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

Human autoimmune diseases share the common feature of an imbalance between the production and destruction of various cell types including lymphocytes (SLE), synovial cells (RA), and fibroblasts (scleroderma). Patients with SLE have increased levels of soluble Fas that inhibit proper apoptosis of lymphocytes. In animal models of autoimmune diseases, mutations of genes involved in apoptosis including Fas, Fas ligand, and the hematopoietic cell phosphatase gene have been identified. Oncogenes, including bcl-2, p53, and myc, that regulate apoptosis are also expressed abnormally. Potent inducers of apoptosis including steroids, azathioprine, cyclophosphamide, and methotrexate are the most efficacious therapies for autoimmune disease currently known. Specific therapies that induce apoptosis without incurring side effects should improve treatment of autoimmune disease.
Arthritis Rheum 1994 Oct
PMID:Autoimmune disease. A problem of defective apoptosis. 752 7

p53, a tumor suppressor and a transcription factor, has been shown to transcriptionally activate the expression of a number of important genes involved in the regulation of cell growth, DNA damage, angiogenesis, and apoptosis. In a computer search for other potential p53 target genes, we identified a perfect p53 binding site in the promoter of the human type IV collagenase (also called 72-kDa gelatinase or matrix metalloproteinase 2 [MMP-2]) gene. This p53 binding site was found to specifically bind to p53 protein in a gel shift assay. Transcription assays with luciferase reporters driven by the promoter or enhancer of the type IV collagenase gene revealed that (i) activation of the promoter activity is p53 binding site dependent in p53-positive cells but not in p53-negative cells and (ii) wild-type p53, but not p53 mutants commonly found in human cancers, transactivates luciferase expression driven by the type IV collagenase promoter as well as by a p53 site-containing enhancer element in the promoter. Significantly, expression of the endogenous type IV collagenase is also under the control of p53. Treatment of U2-OS cells, a wild-type p53-containing osteogenic sarcoma line, with a common p53 inducer, etoposide, induced p53 DNA binding and transactivation activities in a time-dependent manner. Induction of type IV collagenase expression followed the p53 activation pattern. No induction of type IV collagenase expression can be detected under the same experimental conditions in p53-negative Saos-2 cells. All these in vitro and in vivo assays strongly suggest that the type IV collagenase gene is a p53 target gene and that its expression is subject to p53 regulation. Our finding links p53 to a member of the MMP genes, a family of genes implicated in trophoblast implantation, wound healing, angiogenesis, arthritis, and tumor cell invasion. p53 may regulate these processes by upregulating expression of type IV collagenase.
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PMID:Transcriptional activation by p53 of the human type IV collagenase (gelatinase A or matrix metalloproteinase 2) promoter. 934 94

The cosmopolitan nature of current travel practices, as well as significant immigration from endemic areas, has led to increases in the incidence of leprosy. The classic presentation of leprosy usually appears as the indeterminate form, demonstrates hypopigmented macules with a loss of sensation. However, the manifestations can sometimes be quite protean. Sadeghi et al. review the rheumatic manifestations of leprosy with an illustrating case presenting with arthritis. Rheumatic symptoms are common in leprosy patients and may be the presenting manifestations and should be considered in patients with persistent rash and unusual arthritis who have a history of exposure to endemic areas. Significant interest has developed over the past decade in inhibiting cutaneous carcinogenesis with retinoic acid. This has been used as an effective therapy in certain genetically predisposed individuals, including individuals with a DNA repair defect in xeroderma pigmentosa. The molecular mechanisms of retinoids ability to inhibit ultraviolet light induced carcinogenesis have not been determined. Li and co-workers have examined the effect of retinoic acid on ultraviolet light induced programmed cell death (apotosis) as well as expression of the tumour suppressor gene P53. Their studies suggest that retinoic acid does not work on the initiation stages of the cancer development, but may work in the promotion and progression stage. Of more immediate clinical importance, in the Point-Counterpoint section, we have two insightful articles on how physician reimbursement affects patient care. As North American health care continues to evolve, there is constant debate on what model system works best for the ultimate benefit of our patients. Physicians, politicians, and administrators are constantly comparing the United States health care delivery to that of Canada. While no one can accurately predict the future developments in these areas, I think Dr. McElgunn sums the concerns that indeed are applicable on both sides of the border: ".socialized medical system has been of great benefit to patients but the ability of its physicians to continue to carry the system is at or near the breaking point. The ramifications of the issues of access and quality of care are harbingers of a system in turmoil." While these concerns must be dealt with, strong physician input is vital to continuing the effective evolution of our health care system. A vital part of our health care delivery is the increasing use of diagnostic tests. Key treatment decisions and interventions are based on the interpretation of these tests. However, most tests are "imperfect instruments." The article by Binder and Dreiseitl concisely reviews sensitivity, specificity, prevalence, predictive values, and likelihood ratios in a highly informative manner with significant examples. This paper provides a reference with which all physicians should be familiar. Traditionally, Western medicine has focused on a model of disease whereby pathology was regarded as well defined alteration in normal physiology that should respond to appropriate pharmaceutical or surgical interventions. However, in recent years patient focused medicine has become an important aspect of our practices. The concept of health related quality of life has represented an important advance in dealing with these concerns in our treatment of disease. Drs. Price and Harding examine the concept of health related quality of life using the example of a diabetic foot ulcer complications. These types of measures are important to understand, not only in the context of this disease but in the context of any chronic dermatologic condition.
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PMID:Editorial. 1068 19

Matrix metalloproteinases (MMPs) are a family of secreted or transmembrane proteins that can degrade all the proteins of the extracellular matrix and have been implicated in many abnormal physiological conditions including arthritis and cancer metastasis. Recently we have shown for the first time that the human MMP-1 gene is a p53 target gene subject to repression by wild type p53 (Sun, Y., Sun, Y. I., Wenger, L., Rutter, J. L., Brinckerhoff, C. E., and Cheung, H. S. (1999) J. Biol. Chem. 274, 11535-11540). Here, we report that cotransfection of fibroblast-like synoviocytes with p53 expression and hMMP13CAT reporter plasmids revealed that (i) hMMP13, another member of the human MMP family, was down-regulated by wild type p53, whereas all six of the p53 mutants tested lost the wild type p53 repressor activity in fibroblast-like synoviocytes; (ii) this repression of hMMP-13 gene expression by wild type p53 could be reversed by overexpression of p53 mutants p53-143A, p53-248W, p53-273H, and p53-281G; (iii) the dominant effect of p53 mutants over wild type p53 appears to be a promoter- and mutant-specific effect. An intriguing finding was that p53 mutant p53-281G could conversely stimulate the promoter activity of hMMP13 up to 2-4-fold and that it was dominant over wild type p53. Northern analysis confirmed these findings. Although the significance of these findings is currently unknown, they suggest that in addition to the effect of cytokines activation, the gene expression of hMMP13 could be dysregulated during the disease progression of rheumatoid arthritis (or cancer) associated with p53 inactivation. Since hMMP13 is 5-10 times as active as hMMP1 in its ability to digest type II collagen, the dysregulation or up-modulation of MMP13 gene expression due to the inactivation of p53 may contribute to the joint degeneration in rheumatoid arthritis.
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PMID:Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13). 1075 45

To investigate the relationship of chondrocyte apoptosis and cartilage destruction, we performed in situ nick end labeling (ISNEL), electron microscopy, and immunohistochemistry against apoptosis-related proteins, p53 and c-myc, in the articular cartilages of patients with rheumatoid arthritis (RA; n = 12) and osteoarthritis (OA; n = 12), and in control articular cartilages from patients with femoral neck fracture (n = 8). The distribution of stained chondrocytes was evaluated semiquantitatively in relation to the degree of cartilage destruction. ISNEL-positive chondrocytes with apoptotic morphological features were identified in a relatively early phase of cartilage destruction, and correlated positively and significantly in a number with the degree of cartilage degeneration. Comparison of RA and OA revealed a significantly greater number of ISNEL-positive chondrocytes in RA cartilage. In contrast, the specimens of normal subjects contained few cells with apoptotic changes. Similarly to the distribution of ISNEL staining, the expression of p53 and c-myc proteins was observed in chondrocytes within the degraded lesions, and showed a positive correlation with the number of ISNEL-stained cells. These results suggest that the degree of chondrocyte apoptosis is closely related to cartilage destruction and that chondrocytes in RA more readily undergo apoptosis than those in OA. The expression of p53 and c-myc proteins in ISNEL-positive areas may reflect the involvement of these proteins in the apoptotic process in articular chondrocytes in inflammatory arthritis.
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PMID:Apoptosis of articular chondrocytes in rheumatoid arthritis and osteoarthritis: correlation of apoptosis with degree of cartilage destruction and expression of apoptosis-related proteins of p53 and c-myc. 1098 49

STATEMENT OF FINDINGS: The kinetics of apoptosis and the apoptosis-regulating gene p53 in adjuvant arthritis (AA) were investigated to assess the value of the AA rat model for testing apoptosis-inducing therapies. Very few terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL)-positive cells were detected during the early phases of AA, but on day 23 (chronic arthritis) the percentage of TUNEL-positive cells was significantly increased. Expression of p53 in synovial tissue gradually increased from days 5-23, which was markedly higher than p53 levels in rheumatoid arthritis (RA) synovium. Significant apoptosis only occurs late in rat AA and is concordant with marked p53 overexpression, making it useful model for testing proapoptotic therapies, but rat AA is not the best model for p53 gene therapy because dramatic p53 overexpression occurs in the latter stages of the disease.
Arthritis Res 2000
PMID:Apoptosis and p53 expression in rat adjuvant arthritis. 1109 24

The aim of this study was to investigate the p53 status in two autoimmune diseases; juvenile chronic arthritis (JCA) and rheumatoid arthritis (RA). In a PCR-sequencing analysis of exons 4-9 of the p53 gene, no mutation was identified, except for the case of an RA synovectomy sample with two mutations of intron 7. p53 gene polymorphisms for codons 36, 47, and 213 were not detected. Codon 72 polymorphism showed an indication of an increased occurrence of the Pro/Pro allelotype in JCA. Expression of P53 protein was comparable for JCA and RA synovectomy samples. For all RA samples P53 protein was detectable, whereas one sample of a JCA patient failed to express P53 protein.
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PMID:The p53 status in juvenile chronic arthritis and rheumatoid arthritis. 1109 Dec 84

The knowledge of transcription factors and proto-oncogenes has influenced the understanding of cell regulation, cell cycle, and apoptotic cell death in rheumatoid arthritis (RA) synovium. In addition, the development of normal synovial fibroblasts into transformed-appearing aggressive synovial fibroblasts may be triggered by the lack of antiproliferative factors, such as p53, p53-associated molecules, other tumor suppressors, as well as by upregulation of anti-apoptotic genes. Therefore, data derived from experiments such as those performed by Tak and colleagues in this issue of Arthritis Research not only enrich the intensive discussion addressing the impact of p53 on RA pathophysiology, they also may facilitate development of novel therapeutic approaches including p53-targeted gene therapy.
Arthritis Res 2000
PMID:p53 in rheumatoid arthritis: friend or foe? 1105 68

Rheumatoid arthritis (RA) is an autoimmune disease that primarily affects joints. During the pathogenesis of rheumatoid arthritis, the synovial lining becomes dramatically thickened and hyperplastic. This highly aggressive tissue invades and destroys articular cartilage and bone. Several lines of evidence suggest that the proliferation of the synovial tissue may be due to disruption in the control of the cell cycle or apoptotic pathways. In particular, mutations in the tumor suppressor protein p53 have been found in synovial tissue from RA joints. We have examined the effects of overexpression of p53 by adenoviral infection in synovial cells in culture and in synovial tissue in vivo in a rabbit model of arthritis. Here we demonstrate that p53 overexpression resulted in significant apoptosis in human and rabbit synovial cells in culture. Furthermore, intraarticular injection of Ad-p53 resulted in extensive and rapid induction of synovial apoptosis in the rabbit knee without affecting cartilage metabolism. Interestingly, a significant reduction in the leukocytic infiltrate was observed within 24 h postinfection of Ad.p53. These results suggest that intraarticular gene transfer of p53 is able to induce synovial apoptosis as well as reduce inflammation and thus may be useful clinically for the treatment of RA.
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PMID:Gene transfer of p53 to arthritic joints stimulates synovial apoptosis and inhibits inflammation. 1140 4

The role of the tumor suppressor p53 as a key regulator of inflammation was examined in murine collagen-induced arthritis (CIA), a model of rheumatoid arthritis. Wild-type DBA/1 mice develop progressive arthritis in this model, in which p53 expression and apoptosis are evident in the synovial cells. In contrast, the joints of p53(-/-) DBA/1 animals with CIA showed increased severity of arthritis using clinical and histological scoring methods with almost no apoptosis. Consistent with this, collagenase-3 expression and cytokine production (interleukin-1 and interleukin-6) in the joints of p53(-/-) mice with CIA were significantly greater than in wild-type mice. Anti-collagen antibody titers, however, were not different. Therefore, p53 expression occurs during inflammation and acts to suppress local inflammatory responses. Because mutations in p53 have been described in the synovial membrane of rheumatoid arthritis patients, the loss of p53 function in synoviocytes or other cells in the joint because of dominant-negative mutations might contribute to invasion and destruction of the joint in this disease.
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PMID:Regulation of joint destruction and inflammation by p53 in collagen-induced arthritis. 1178 6


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