observations suggest that chondrocytes are an important source of reactive oxygen intermediates. Furthermore, the production of reactive oxygen intermediates by chondrocytes may be an important mechanism by which chondrocytes induce structural and functional alterations in cartilage matrix observed during arthritis.
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PMID:Production of hydrogen peroxide by rabbit articular chondrocytes. Enhancement by cytokines. 211 47

This review has summarized some of the evidence suggesting that cytokines may play an important role in mediating pathophysiologic events in RA. However, these proteins are capable of mediating both stimulatory (agonist) and inhibitory (antagonist) effects in the rheumatoid synovium. GM-CSF, IL-1, TNF alpha, and PDGF are all produced in the rheumatoid synovium and may function to induce inflammation, enzyme release, fibroblast proliferation, and tissue destruction. Local release of IL-6 may alter the effects of IL-1 and TNF alpha, as well as induce Ig production and hepatic synthesis of acute-phase proteins. However, specific inhibitors of IL-1 and TNF alpha exist, which, if also released into the synovium, may antagonize the proinflammatory effects of these cytokines. In addition, IL-1 may have antiinflammatory effects, such as the induction of the synthesis of collagen and enzyme inhibitors by chondrocytes and synovial fibroblasts. Stimulation of these latter cells by TGF beta also may result in decreased matrix degradation and increased formation of scar tissue. The developing scenario is one of cell-cell interactions that are influenced in positive and negative manners by the local release of various mediators. A further understanding of cytokines and cytokine inhibitors in the rheumatoid synovium may lead to the development of more specific and effective therapeutic agents.
Arthritis Rheum 1990 Mar
PMID:Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. 218 Apr 3

In this study we have examined the effects of recombinant cytokine preparations on the production of prostaglandin E2 (PGE2) by human articular chondrocytes in both chondrocyte monolayer and cartilage organ cultures. The cytokines chosen for this study included only those reported to be present in rheumatoid synovial fluids and which therefore could conceivably play a role in chondrocyte activation in inflammatory arthritis. Of the cytokines tested, interleukin-1 (IL-1; alpha and beta forms) consistently induced the highest levels of PGE2 production followed, to a lesser extent, by tumour necrosis factor (TNF; alpha and beta forms). The IL-1s were effective at concentrations 2-3 orders of magnitude less than the TNFs, with each cytokine demonstrating a dose-dependent increase in PGE2 synthesis for the two culture procedures. The increased PGE2 production by the chondrocytes exhibited a lag phase of 4-8 h following the addition of the IL-1 or TNF and was inhibited by actinomycin D and cycloheximide, indicating a requirement for de novo RNA and protein synthesis, respectively. Our results suggest that IL-1 may be the key cytokine involved in modulating chondrocyte PGE2 production in inflammatory arthritis; they further extend the list of human chondrocyte responses which are affected by both IL-1 and TNF.
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PMID:Stimulation of human chondrocyte prostaglandin E2 production by recombinant human interleukin-1 and tumour necrosis factor. 231 Jul 81

In cultured human articular chondrocytes, addition of tumor necrosis factor alpha (TNF alpha) stimulated caseinase activity over the range of 10(-11) M to 10(-7) M and stimulated prostaglandin E (PGE) production over the range of 10(-10) M to 10(-7) M. Maximal stimulation was observed at 10(-8)M TNF alpha for both activities. Gamma-interferon (gamma-IFN) had a variable effect on PGE production and no significant effect on caseinase activity in articular chondrocyte cultures over a concentration range of 0.1-1,000 units/ml. Co-incubation of TNF alpha with gamma-IFN enhanced PGE production and decreased caseinase activity. Concentrations as low as 1 unit/ml of gamma-IFN had significant effects on TNF-stimulated production of PGE and on caseinase activity. Resorption of human articular cartilage was stimulated by TNF alpha (10(-7) M) and was inhibited by gamma-IFN (1,000 units/ml). It is possible that cartilage breakdown in vivo may be modulated by such interactions between cytokines.
Arthritis Rheum 1989 Jun
PMID:The effect of tumor necrosis factor alpha and gamma-interferon on the resorption of human articular cartilage and on the production of prostaglandin E and of caseinase activity by human articular chondrocytes. 250 Jan 31

Many cells and their cytokines produce a significant effect on bone metabolism. Bone matrix synthesis is a function of the osteoblast (Fig 1), influenced directly by numerous local and systemic factors (Tables 1 and 2). Locally synthesized factors such as SGF, BMP, and BDGF may be particularly important in stimulating new bone formation at sites of bone resorption or following bony injury. Of the systemic factors, GH; somatomedin C (IGF-1); high concentrations of insulin, testosterone, PDGF and TGF beta; and low concentrations of PGE2 and IL-1 appear to stimulate bone formation in vitro. These latter factors may be more important in maintaining skeletal growth and bone mass. Bone resorption by osteoclasts (Figs 2 and 3) is also controlled by the osteoblast, as this cell produces a leukotriene-dependent polypeptide that stimulates osteoclastic bone resorption. Osteoblasts cover the periosteal and endosteal bone-surfaces and limit exposure of the underlying bone to osteoclasts. PTH, vitamin D, PGE2, and other systemic factors interact directly with the osteoblast, not the osteoclast. Surface receptor binding of PTH increases intracellular cAMP and calcium and results in release of the factor that stimulates osteoclastic bone resorption. PGE2 induces osteoblasts to activate osteoclasts and is a major controlling factor in bone metabolism; the osteoblast produces PGE2, which can then modify osteoblastic function by positive feedback. Although low concentrations of PGE2 stimulate bone formation, higher concentrations promote osteoblast-mediated bone resorption. Furthermore, many of the systemic factors stimulate bone resorption via a PGE2-associated mechanism. Immune cytokines also appear to exert a profound influence on bone metabolism. INF-gamma inhibits osteoclastic resorption, whereas IL-1, TNF, and LT strongly stimulate bone resorption. However, low concentrations of IL-1 paradoxically result in stimulation of bone formation. These cytokines, particularly in various combinations, may prove extremely important in understanding and treating the bone loss associated with malignancies, osteoporosis, and rheumatoid arthritis.
Semin Arthritis Rheum 1989 Aug
PMID:The metabolism and immunology of bone. 267 41

Articular chondrocytes cultured in the presence of recombinant human interleukin 1 alpha (rhIL-1 alpha) or recombinant human tumor necrosis factor alpha (rhTNF alpha) caused increased production of the latent metalloproteinase (collagenase and caseinase) and the proteoglycan release from cartilage. The existences of IL-1 and TNF alpha in the chondrocytes of human articular cartilage were also shown by immunohistochemical staining using polyclonal antibodies. Furthermore, chondrocyte was found to be a producer of interleukin 6 (IL-6), known as a pleiotropic cytokine and thought to be an important mediator of the cell interactions in arthritis. In addition, the production of IL-6 was also shown to be stimulated by rhIL-1 alpha or rhTNF alpha. From our findings, we suggest there exists a very complicated autocrine control system of chondrolysis by the chondrocyte itself.
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PMID:The role of cytokines in chondrocyte mediated cartilage degradation. 281 Feb 94

MRL/MpJ-lpr/lpr (lpr/lpr) mice are congenic mice of the lpr gene which encodes the massive proliferation of unusual T cells characteristic of Thy 1+, Lyl1+, L3T4-, Lyt2- and B220+ on cell surface. These mice spontaneously develop a progressive autoimmune disease such as glomerulonephritis, arthritis and granulomatous arteritis. Until now, it has been reported that peritoneal exudate macrophages (PEM) from lpr/lpr mice are activated in comparison with those from MRL/MpJ-+/+ (+/+) mice. In this paper, five PEM functions [anti-tumor activity, IL-1 activity, TNF activity, superoxide (O2-) production and proliferative capacity] were analysed to elucidate the mechanism of activation of PEM from lpr/lpr mice. The results indicated that lpr/lpr PEM had a significant increase in cytostasis and O2- production and a significant decrease in proliferative capacity, suggesting that PEM from lpr/lpr mice were activated to the level of primed macrophage. To examine the effect of contaminated nonadherent peritoneal exudate cells (NAPEC) from lpr/lpr mice on PEM activity, cell mixing experiments were performed. B220- cells out of NAPEC from lpr/lpr mice significantly enhanced O2- production by +/+ PEM. Furthermore, Lyt2+ splenic T cells also enhanced O2- production by +/+ PEM. The culture supernatants of spleen cells from lpr/lpr mice contained so called "MAF" activity, because they enhanced O2- production by +/+ PEM significantly. Moreover, the culture supernatants of Con A-stimulated spleen cells from lpr/lpr mice showed higher IFN-gamma activity than those from +/+ mice. Such higher IFN-gamma activity was present in the supernatants of Con A-stimulated B220- splenic T cells. These results suggested that Lyt2+ NAPEC from lpr/lpr mice produced MAF-like-lymphokine, possibly IFN-gamma, which activated PEM in vivo. While the culture supernatants of non-stimulated PEM from MRL mice had no IL-1 and TNF activity, those of recombinant IFN-gamma-stimulated PEM from lpr/lpr mice had higher IL-1 and TNE activity than those from +/+ mice. These data indicated that lpr/lpr PEM were more sensitive to IFN-gamma than +/+ PEM.
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PMID:[A study on the mechanism of activation of peritoneal exudate macrophages from MRL/MpJ-lpr/lpr mice]. 285 94


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