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)

Gelatin degrading matrix metalloproteinases in synovial fluid from 21 patients with inflammatory arthritis were shown to consist of two distinct gene products, 92 and 70 kDa gelatinases. The gelatinolytic activity of 92 kDa enzyme, which is released from stimulated neutrophils, was positively correlated to neutrophil count in the fluid. By contrast, 70 kDa molecule did not correlate with neutrophil cell count. Purification of these enzymes revealed they could degrade type XI collagen, a cartilage component resistant to interstitial collagenase. The elevated levels of 92 kDa gelatinase in rheumatoid arthritis samples compared to osteoarthritis suggest a role of this enzyme in cartilage destruction.
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PMID:Characterization of type V collagenase (gelatinase) in synovial fluid of patients with inflammatory arthritis. 131 54

There are two types of collagenases, products of two distinct genes, called MMP-1 (matrix metalloproteinase 1 or "fibroblast-type collagenase") and MMP-8 ("neutrophil collagenase"). In synovial fluid, MMP-8 is stored as latent proenzyme in polymorphonuclear neutrophils. MMP-8 is activated by hypochlorous acid produced by myeloperoxidase from hydrogen peroxide and chloride ion and by the hydroxyl radical produced in Haber Weiss reaction fed by superoxide produced by, eg, NADPH (reduced nicotinamide adenine dinucleotide) oxidase and xanthine oxidase. In addition to activation upon secretion, oxidatively modified MMP-8 is susceptible to a subsequent proteolytic attack and activation by cathepsin G. The authors suggest that activation of neutrophil-derived MMP-8 involves oxidative, nonproteolytic activation upon secretion and a more slowly progressive proteolytic activation by cathepsin G (or chymases and tryptases), and that these oxidative and proteolytic activation mechanisms act in concert. In contrast to MMP-8, MMP-1 is synthesized de novo and secreted immediately after synthesis by fibroblasts, macrophages, and some epithelial cells. Human rheumatoid synovial tissue contains mainly fibroblast-type MMP-1 collagenase as assessed by collagenase extracted from synovial tissue and by MMP-1 and MMP-8 immunostaining. It is suggested that in vivo, MMP-1 in synovitis tissue is activated by a plasminogen activator/plasminogen/prostromelysin (alternatively tryptases)/proMMP-1 cascade. In conclusion, MMP-8 and MMP-1 show type-specific compartmentalization and modes of activation in rheumatoid synovial fluid and tissue.
Semin Arthritis Rheum 1992 Aug
PMID:Collagenase in synovitis of rheumatoid arthritis. 141 81

Interleukin-1 (IL-1) may contribute to tissue destruction in rheumatoid arthritis, in part, by inducing messenger RNA (mRNA) that encodes interstitial collagenase. In human synovial fibroblasts in vitro, IL-1 induced collagenase mRNA accumulation 6 hours after being added to the cells. High levels of mRNA remained present for at least 48 hours after treatment. The rate of transcription of collagenase in isolated nuclei peaked after approximately 6 hours of treatment with IL-1 and declined thereafter, becoming nearly undetectable by 24 hours. The persistence of mRNA, in view of the transient peak of transcription, suggested that collagenase mRNA was stable in synovial fibroblasts. The half-life of collagenase mRNA after the synoviocytes were treated with actinomycin D was approximately 27 hours, both in the presence and in the absence of IL-1. It has been noted that induction of the expression of collagenase by phorbol esters requires fos protein synthesis and is mediated through a tetradecanoyl phorbol acetate response element in the 5'-flanking region of the gene. However, we found that cycloheximide, when added to synovial fibroblast cultures up to 6 hours after treatment with IL-1, inhibited the expression of collagenase mRNA. These results suggest that fos alone is unlikely to be sufficient for collagenase expression, and that additional factors, or alternative pathways, are involved in the induction of collagenase by IL-1.
Arthritis Rheum 1989 Dec
PMID:Regulation of human synovial fibroblast collagenase messenger RNA by interleukin-1. 255 44

Tumor growth is dependent upon angiogenesis. There is an intense search for pharmacological inhibitors of angiogenesis as a novel approach to treat angiogenic diseases, e.g., arthritis, diabetic retinopathy or cancer. A series of compounds, originally studied as potential protein kinase C inhibitors, included the diaminoanthraquinone NSC 639366 (1-[[3-(diethylamino)-2-hydroxypropyl]amino]-4-[(2,3- epoxypropyl)amino]-9,10-anthracenedione fumaric acid salt) (SPC-100097), was found to reversibly inhibit bovine endothelial cell growth with an IC50 that ranged between 1 and 4 nM. NSC 639366 reversibly inhibited endothelial cell migration, particularly endothelial cells stimulated by the potent angiogenic molecule, basic fibroblast growth factor. The activity of secreted urokinase-type plasminogen activator and active interstitial collagenase, but not gelatinase, was inhibited by NSC 639366. In vivo, angiogenesis was significantly inhibited by NSC 639366 by using the chick chorioallantoic membrane or the rat corneal bioassay. Two analogs of NSC 639366 did not inhibit endothelial cell growth. These experiments introduce a novel compound that could be clinically useful against angiogenic diseases and encourage further development of compounds that inhibit the plasminogen-plasmin system known to be a key regulator of angiogenesis.
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PMID:A diaminoantraquinone inhibitor of angiogenesis. 752 34

A simple in vivo model of collagen degradation has been developed, and the effects of various agents have been tested. Type I collagen was prepared from rat skin and acetylated with either [3H]- or [14C] acetic anhydride. The radiolabelled collagen was added to sterile cotton buds and incubated at 37 degrees C to allow the collagen to form native fibrils that were firmly adsorbed to the cotton matrix. After subcutaneous implantation of the collagen-gelled cotton buds into rats, the radiolabelled collagen was progressively removed over a period of weeks by an infiltrating granuloma. Of the agents that were administered directly into the cotton buds using subcutaneously implanted osmotic mini-pumps, only the synthetic collagenase inhibitors CI-A (containing a hydroxamate moiety as a zinc ligand) and CI-C (containing a thiol moiety as a zinc ligand) were able to prevent the removal of collagen: their efficacy correlated with the level of collagenase inhibitory activity assayed in the exudate fluid sequestered within the cotton bud granuloma. Of the agents that were administered systemically, including anti-inflammatory drugs and other compounds used as therapies for arthritis, only hydrocortisone was able to inhibit the removal of radiolabelled collagen. These results suggest that, in this model, interstitial collagenase, a member of the matrix metalloproteinase family, comprised the major degradative pathway for collagen. The collagen-gelled cotton bud model is a useful test system for delineating those processes that result in collagen catabolism. In addition, the model can be used for testing agents, including those of limited or unknown systemic bioavailability, in order to discover novel therapeutic agents for preventing collagen degradation in connective tissue diseases such as arthritis.
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PMID:A simple in vivo model of collagen degradation using collagen-gelled cotton buds: the effects of collagenase inhibitors and other agents. 766 28

We studied the in vivo effect of long-term doxycycline treatment combined with NSAID on human interstitial collagenases, other matrix metalloproteinases, serine proteinases, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and lactoferrin from saliva and serum during the course of acute reactive arthritis (ReA). Collagenase activity and serine proteases (elastase-like, cathepsin G-like and trypsin-like activities) of saliva (n = 10) and gelatinase, lactoferrin and TIMP-1 of saliva (n = 10) and serum (n = 10) samples before and after 2 months doxycycline treatment, combined with NSAID, were studied by quantitative SDS-PAGE assay, ELISA assay and by spectrophotometric assay. The cellular source and molecular forms of salivary collagenase were characterized by immunoblotting using specific antisera. We found that activities of total and endogenously active interstitial collagenase reduced significantly. The salivary collagenase was found to originate from neutrophils. No fragmentation of either pro 75-kD and active 65-kD MMP-8 was detected after 2 months doxycycline treatment. However, during 2 months doxycycline and NSAID treatment no reduction of salivary and serum gelatinase, lactoferrin and TIMP-1-levels and salivary serine protease activities were detected. The in vivo inhibition of collagenase (MMP-8) activity during long-term doxycycline therapy in human saliva containing inflammatory exudate of ReA patients may contribute to the reduced tissue destruction observed in recent clinical and animal model studies in arthritides during long-term doxycycline/tetracycline treatment.
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PMID:In vivo inhibition of human neutrophil collagenase (MMP-8) activity during long-term combination therapy of doxycycline and non-steroidal anti-inflammatory drugs (NSAID) in acute reactive arthritis. 792 79

Members of the matrix metalloproteinase (MMP) family have been implicated in disease states such as arthritis, periodontal disease, and tumor cell invasion and metastasis. Stromelysin 1 (MMP-3) has a broad substrate specificity and participates in the activation of several MMP zymogens. We examined known sequences of MMP-3 cleavage sites in natural peptides and proteins and compared sequence specificities of MMP-3 and interstitial collagenase (MMP-1) in order to design fluorogenic substrates that (i) would be hydrolyzed rapidly by MMP-3, (ii) would discriminate between MMP-3 and MMP-1, and (iii) could be monitored continuously without interference from MMP amino acid residues. Designed substrates were then screened for activity toward MMP-1, gelatinase A (MMP-2), MMP-3, and gelatinase B (MMP-9). The first of these substrates, NFF-1 (Mca-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Lys-(Dnp)-Gly, where Mca is (7-methoxycoumarin-4-yl)acetyl and Dnp is 2,4-dinitrophenyl), was hydrolyzed equally well by MMP-3 and MMP-2 (kcat/Km approximately 11,000 s-1 M-1). MMP-1 had 25% of the activity of MMP-3 toward NFF-1. The second substrate, NFF-2 (Mca-Arg-Pro-Lys-Pro-Tyr-Ala-Nva-Trp-Met-Lys(Dnp)-NH2, where Nva is norvaline), was hydrolyzed 60 times more rapidly by MMP-3 (kcat/Km = 59,400 s-1 M-1) than MMP-1. Unfortunately, NFF-2 showed little discrimination between MMP-3, MMP-2 (kcat/Km = 54,000 s-1 M-1), and MMP-9 (kcat/Km = 55,300 s-1 M-1). The third substrate, NFF-3 (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH2), was hydrolyzed rapidly by MMP-3 (kcat/Km = 218,000 s-1 M-1) and very slowly by MMP-9 (kcat/Km = 10,100 s-1 M-1), but there was no significant hydrolysis by MMP-1 and MMP-2. NFF-3 is the first documented synthetic substrate hydrolyzed by only certain members of the MMP family and thus has important application for the discrimination of MMP-3 activity from that of other MMPs. Although NFF-3 was designed by assuming that substrate subsites were independent and hence free energy changes derived from single mutation experiments were additive, we found discrepancies between predicted and experimental kcat/Km values, one on the order of 2000-5000. Thus, the design of additional discriminatory MMP substrates may require approaches other than assuming additive free energy changes, such as screening synthetic libraries and consideration of secondary and tertiary structures of substrates and the enzyme.
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PMID:Design and characterization of a fluorogenic substrate selectively hydrolyzed by stromelysin 1 (matrix metalloproteinase-3). 806 13

Death from cancer results from the development of metastases or local progression of tumour. Metastasis and local progression may result from the inappropriate activity of metalloproteinases released by tumour cells or of their regulatory peptides. We have developed quantitative assays for interstitial collagenase, stromelysin 1 and tissue inhibitors of metalloproteinase (TIMP) 1 and 2, which have allowed the study of serum levels of these proteins. Sera from 40 patients with prostatic cancer, stored prior to and after 6 and 12 months' treatment with a gonadotrophin-releasing hormone agonist and an anti-androgen were analysed. Levels were compared with two control groups, comprising 21 patients with active rheumatoid arthritis and 56 age-matched hospital attenders without arthritis or cancer. Contrasting levels have been found in patients with prostatic cancer as compared with hospital controls without cancer and patients with rheumatoid arthritis. Patients with prostatic cancer had higher levels of TIMP-1 and collagenase (P = 0.0001) and lower levels of TIMP-2 (P = 0.003) than controls. Patients with metastatic cancer had significantly higher levels of collagenase than those without metastases (P = 0.02). Patients with rheumatoid arthritis had significantly higher levels of stromelysin than either controls (P = 0.002) or patients with cancer (P = 0.008). Serum tissue inhibitor of metalloproteinase 1 in combination with collagenase levels was as sensitive as prostate-specific antigen as a marker of metastatic disease. These findings provide a basis for the investigation of the role of metalloproteinases and their inhibitors in other malignancies.
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PMID:Serum metalloproteinases and their inhibitors: markers for malignant potential. 808 Jul 38

The aim of this work was to determine whether human polymorphonuclear neutrophilic interstitial collagenase (matrix metalloproteinase 8 [MMP-8]) levels are reduced during long-term doxycycline treatment in humans with reactive arthritis. Serum MMP-8 levels were reduced (mean +/- standard error of the mean, 678.9 +/- 185.6 versus 491.2 +/- 144.8 ng of MMP-8 per ml), but not statistically significantly. However, the reduction of salivary MMP-8 levels was statistically significant (3,729 +/- 1,905.3 versus 1,866 +/- 780.0 ng of MMP-8 per ml, P < 0.05). This study demonstrated that a 2-month regimen of doxycycline can reduce MMP-8 levels in serum and especially in body fluids (i.e., saliva) containing inflammatory exudates and thus may contribute to reduced tissue destruction.
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PMID:Reduction of matrix metalloproteinase 8-neutrophil collagenase levels during long-term doxycycline treatment of reactive arthritis. 819 76

Gelatinase B (MMP-9), a member of the matrix metalloproteinase family, is a zinc- and calcium-dependent endopeptidase that is known to play a role in tumor cell invasion and in destruction of cartilage in arthritis. It contains a conserved sequence. 400His-(X)3-His-(X)28-Asp-Asp-(X)2-436Gly, the function of which is under investigation. The conserved Asp-432 and Asp-433 residues were individually replaced with Gly; these substitutions reduced the gelatinolytic activity of the enzyme to 23% and 0%, respectively. Replacing Asp-433 with Glu, however, decreased the gelatinolytic activity of the enzyme by 93% and proteolytic activity of the enzyme for the Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 substrate by 79%. The wild-type and D432G and D433E, mutant enzymes had similar Km values for the synthetic substrate and similar Ki values for the competitive inhibitor, GM6001. The kcat/Km values for D432G and D433E mutant enzymes, however, were reduced by a factor of approximately 4 and their KaCa values were increased by four- and sixfold, respectively. The significance of His-400 in the activity of the enzyme was assessed by replacing this residue with Ala and Phe. Both H400A and H400F mutants were inactive toward gelatin substrate. These data demonstrate that Asp-432, Asp-433, and His-400 residues are important for the activity of gelatinase B. His-400 may act as a zinc-binding ligand similar to the His-197 in interstitial collagenase (MMP-7) and Asp-432 and Asp-433 residues are probably involved in stabilization of the active site of the enzyme. The His-400 and Asp-433 residues are conserved in all members of the MMP family. Therefore, our results are relevant to this group as a whole.
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PMID:Role of the conserved histidine and aspartic acid residues in activity and stabilization of human gelatinase B: an example of matrix metalloproteinases. 856 49


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