Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of continuous passive motion (CPM) in the management of septic arthritis and inflammatory arthritis remains of interest. CPM produces cyclic variations in intraarticular pressure that facilitates transport of fluid, nutrients, and solutes within and/or across the joint and stimulates chondrocyte metabolism. However, the precise mechanisms mediating the responses of chondrocytes to joint motion remain unclear. This study tested the hypothesis that dynamic mechanical loading counteracts effects of bacterial lipopolysaccharide (LPS), an inflammatory mediator, on chondrocyte metabolism. Intermittent hydrostatic pressure (IHP) (10 MPa for 4 h) was applied to human chondrocytes pretreated with LPS (1 microg/ml for 18 h). LPS activation of chondrocytes decreased mRNA signal levels of type II collagen by 67% and aggrecan by 56% and increased nitric oxide by 3.1-fold, monocyte chemotactic protein-1 mRNA signal levels by 6.5-fold, and matrix metalloproteinase-2 mRNA signal levels by 1.3-fold. Application of IHP to LPS-activated chondrocytes decreased nitric oxide synthase mRNA signal levels and nitric oxide levels in the culture medium. Exposure of LPS-activated chondrocytes to IHP upregulated type II collagen and aggrecan mRNA signal levels by 1.7-fold, relative to chondrocytes activated by LPS and maintained without loading. In addition, application of IHP decreased the upregulation in signal levels of monocyte chemotactic factor-1 and matrix metalloproteinase-2 following LPS activation by 45% and 15%, respectively. These data show that mechanical loading counteract effects of inflammatory agents, such as bacterial LPS, and suggest that postinfection sequelae are influenced by the presence or absence of joint loading.
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PMID:Protective effects of intermittent hydrostatic pressure on osteoarthritic chondrocytes activated by bacterial endotoxin in vitro. 1250 88

The current study evaluated the relative correlation of apatite crystal-induced inflammation and rotator cuff deficiency in the development of cuff tear arthropathy. Thirty-seven patients with full thickness rotator cuff tears were evaluated by history, physical examination, and plain radiographs. Thirty patients had surgical intervention for their rotator cuff defects, and calipers were used intraoperatively to quantify the size of the tear in its largest diameter. The remaining seven patients were treated nonoperatively and the size of the tear was quantified using magnetic resonance imaging. Synovial fluid was obtained from all patients and analyzed for crystal content using an alizarin red stain. Synovial fluid also was analyzed for leukocyte count and differential, prostaglandin E, and matrix metalloproteinase. An unpaired Student's t test revealed that significantly higher levels of prostaglandin E were found in the synovial fluid of patients with apatite crystals, shown by alizarin red stain. Chi squared analysis showed that patients with elevated crystal levels were significantly more likely to have large rotator cuff tears or glenohumeral arthritis. Establishing such relations potentially can elucidate the etiology and treatment of this complex disorder.(2) (2)
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PMID:Milwaukee shoulder: correlating possible etiologic variables. 1256 34

Matrix metalloproteinases (MMPs) play a key role in the physiology of connective tissue development, morphogenesis and wound healing, but their unregulated activity has been implicated in numerous disease processes including arthritis, tumor cell metastasis and atherosclerosis. MMP family consists of at least 20 members; MMPs are produced by the different cell types (vascular smooth muscle cells, monocytes, endothelial cells) involved in the atheromatous plaque formation and participate to extracellular matrix remodelling and cell infiltration or migration. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression (including plaque disruption), MMPs represent a potential target for therapeutic intervention to modify vascular pathology, by restoring the MMP/TIMP physiological equilibrium. This review highlights the structures of MMPs and their physiological inhibitors, the Tissue Inhibitors of MMPs (TIMPs), and describes the current developments in pharmacological MMP inhibition.
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PMID:[Matrix metalloproteinases and atherosclerosis. Therapeutic aspects]. 1270 69

The destruction of bone and cartilage is characteristic of the progression of musculoskeletal diseases. The present review discusses the developments made with two different classes of drugs, the bisphosphonates and matrix metalloproteinase inhibitors. Bisphosphonates have proven to be an effective and safe treatment for the prevention of bone loss, especially in osteoporotic disease, and may have a role in the treatment of arthritic diseases. The development of matrix metalloproteinase inhibitors and their role as potential therapies are also discussed, especially in the light of the disappointing human trials data so far published.
Arthritis Res Ther 2003
PMID:Drugs in development: bisphosphonates and metalloproteinase inhibitors. 1271 43

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins. Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis. Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases. The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.
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PMID:Synthesis and structure-activity relationship of alpha-sulfonylhydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis. 1277 41

Using various FcgammaR-deficient mice, we have obtained suggestive evidence that FcgammaRI on macrophages is responsible for severe cartilage destruction during arthritis mediated by immune complexes (ICs). This role of FcgammaRI is pronounced in the presence of activated Th1 cells and a likely Th1 cell-derived cytokine mediating up-regulation of FcgammaRI expression is interferon (IFN)-gamma. We now investigated whether local overexpression of IFN-gamma using an adenoviral vector is able to elevate cartilage destruction during experimental immune complex-mediated arthritis (ICA) and to what extent this process is FcgammaRI-mediated. IFN-gamma overexpression during ICA had no significant effect on the total cell mass infiltrating the knee joint. However, a higher percentage of macrophages expressing markers for a proinflammatory phenotype was found and these macrophages were situated in close proximity of the cartilage surface. Interestingly, cartilage destruction as studied by matrix metalloproteinase (MMP)-mediated proteoglycan damage (VDIPEN expression), chondrocyte death, and erosion was significantly increased. This effect of IFN-gamma was only found in the presence of ICs, as IFN-gamma overexpression during zymosan-induced arthritis, which is not IC-dependent, did not lead to severe cartilage destruction. These results imply a crucial role for ICs and the IgG-binding receptors in the aggravation of cartilage damage by IFN-gamma. Local overexpression of IFN-gamma induced increased FcgammaRI mRNA levels in synovium. To study whether this up-regulation of FcgammaRI mediates aggravation of cartilage destruction, ICA was raised in FcgammaRI(-/-) and their wild-type controls. IFN-gamma resulted in elevated VDIPEN expression, which was still present in FcgammaRI(-/-). Of great interest, chondrocyte death remained low in FcgammaRI(-/-). These results indicate that IFN-gamma overexpression deteriorates cartilage destruction in the presence of ICs and that FcgammaRI is crucial in the development of chondrocyte death.
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PMID:FcgammaRI up-regulation induced by local adenoviral-mediated interferon-gamma production aggravates chondrocyte death during immune complex-mediated arthritis. 1287 93

Tumor necrosis factor alpha (TNF-alpha), a major proinflammatory cytokine, induces arthritic joint inflammation and resorption of cartilage by matrix metalloproteinase-13 (MMP-13). RNA for MMP-13 is increased in human arthritic femoral cartilage. Mechanisms of this induction were investigated by pretreating primary human osteoarthritic (OA) femoral head chondrocytes or chondrosarcoma cells with the potential inhibitors of TNF-alpha signal transduction and downstream target transcription factors followed by stimulation with TNF-alpha and analysis of MMP-13 RNA/protein. TNF-alpha rapidly activated phosphorylation of extracellular signal-regulated kinases (ERKs), p38, and c-jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases in human chondrocytes. Inhibitors of ERK (U0126, PD98059, and ERK1/2 antisense phosphorothioate oligonucleotide), JNK (SB203580, SP600125, and curcumin), and p38 (SB203580 and SB202190) pathways down-regulated the TNF-stimulated expression of MMP-13. Inhibitors of the transcription factors AP-1 (nordihydroguaiaretic acid, NDGA) and NF-kappaB (curcumin, proteasome inhibitors, and Bay-11-7085) suppressed TNF-alpha-induced MMP-13 expression in primary chondrocytes and SW1353 cells. These results suggest that induction of the MMP-13 gene by TNF-alpha is mediated by ERK, p38, and JNK MAP kinases as well as AP-1 and NF-kappaB transcription factors. Blockade of TNF-alpha signaling and its target transcription factors by the approaches tested here may be beneficial for reducing cartilage breakdown by MMP-13 in arthritis.
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PMID:Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes. 1287 72

The matrix metalloproteinases (MMPs) constitute a family of multidomain zinc endopeptidases with a metzincin-like catalytic domain, which are involved in extracellular matrix degradation but also in a number of other important biological processes. Under healthy conditions, their proteolytic activity is precisely regulated by their main endogenous protein inhibitors, the tissue inhibitors of metalloproteinases. Disruption of this balance results in pathophysiological processes such as arthritis, tumor growth and metastasis, rendering the MMPs attractive targets for inhibition therapy. Knowledge of their tertiary structures is crucial for a full understanding of their functional properties and for rational drug design. Since the first appearance of atomic MMP structures in 1994, a large amount of structural information has become available on the catalytic domains of MMPs and their substrate specificity, interaction with synthetic inhibitors and the TIMPs, the domain organization, and on complex formation with other proteins. This review will outline our current structural knowledge of the MMPs and the TIMPs.
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PMID:Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases. 1288 53

The mechanisms and agents involved in cartilage matrix destruction are poorly understood and at present there are no means of therapeutic intervention that halt or slow the degradative processes that result in tissue loss, joint space narrowing and the eventual need for surgery with total joint replacement. In recent years our laboratory has pioneered the development and use of monoclonal antibody (MAb) technologies for the study of changes in cartilage matrix metabolism in health and disease. In this chapter we have summarized results coming from our recent studies examining the mechanisms of cartilage proteoglycan (aggrecan) catabolism that precedes cartilage destruction in arthritis. This research has used two approaches. The first is our access to a panel of MAbs that recognize both constitutive structural epitopes and catabolic neoepitopes on cartilage proteoglycan metabolites. These antibodies have allowed us to determine whether the unknown proteolytic agent 'aggrecanase' or known matrix metalloproteinases (MMPs) are involved in the increased aggrecan catabolism that is observed in arthritis. Secondly, we have used reverse transcription-polymerase chain reaction (RT-PCR) techniques to profile the expression of members of the MMP family or ADAMs (A disintegrin and metalloproteinase) that are potentially involved in this degenerative process. Collectively, these investigations have established that aggrecanase is the major proteolytic activity responsible for aggrecan loss in the early stages that lead to cartilage degradation in arthritis. In addition, our studies have allowed us to determine many important biochemical properties of aggrecanase without knowing the identity of the enzyme. Our data also calls into question the role that MMPs may play in the early stages of cartilage destruction that lead to surface fibrillation. However, MMPs may be involved in later stages where collagen degradation is prevalent. The role that ADAMs play is still unknown, although they are postulated to play an important role in shedding or activation of different classes of matrix proteases. Furthermore, we have observed changes in the patterns of cartilage expression in fresh tissue and model culture systems. This work has indicated clearly that there are several different classes of enzyme that can be targeted for innovative therapies which could slow or halt cartilage destruction in arthritis.
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PMID:Mechanisms of proteoglycan metabolism that lead to cartilage destruction in the pathogenesis of arthritis. 1297 42

Recent studies indicated that the nicotinamide dinucleotide phosphate oxidase (NADPH) oxidase-derived oxygen radicals plays a deleterious role in arthritis. To study this in more detail, gonarthritis was induced in NADPH oxidase-deficient mice. Mice received an intraarticular injection of either zymosan, to elicit an irritant-induced inflammation, or poly-L-lysine coupled lysozyme, to evoke an immune-complex mediated inflammation in passively immunized mice. In contrast to wild-type mice, arthritis elicited in both p47phox(-/-) and gp91(-/-) mice showed more severe joint inflammation, which developed into a granulomatous synovitis. Treatment with either Zileuton or cobra venom factor showed that the chemokines LTB4 and complement C3 were not the driving force behind the aggravated inflammation in these mice. Arthritic NADPH oxidase-deficient mice showed irreversible cartilage damage as judged by the enhanced aggrecan VDIPEN expression, and chondrocyte death. Furthermore, only in the absence of NADPH oxidase-derived oxygen radicals, the arthritic joints showed osteoclast-like cells, tartrate-resistant acid phosphatase (TRAP)-positive/multinucleated cells, extensive bone erosion, and osteolysis. The enhanced synovial gene expression of tumor necrosis factor-alpha, interleukin-1alpha, matrix metalloproteinase (MMP)-3, MMP-9 and receptor activator of NF-kappaB ligand (RANKL) might contribute to the aggravated arthritis in the NADPH oxidase-deficient mice. This showed that the involvement of NADPH oxidase in arthritis is probably far more complex and that oxygen radicals might also be important in controlling disease severity, and reducing joint inflammation and connective tissue damage.
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PMID:Deficiency of NADPH oxidase components p47phox and gp91phox caused granulomatous synovitis and increased connective tissue destruction in experimental arthritis models. 1450 59


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