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)

Breakdown of triple-helical interstitial collagens is essential in embryonic development, organ morphogenesis and tissue remodelling and repair. Aberrant collagenolysis may result in diseases such as arthritis, cancer, atherosclerosis, aneurysm and fibrosis. In vertebrates, it is initiated by collagenases belonging to the matrix metalloproteinase (MMP) family. The three-dimensional structure of a prototypic collagenase, MMP-1, indicates that the substrate-binding site of the enzyme is too narrow to accommodate triple-helical collagen. Here we report that collagenases bind and locally unwind the triple-helical structure before hydrolyzing the peptide bonds. Mutation of the catalytically essential residue Glu200 of MMP-1 to Ala resulted in a catalytically inactive enzyme, but in its presence noncollagenolytic proteinases digested collagen into typical 3/4 and 1/4 fragments, indicating that the MMP-1(E200A) mutant unwinds the triple-helical collagen. The study also shows that MMP-1 preferentially interacts with the alpha2(I) chain of type I collagen and cleaves the three alpha chains in succession. Our results throw light on the basic mechanisms that control a wide range of biological and pathological processes associated with tissue remodelling.
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PMID:Collagenase unwinds triple-helical collagen prior to peptide bond hydrolysis. 1525 88

Gelatinase B/matrix metalloproteinase-9 (MMP-9) is an inflammatory mediator and effector. Considerable amounts of gelatinase B are released by neutrophils in the synovial cavity of patients with rheumatoid arthritis, and gelatinase B-deficient mice are resistant against antibody-induced arthritis. Native human collagen type II is susceptible to cleavage by various collagenases (MMP-1, MMP-8, and MMP-13), which cleave at a single position in the triple helix. Although the triple-helical structure may persist after this single cleavage, we show that gelatinase B degrades the resulting fragments into small remnant peptides. These were identified by mass spectrometry and Edman degradation. Localization of 31 cleavage sites shows that the immunodominant epitopes remain intact after cleavage and may become available, processed as antigens and presented in MHC-II molecules. Furthermore, most post-translational modifications were identified on the fragments, including nine glycosylation sites. In particular, it is shown for the first time by structural analysis that in natural human collagen II, lysines in the main immunodominant epitope are modified by partial hydroxylation and partial glycosylation. Determination of T-cell reactivity against such fragments indicates that, besides the two known main immunodominant epitopes, other glyco-epitopes may be present in collagen II. This reinforces the role of glycopeptide antigens in autoimmunity.
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PMID:Generation of glycosylated remnant epitopes from human collagen type II by gelatinase B. 1531 42

This investigation was planned to assess the therapeutic efficacy of glucuronoxylomannan (GXM) in collagen-induced arthritis (CIA). GXM was isolated from culture filtrate of Cryptococcus neoformans var. gattii, serotype C. CIA was induced by the immunization of Dark Agouti rats with bovine type II collagen in incomplete Freund's adjuvant. GXM solution at two doses, 25 and 50 mg/kg, was administered intraperitoneally. Onset of i.p. injections of GXM to prevention and treatment groups was days 0 and 10 postimmunization, respectively. The WEHI-164 cell line was used for assaying tolerability, matrix metalloproteinase type 2 (MMP-2) activity and apoptosis. MMP-2 activity was assessed using zymography. For assessment of apoptosis, the terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labelling method was used. The results of this experiment showed that the treatment of CIA with GXM at a dose of 50 mg/kg could suppress disease development both prophylactically and therapeutically. This beneficial effect of GXM was associated with a significant decrease in the anti-CII antibody response compared with untreated rats. Moreover, GXM therapy could diminish MMP-2 activity, but it had no notable effect on apoptosis. GXM also showed a high tolerability compared with certain steroidal and non-steroidal anti-inflammatory drugs. We conclude that GXM suppresses the development of disease in CIA and it could be recommended as a new immunosuppressive and anti-inflammatory agent for further investigations.
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PMID:Tolerability and anti-inflammatory effects of glucuronoxylomannan in collagen-induced arthritis. 1532 Aug 78

Intra-articular administration of hyaluronate (HA) is an effective treatment for arthritis. HA injections can decrease not only joint pain but also synovial effusion, although little is known concerning the mechanism of HA action. The aim of this study was to investigate the role of HA on the expression and production of matrix metalloproteinase (MMP) in synovial cells activated by interleukin (IL)-1beta in order to achieve a better understanding of exogenous HA function in the extracellular matrix degradation in arthritic joints. Human synovial cells were incubated with HA (0.1-1000 microg/ml) and/or IL-1beta (1 ng/ml). The expression of MMP-1 and MMP-3 mRNAs was analyzed by quantitative real-time polymerase chain reaction. The protein levels of MMP-1 and MMP-3 in cultured media were measured by immunoblotting. Expression of MMP-1 and MMP-3 mRNAs was induced by IL-1beta. The IL-1beta-mediated induction of MMP-1 mRNA expression was attenuated by 10 microg/ml HA (p=0.026) and that of MMP-3 mRNA was strongly down-regulated in the presence of 10 or 1000 microg/ml HA (p<0.001). The increased protein levels of MMP-1 and MMP-3 were also reduced by 1000 microg/ml HA. These data suggest that HA inhibits the expression and production of MMP-1 and MMP-3 in IL-1beta-stimulated human synovial cells. We therefore prepose that intra-articular HA may rescue inflamed joints from bone and cartilage destruction by reducing the production of MMP-1 and MMP-3.
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PMID:Hyaluronate inhibits the interleukin-1beta-induced expression of matrix metalloproteinase (MMP)-1 and MMP-3 in human synovial cells. 1538 90

Matrix metalloproteinases are a family of endopeptidases that collectively degrade all components of the extracellular matrix at neutral pH. During the progression of arthritis, MMPs mediate the degradation of cartilage, which consists largely of Type II collagen fibrils and proteoglycans. The collagenases, a subgroup of MMPs, have the singular ability to cleave intact collagens and may provide a rate-limiting step in cartilage destruction. In arthritic lesions, collagenase-1 (matrix metalloproteinase-1) and collagenase-3 (matrix metalloproteinase-13) mediate the irreversible destruction of cartilage, suggesting that these enzymes are therapeutic targets. We describe the role of metalloproteinases in the destruction of connective tissues in arthritis and the treatment strategies that have been developed to block matrix metalloproteinases in an attempt to prevent this destruction. We also discuss novel compounds that may selectively inhibit these cartilage-degrading enzymes, providing opportunities to develop new therapeutic approaches.
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PMID:Novel inhibitors of matrix metalloproteinase gene expression as potential therapies for arthritis. 1548 55

We hypothesized that more gelatinases appear in effusions of septic arthritis than aseptic arthritis. This study examined the laboratory variables of inflammation and the levels of gelatinase A and B (matrix metalloproteinases-2 and -9) in 75 effusions from the knees of 37 patients with inflammatory arthritis and compared them with effusions of septic and aseptic arthritis. Gelatin zymography revealed that the levels of the latent matrix metalloproteinase-9 were higher in 24 effusions of septic arthritis than in 51 effusions of aseptic arthritis. The latent matrix metalloproteinase-9 levels of septic arthritis also correlated with the neutrophil counts in effusions. Significantly more activated matrix metalloproteinases-2 and -9 appeared in effusions of septic arthritis in native and replaced knees than in effusions of aseptic arthritis. A high matrix metalloproteinase-9 level and the appearance of activated matrix metalloproteinases-2 and -9 may distinguish septic from aseptic arthritis, even in cases with a low neutrophil count in the replaced knee. Joint aspiration may not only reduce the bacteria counts, endotoxins, and proinflammatory cytokines, but also decrease the amount of matrix metalloproteinases in effusions that attack the extracellular matrix of native and artificial joints.
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PMID:Clinical significance of gelatinases in septic arthritis of native and replaced knees. 1555 55

Osteoarthritis (OA) is the most common form of arthritis that occurs in humans. Despite its prevalence, the pathogenesis of OA is not fully understood. Intraarticular basic calcium phosphate (BCP) (an inclusive term for partially carbonate-substituted hydroxyapatite, octacalcium phosphate and tricalcium phosphate) crystals are implicated in OA and are associated with severe degenerative arthritis characterized by marked synovial hyperplasia, aggravated joint degeneration and large joint effusions. Their pathogenicity relates, at least in part, to their ability to stimulate cellular mitogenesis in a number of cell types including macrophages, porcine articular chondrocytes (PAC) and human fibroblasts (HF) and induce prostaglandin, cytokine and matrix metalloproteinase synthesis and secretion in HF and PAC. Identification of BCP crystals in OA joints remains problematic because of the lack of a simple and reliable analytic procedure. There is currently no drug available that prevents the formation or modifies the biological effects of BCP crystals. This review highlights the recent advances in our knowledge of BCP crystal deposition diseases and discusses the potential therapeutic strategies for BCP crystal-associated OA.
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PMID:Basic calcium phosphate crystals as a unique therapeutic target in osteoarthritis. 1557 90

The zinc-dependent enzymes known as matrix metalloproteinases (MMPs) are medicinal targets due to the activity of these enzymes associated with diseases such as cancer, heart disease, and arthritis. The development of most MMP inhibitors (MPIs) has followed a basic design formula: a peptidomimetic backbone is attached to a zinc-binding group (ZBG). MPI backbones have varied enormously and improved with increased knowledge of MMP structure and function while hydroxamic acids have been used as the ZBG in most inhibitors. The problems associated with hydroxamic acid and other current ZBGs have been identified; the incorporation of more potent and selective ZBGs for the active site zinc(II) ion is necessary to improve the development of second-generation inhibitors. Herein, we highlight ZBGs that have been proposed as alternatives to hydroxamic acids. In addition, techniques used to identify new ZBGs are also discussed. New insights from a bioinorganic approach using model complexes of the MMP active site are presented as tools in examining the mode of binding for various known and novel ZBGs. Novel computational methods are highlighted that allow for modeling the drug-protein interactions with non-hydroxamate inhibitors of MMPs. We suggest that significant efforts to augment ZBGs combined with the available information on inhibitor backbone design will accelerate the discovery of improved MPIs. Newly devised drug design methods will help to realize this proposal.
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PMID:A bioinorganic perspective on matrix metalloproteinase inhibition. 1557 96

Vertebrate collagenases, members of the matrix metalloproteinase (MMP) family, initiate interstitial fibrillar collagen breakdown. It is essential in many biological processes, and unbalanced collagenolysis is associated with diseases such as arthritis, cancer, atherosclerosis, aneurysm, and fibrosis. These metalloproteinases are secreted from the cell as inactive precursors, procollagenases (proMMPs). To gain insights into the structural basis of their activation mechanisms and collagen binding, we have crystallized recombinant human proMMP-1 and determined its structure to 2.2 A resolution. The catalytic metalloproteinase domain and the C-terminal hemopexin (Hpx) domain show the classical MMP-fold, but the structure has revealed new features in surface loops and domain interaction. The prodomain is formed by a three-helix bundle and gives insight into the stepwise activation mechanism of proMMP-1. The prodomain interacts with the Hpx domain, which affects the position of the Hpx domain relative to the catalytic domain. This interaction results in a "closed" configuration of proMMP-1 in contrast to the "open" configuration observed previously for the structure of active MMP-1. This is the first evidence of mobility of the Hpx domain in relation to the catalytic domain, providing an important clue toward the understanding of the collagenase-collagen interaction and subsequent collagenolysis.
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PMID:X-ray structure of human proMMP-1: new insights into procollagenase activation and collagen binding. 1561 Oct 40

A hallmark of rheumatoid- and osteoarthritis (OA) is proinflammatory cytokine-induced degeneration of cartilage collagen and aggrecan by matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS). Effects of the Chinese herb, Tripterygium wilfordii Hook F (TWHF), on cartilage and its anti-arthritic mechanisms are poorly understood. This study investigated the impact of a purified derivative of TWHF, PG490 (triptolide), on cytokine-stimulated expression of the major cartilage damaging proteases, MMP-3, MMP-13, and ADAMTS4. PG490 inhibited cytokine-induced MMP-3, MMP-13 gene expression in primary human OA chondrocytes, bovine chondrocytes, SW1353 cells, and human synovial fibroblasts. Triptolide was effective at low doses and blocked the induction of MMP-13 by IL-1 in human and bovine cartilage explants. TWHF extract and PG490 also suppressed IL-1-, IL-17-, and TNF-alpha-induced expression of ADAMTS-4 in bovine chondrocytes. Thus, PG490 could protect cartilage from MMP- and aggrecanase-driven breakdown. The immunosuppressive, cartilage protective, and anti-inflammatory properties could make PG490 potentially a new therapeutic agent for arthritis.
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PMID:Triptolide suppresses proinflammatory cytokine-induced matrix metalloproteinase and aggrecanase-1 gene expression in chondrocytes. 1562 65


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