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)

1. The amounts of latent and active collagenase and of collagenase inhibitor (TIMP) produced by two normal, three rheumatoid and two osteoarthritic synovial specimens in culture were compared. Normal synovia produced TIMP, but little latent enzyme. Rheumatoid synovia produced higher levels of total collagenase activity than normal, of which up to 50% in one sample was present in the medium in an active form, whereas no specific inhibitory activity due to TIMP was detectable. The amounts of collagenase and TIMP produced by osteoarthritic synovia were more variable and appeared to reflect the degree of inflammation in the tissue at the time of initiating the cultures. 2. Concentrations of TIMP were usually higher in the culture media of normal, rheumatoid and osteoarthritic synovia when hydrocortisone was present. Correspondingly, amounts of total collagenase were reduced. Production of prostaglandin E (PGE) were inhibited in a dose-dependent manner by hydrocortisone. 3. Indomethacin had no consistent effect on the production of TIMP by rheumatoid and osteoarthritic synovia, although it tended to depress production of collagenase. The production of TIMP by normal synovia was depressed by indomethacin. No PGE was detectable in the media when indomethacin was present. 4. These results are consistent with those from previous animal studies, and we conclude that the balance between production of collagenase and TIMP may be critical in determining the extent of the destructive processes in arthritis. The ability of hydrocortisone to suppress production of collagenase and to increase free TIMP concentration, as well as to inhibit synthesis of prostaglandin, may explain in part how the drug exerts its therapeutic effects in patients with rheumatoid arthritis.
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PMID:Production of collagenase and inhibitor (TIMP) by normal, rheumatoid and osteoarthritic synovium in vitro: effects of hydrocortisone and indomethacin. 627 49

Destruction of joint structures in arthritis may result from failure of normal mechanisms controlling interactions among cells of the various tissues of the joint. Normal synovium in culture produces less prostaglandin E (PGE) and collagenase than rheumatoid. When rheumatoid synovium is dissociated into cells, the adherent cell cultures rapidly lose the ability to synthesize large amounts of PGE and collagenase and become indistinguishable from normal synovial cells. A mononuclear cell factor (MCF) derived from supernatant media of cultured human blood mononuclear cells and a 'synovial factor(s)' (SF) from cultures of either normal or rheumatoid synovial fragments both stimulate production of PGE and proteinase by cells derived from human synovium, cartilage and bone. The activities of factors which may be present in these stimulatory supernatants may be unmasked in vitro when they are removed from the normal control present in vivo. Normal synovium probably contains cells which, with the appropriate stimulus, may be recruited to participate in joint tissue degradation. Normal connective tissue turnover may also be controlled by a neutral metallo-proteinase inhibitor (TIMP), which is produced in considerable amounts by normal synovium, but which cannot be detected in cultures of rheumatoid synovium. While corticosteroids inhibit the production and action of MCF and SF, they stimulate production of TIMP by normal or rheumatoid synovial tissue in vitro and may contribute to the endogenous control mechanisms. PGE may also have a modulatory role in these cellular interactions.
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PMID:Messenger function of prostaglandins in cell to cell interactions and control of proteinase activity in the rheumatoid joint. 628 64

Using a rabbit model arthritis we have investigated the ability of dexamethasone to alter the production of collagenase and the specific metallo-proteinase inhibitor TIMP by explants of synovium and cartilage in vitro. The patterns of collagenase and TIMP production by untreated explants from arthritic joint tissues in culture were similar to those described previously [1, 2]. Dexamethasone dramatically altered the patterns of production of collagenase and TIMP. At a dose of 10 nM, or above, the patterns of production by treated synovium resembled those of normal rabbit synovium: collagenase production was suppressed and TIMP increased compared with untreated arthritic synovium. The levels of latent collagenase in cartilage also fell with increasing doses of dexamethasone and TIMP levels were higher, although normal levels were not reached. These experiments have been conducted as a prelude to testing the effects of various anti-rheumatic drugs in vivo, and attempting to correlate changes in clinical parameters with the subsequent production of collagenase and TIMP in vitro. The data are discussed in relation to the therapeutic use of corticosteroids and to their mode of action on joint tissues.
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PMID:The effects of dexamethasone in vitro on the production of collagenase and inhibitor by synovial and cartilage explants from the joints of rabbits with a proliferative arthritis. 628 61

Collagenase and stromelysin have a premier role in the irreversible degradation of the extracellular matrix seen in rheumatic disease. It is therefore no surprise that considerable attention has been devoted to developing strategies to reduce their levels in diseased joints. Most efforts have focused on inhibiting the activity of the enzymes, either by increasing the concentration of natural inhibitors such as the TIMPs or by introducing into the joint synthetic compounds that will complex with the enzymes and inactivate them. There have also been studies directed at inhibiting enzyme synthesis. These preclinical studies have been carried out in cell-free and/or cell culture systems and in animal models. Despite promising preclinical data, there have been no stunning successes in the clinical arena. The reasons for this are several. In part, they are rooted in the technical difficulties associated with designing inhibitors of enzyme activity that are of high affinity, and then delivering them to the affected joints while still maintaining specificity and efficacy. The complicated structure of the proteoglycan and collagen that comprise articular cartilage, along with the biochemistry of inflamed synovial tissue, only compound the difficulties. In addition to these technical problems, the lack of fundamental knowledge about the biochemistry and molecular biology of the enzymes has handicapped our efforts. We are just resolving the crystal structure of the metalloproteinases (108) and beginning to understand the mechanisms controlling gene expression (67, 68, 70-72). These advances represent significant achievements in metalloproteinase enzymology and biology and should form the scientific basis for a new generation of effective therapies. For example, knowledge of the active site as derived from the crystal structure of the enzymes may facilitate the development of tightly-binding specific inhibitors which function well in vivo. Similarly, based on our current understanding of mechanisms controlling the regulation of both the TIMP genes and the MMP genes, we are beginning to elucidate how to turn these genes on or off, and hopefully, to modulate disease accordingly. Indeed, although some studies are still at a preclinical level, these possible approaches are becoming a reality (109). Arthritic diseases in general, and rheumatoid arthritis in particular, represent a complicated multifaceted set of clinical disorders. The clinical symptoms and pathologic features result from a cascade of biologic pathways that involve acute and chronic inflammation, the immune response, and metalloproteinase biochemistry.(ABSTRACT TRUNCATED AT 400 WORDS)
Arthritis Rheum 1994 Aug
PMID:Using inhibitors of metalloproteinases to treat arthritis. Easier said than done? 771 15

Mouse TIMP-1, one of the tissue inhibitors of metalloproteinases important in regulating turnover of extracellular matrix in both normal and pathological tissues, was previously expressed in E. coli in an inactive, nonglycosylated state that required refolding to become functional. Due to the difficulty of renaturation, an alternative to the prokaryotic expression system was sought. Since we are interested in studying the pharmacodynamics and pharmacokinetics of TIMP locally administered by controlled delivery to mice with experimentally induced arthritis, we also needed an efficient way of producing active TIMP in large quantities. Using the pBlueBacII transfer vector, we generated a recombinant baculovirus that in Sf9 cells could express glycosylated mouse TIMP-1 to about 3 mg of active protein/liter conditioned medium.
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PMID:Expression and secretion of active mouse TIMP-1 using a baculovirus expression vector. 820 45

Residues 1-127 of human TIMP-2 (N-TIMP-2), comprising three of the disulfide-bonded loops of the TIMP-2 molecule, is a discrete protein domain that folds independently of the C-terminal domain. This domain has been shown to be necessary and sufficient for metalloproteinase inhibition and contains the major sites of interaction with the catalytic N-terminal domain of active matrix metalloproteinases (MMPs). Residues identified as being involved in the interaction with MMPs by NMR chemical shift perturbation studies and TIMP/MMP crystal structures have been altered by site-directed mutagenesis. We show, by measurement of association rates and apparent inhibition constants, that the specificity of these N-TIMP-2 mutants for a range of MMPs can be altered by single site mutations in either the TIMP "ridge" (Cys1-Cys3 and Ser68-Cys72) or the flexible AB loop (Ser31-Ile41). This work demonstrates that it is possible to engineer TIMPs with altered specificity and suggests that this form of protein engineering may be useful in the treatment of diseases such as arthritis and cancer where the selective inhibition of key MMPs is desirable.
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PMID:The specificity of TIMP-2 for matrix metalloproteinases can be modified by single amino acid mutations. 1040 Jun 63

Elevated MMP activities are implicated in tissue degradation in, e.g., arthritis and cancer. The present study was designed to measure MMP enzyme activity in plasma. Free active MMP is unlikely to be present in plasma: upon entering the circulation, active MMP is expected to be captured by the proteinase inhibitor alpha 2-macroglobulin (alpha 2M). Reconstituted MMP-13/alpha 2M complex was unable to degrade collagen (MW 300,000) in contrast to the low-molecular-weight fluorogenic substrate (MW < 1500). Limited access of high-MW substrates to the active site of MMPs captured by alpha 2M presents the most likely explanation. Consistently, the high-MW inhibitor TIMP (MW approximately 28,000) was unable to inhibit MMP/alpha 2M enzyme activity, whereas the low-MW inhibitor BB94 (MW approximately 500) effectively suppressed enzyme activity. By using fluorogenic substrates with Dabcyl/Fluorescein as quencher/fluorophore combin-ation, sensitive MMP-activity assays in plasma were achieved. Spiking of active MMP-13 and MMP-13/alpha 2M complex, and inhibitor studies with TIMP-1 and BB94, indicated that active MMPs are efficiently captured by alpha 2M in plasma. MMP activity was even detected in control plasma, and was significantly increased in plasma from rheumatoid arthritis patients.
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PMID:Fluorogenic MMP activity assay for plasma including MMPs complexed to alpha 2-macroglobulin. 1041 27

The matrix metalloproteinases (MMPs) play a key role in the normal physiology of connective tissue during development, morphogenesis and wound healing, but their unregulated activity has been implicated in numerous disease processes including arthritis, tumor cell metastasis and atherosclerosis. An important mechanism for the regulation of the activity of MMPs is via binding to a family of homologous proteins referred to as the tissue inhibitors of metalloproteinases (TIMP-1 to TIMP-4). The two-domain TIMPs are of relatively small size, yet have been found to exhibit several biochemical and physiological/biological functions, including inhibition of active MMPs, proMMP activation, cell growth promotion, matrix binding, inhibition of angiogenesis and the induction of apoptosis. Mutations in TIMP-3 are the cause of Sorsby's fundus dystrophy in humans, a disease that results in early onset macular degeneration. This review highlights the evolution of TIMPs, the recently elucidated high-resolution structures of TIMPs and their complexes with metalloproteinases, and the results of mutational and other studies of structure-function relationships that have enhanced our understanding of the mechanism and specificity of the inhibition of MMPs by TIMPs. Several intriguing questions, such as the basis of the multiple biological functions of TIMPs, the kinetics of TIMP-MMP interactions and the differences in binding in some TIMP-metalloproteinase pairs are discussed which, though not fully resolved, serve to illustrate the kind of issues that are important for a full understanding of the interactions between families of molecules.
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PMID:Tissue inhibitors of metalloproteinases: evolution, structure and function. 1070 63

Total hip arthroplasty (THA) has provided dramatic pain relief and improvement in function for millions of patients with end-stage arthritis; however, periprosthetic osteolysis following THA has become increasingly recognized as a major clinical problem in both cemented and cementless reconstructions. An aggressive granulomatous tissue (interfacial membrane) consisting predominantly of fibroblasts, aggregates of macrophages, and foreign body giant cells develops at the interface of bone/prostheses or bone/cement. It is believed that particulate wear debris from prosthetic materials and/or bone cement are phagocytized by histiocytic cells of interfacial membrane and then these cells produce inflammatory mediators and proteolytic enzymes to provoke a cascade of osteolytic events. In this paper, we studied in vitro responsiveness of various cell types to particulate wear debris. Although titanium and titanium alloys demonstrate excellent biocompatibility in bulk from, titanium in particulate form can provoke a variety of cellular responses. We have found that small-sized Ti particles of phagocytosable size, a commonly encountered particle species in the periprosthetic tissues of failed THAs, stimulate macrophages to secrete various mediators of bone resorption (prostaglandin E(2), interleukin-1, interleukin-6, and tumor necrosis factor-alpha from macrophages and cause bone resorption in organ culture. In addition, we have shown that phagocytosable titanium particles stimulate fibroblasts to up-regulate the expression of matrix metalloproteinases (stromelysin and collagenase) without a substantial effect on the tissue inhibitor of these enzymes (TIMP). Titanium particulates also have a suppressive effect on procollagen synthesis by osteoblast-like cell line. Thus, titanium particulates have the capacity to stimulate bone resorption and inhibit bone matrix formation. In this series of experiments, we have also shown in vitro inhibitory effect of certain pharmaceutical components (indomethacin, misoprostol) upon bone resorption in organ culture, which may indicate a potential therapeutic intervention to prevent or treat particulate-induced pathological bone resorption in total joint arthroplasties.
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PMID:Particulate-Induced, Prostaglandin- and Cytokine-Mediated Bone Resorption in an Experimental System and in Failed Joint Replacements. 1185 95

Matrix metalloproteinases (MMPs), also called matrixins, are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are precisely regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in diseases such as cancer, fibrosis, arthritis and atherosclerosis. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. 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 aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review describes the members of the MMP and TIMP families and discusses the structure, function and regulation of MMP activity; finally, pharmacological approaches to MMP inhibition are highlighted.
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PMID:Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives. 1506 49


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