Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long term loosening of hip prostheses remains an important problem in orthopedics. Although various loosening mechanisms have been proposed, the exact process is still unclear. Particle disease and the pressure theory are widely known and generally accepted hypotheses to explain long term implant failure. Each proposed mechanism recognizes a local inflammatory response in which macrophages represent the main cell-type and several proinflammatory and antiinflammatory cytokines (IL-1beta, IL-6, TNFalpha, IL-10, TGFbeta), chemokines (IL-8/CXCL8, MCP-1/CCL2, RANTES/CCL5, MIP-1alpha/CCL3) and other mediators (GM-CSF, M-CSF, MMP-1, PDGF-alpha, PGE(2), IL-11) are identified. The cytokines have different functions and some are capable of stimulating bone resorption in various ways; either directly or indirectly. Even though the implant loosening is thought to be "aseptic", several studies suggested a possible role for bacteria and a bacterial biofilm in implant failure. Biofilm-derived bacteria and bacterial products might have an underestimated and potential role in the loosening process. In this article we will discuss the possible role of a bacterial biofilm and the importance of the local surrounding environment in "aseptic" loosening of hip prostheses.
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PMID:The local inflammatory environment and microorganisms in "aseptic" loosening of hip prostheses. 1809

This report evaluated systemic inflammatory and immune biomarkers in a cohort of Macaca mulatta (rhesus monkeys) maintained as a large family social unit, including an age range from <1 year to >24 years. We hypothesized that the systemic host responses would be affected by the age, gender, and clinical oral presentation of the population, each contributing to inflammatory and immune responses that would reflect chronic oral infections. The results demonstrated that the prevalence and severity of periodontitis, including missing teeth, increased significantly with age. Generally, minimal differences in clinical parameters were noted between the genders. Systemic inflammatory mediators, including acute-phase reactants, prostaglandin E(2) (PGE(2)), cytokines/chemokines, and selected matrix metalloproteinases (MMP), demonstrated significant differences among the various age groups of animals. Levels of many of these were increased with age, although PGE(2), RANTES, bactericidal permeability-inducing factor (BPI), MMP-1, and MMP-9 levels were significantly increased in the young group ( approximately 1 to 3 years old) relative to those for the older animals. We observed that in the adult and aged animals, levels of the systemic inflammatory mediators related to gingival inflammation and periodontal tissue destruction were significantly elevated. Serum antibody levels in response to a battery of periodontal pathogens were generally lower in the young animals, <50% of those in the adults, and were significantly related to aging in the cohort. The levels of antibodies, particularly those to Porphorymonas gingivalis, Fusobacterium nucleatum, and Tannerella forsythia, were most significantly elevated in animals with periodontal disease, irrespective of the age of the animal. These results provide a broad description of oral health and host responses in a large cohort of nonhuman primates from very young animals to the aged of this species. The findings afford a base of data with which to examine the ontogeny of host responses at mucosal sites, such as the gingival tissues.
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PMID:Effects of age and oral disease on systemic inflammatory and immune parameters in nonhuman primates. 1844 17

Siegesbeckia pubescens (S. pubescens) was widely used to alleviate symptoms of osteoarthritis (OA) in traditional medicine. However, the mechanism of action of S. pubescens remains unresolved. In the present study, we determined the physiological relevance of S. pubescens on cartilage protection in collagenase-induced osteoarthritis (CIA) in rabbits. The right knees of rabbits were injected intra-articularly with collagenase, and rabbits were orally administered with distilled water (vehicle), S. pubescens (100, 400 mg/kg) or celecoxib (100 mg/kg) once a day for 28 days after the initiation of the CIA. S. pubescens significantly suppressed the stiffness and global histological score including articular cartilage and synovial layer in CIA. Proteoglycan, aggrecan, and type II collagen expression was significantly increased in the rabbit knee joints of the S. pubescens-treated group. However, celecoxib had no effect on cartilage protection in CIA. The expression level of ADAMTS-4, ADAMTS-5, MMP-1, MMP-3, and MMP-13 were dose-dependently decreased in the S. pubescens-treated group. In contrast, the level of TIMP-1 dose-dependently increased. The pro-inflammatory cytokines involved in cartilage destruction, such as IL-1beta, and inflammatory mediators containing PGE(2) and NO were also inhibited in the S. pubescens-treated group. These results indicate that the cartilage protective effect of S. pubescens works through down-regulation of inflammatory mediators and aggrecanases and MMPs, while up-regulating TIMP-1 in the CIA rabbit model.
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PMID:Therapeutic effect of Siegesbeckia pubescens on cartilage protection in a rabbit collagenase-induced model of osteoarthritis. 1863 22

Microenvironment molecular cues direct T helper (Th) cell differentiation; however, Th17 fate determination is still imprecisely understood in humans. To assess the role of prostaglandin E(2) (PGE(2)) in Th expansion, we activated peripheral blood mononuclear cells by CD3 cross-linking. In the presence of exogenous PGE(2), peripheral blood mononuclear cells produced higher interleukin-17 (IL-17), C-C chemokine ligand 20 (CCL20)/macrophage inflammatory protein 3alpha (MIP-3alpha), CXC chemokine ligand 8 (CXCL8)/IL-8, and lower interferon-gamma and IL-22 levels than in control cultures. Exogenous PGE(2) and IL-23 synergized in inducing IL-17, whereas indomethacin and IL-23 blockade drastically reduced IL-17 but not interferon-gamma production. Furthermore, IL-1 but not tumor necrosis factor was absolutely required for IL-17 production. PGE(2) doubled the frequency of CD4+ T cells producing IL-17 and within the CD4+ subset enhanced C-C chemokine receptor 6 (CCR6) and CCR4 while decreasing CXC chemokine receptor 3 (CXCR3) expression. Furthermore, in CD4+ T-cell lines, the production of IL-17 segregated with the CCR6+ subset. In the presence of CCR6+ compared with CXCR3+ Th cells, monocytes/macrophages produced much higher levels of matrix metalloproteinase-1, -3, and -9 but similar levels of CXCL10 and IL-1beta. These results identify PGE(2) and IL-23 as participating in the expansion of CD4+ T cells endowed with high IL-17 production capacity, which in turn favors monocyte production of mediators important for host defense and tissue destruction.
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PMID:Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion. 1869 5

Elevated levels of PGE(2) have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA). However, the functions of PGE(2) in cartilage metabolism have not previously been studied in detail. To do so, we cultured cartilage explants, obtained from patients undergoing knee replacement surgery for advanced OA, with PGE(2) (0.1-10 muM). PGE(2) inhibited proteoglycan synthesis in a dose-dependent manner (maximum 25% inhibition (p < 0.01)). PGE(2) also induced collagen degradation, in a manner inhibitable by the matrix metalloproteinase (MMP) inhibitor ilomastat. PGE(2) inhibited spontaneous MMP-1, but augmented MMP-13 secretion by OA cartilage explant cultures. PCR analysis of OA chondrocytes treated with PGE(2) with or without IL-1 revealed that IL-1-induced MMP-13 expression was augmented by PGE(2) and significantly inhibited by the cycolooygenase 2 selective inhibitor celecoxib. Conversely, MMP-1 expression was inhibited by PGE(2), while celecoxib enhanced both spontaneous and IL-1-induced expression. IL-1 induction of aggrecanase 5 (ADAMTS-5), but not ADAMTS-4, was also enhanced by PGE(2) (10 muM) and reversed by celecoxib (2 muM). Quantitative PCR screening of nondiseased and end-stage human knee OA articular cartilage specimens revealed that the PGE(2) receptor EP4 was up-regulated in OA cartilage. Moreover, blocking the EP4 receptor (EP4 antagonist, AH23848) mimicked celecoxib by inhibiting MMP-13, ADAMST-5 expression, and proteoglycan degradation. These results suggest that PGE(2) inhibits proteoglycan synthesis and stimulates matrix degradation in OA chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for OA disease modification.
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PMID:Prostaglandin E2 exerts catabolic effects in osteoarthritis cartilage: evidence for signaling via the EP4 receptor. 1880 12

Matrix metalloproteinases (MMP) can degrade all components of pulmonary extracellular matrix. Mycobacterium tuberculosis induces production of a number of these enzymes by human macrophages, and these are implicated in the pathogenesis of pulmonary cavitation in tuberculosis. The active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], has previously been reported to inhibit secretion of MMP-9 in human monocytes (MN), but its influence on the secretion and gene expression of MMP and tissue inhibitors of MMP (TIMP) in M. tuberculosis-infected cells has not previously been investigated. We therefore determined the effects of 1alpha,25(OH)(2)D(3) on expression, secretion and activity of a number of MMP and TIMP in M. tuberculosis-infected human leucocytes; we also investigated the effect of 1alpha,25(OH)(2)D(3) on the secretion of interleukin-10 (IL-10) and prostaglandin E(2) (PGE(2)), both transcriptional regulators of MMP expression. We found that M. tuberculosis induced expression of MMP-1, MMP-7 and MMP-10 in MN and MMP-1 and MMP-10 in peripheral blood mononuclear cells (PBMC). 1alpha,25(OH)(2)D(3) significantly attenuated M. tuberculosis-induced increases in expression of MMP-7 and MMP-10, and suppressed secretion of MMP-7 by M. tuberculosis-infected PBMC. MMP-9 gene expression, secretion and activity were significantly inhibited by 1alpha,25(OH)(2)D(3) irrespective of infection. In contrast, the effects of 1alpha,25(OH)(2)D(3) on the expression of TIMP-1, TIMP-2 and TIMP-3 and secretion of TIMP-1 and TIMP-2 were small and variable. 1alpha,25(OH)(2)D(3) also induced secretion of IL-10 and PGE(2) from M. tuberculosis-infected PBMC. These findings represent a novel immunomodulatory role for 1alpha,25(OH)(2)D(3) in M. tuberculosis infection.
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PMID:1alpha,25-dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection. 1917 94

Mycobacterium tuberculosis (M. tb) must cause lung disease to spread. Matrix metalloproteinases (MMPs) degrade the extracellular matrix and are implicated in tuberculosis-driven tissue destruction. We investigated signaling pathways regulating macrophage MMP-1 and -7 in human pulmonary tuberculosis and examine the hypothesis that the antimycobacterial drug p-aminosalicylic acid acts by inhibiting such pathways. In primary human macrophages, M. tb up-regulates gene expression and secretion of MMP-1 (interstitial collagenase) and MMP-7 (matrilysin). In tuberculosis patients, immunohistochemical analysis of lung biopsies demonstrates that p38 MAPK is phosphorylated in macrophages surrounding granulomas. In vitro, M. tb drives p38 phosphorylation. p38 inhibition suppresses M. tb-dependent MMP-1 secretion by 57.8% and concurrently increases secretion of its specific inhibitor TIMP-1 by 243.7%, demonstrating that p38 activity regulates matrix degradation by macrophages. p38 signals downstream to the cyclooxygenase 2/PGE(2) pathway. p-Aminosalicyclic acid, an agent used to treat drug-resistant tuberculosis, inhibits M. tb-driven MMP-1 but not MMP-7 gene expression and secretion. PAS acts by blocking PGE(2) production without affecting M. tb growth. In summary, p-aminosalicyclic acid decreases MMP-1 activity by inhibiting a p38 MAPK-PG signaling cascade, suggesting that this pathway is a therapeutic target to reduce inflammatory tissue destruction in tuberculosis.
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PMID:Matrix metalloproteinase-1 is regulated in tuberculosis by a p38 MAPK-dependent, p-aminosalicylic acid-sensitive signaling cascade. 1938 Aug 35

The present study investigated the influence of PGE(2), E prostanoid (EP) receptors, and their signaling pathways on matrix metalloproteinase (MMP)-1 and IL-6 expression in synovial fibroblasts (SFs) from rheumatoid arthritis (RA) patients. RASFs expressed all four EP receptors, with selective induction of EP2 by TNF-alpha. TNF-alpha time-dependently increased intracellular cAMP/protein kinase A signaling (maximum, 6-12 h) and PGE(2) secretion (maximum, 24 h). PGE(2) and the EP2 agonists butaprost or ONO-AE1-259 ((16)-9-deoxy-9beta-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydro PGE(1)), in turn, induced a rapid, time-dependent (maximum, 15-30 min) increase of cAMP. Additionally, cyclooxygenase-2 inhibition by NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide) reduced the TNF-alpha-induced increase in IL-6 mRNA/protein, which was restored by stimulation with PGE(2) or EP2, EP3, and EP4 agonists. In contrast, TNF-alpha-induced MMP-1 secretion was not influenced by NS-398 and diminished by PGE(2) via EP2. Finally, 3-isobutyl-1-methylxanthine enhanced the effects of PGE(2) on MMP-1, but not on IL-6 mRNA. In conclusion, PGE(2) differentially affects TNF-alpha-induced mRNA expression of proinflammatory IL-6 and prodestructive MMP-1 regarding the usage of EP receptors and the dependency on cAMP. Although specific blockade of EP2 receptors is considered a promising therapeutic strategy in RA, opposite regulation of proinflammatory IL-6 and prodestructive MMP-1 by PGE(2) via EP2 may require more complex approaches to successfully inhibit the cyclooxygenase-1/2 cAMP axis.
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PMID:Prostaglandin E2 differentially modulates proinflammatory/prodestructive effects of TNF-alpha on synovial fibroblasts via specific E prostanoid receptors/cAMP. 1954 67

Oxidative stress may play a relevant role in synovial inflammation and subsequently on cartilage damage during osteoarthritis development. We have assessed how the antioxidant N-acetylcysteine (NAC) affects the expression of different proinflammatory and structural mediators in human stimulated osteoarthritic synoviocytes and chondrocytes. Synovial membrane and articular cartilage were obtained from the osteoarthritis knees of patients who underwent joint replacement surgery. In cells stimulated with IL-1beta (10U/mL), the effects of NAC (2mmol/L) were tested at the mean peak plasma level following oral administration of therapeutic doses and its influence on prostaglandin E2 (PGE(2)) production, cyclooxigenase-2 (COX-2) expression, nitric oxide (NO) synthesis, nuclear factor kappa B (NF-kappaB) activation, and metalloproteinase-1 (MMP-1) and metalloproteinase-13 (MMP-13) expression were evaluated. While NAC significantly diminished PGE(2) release and the expression of both COX-2 and MMP-13 protein in IL-1beta-stimulated synoviocytes, it failed to modify their production in stimulated chondrocytes. Likewise, NAC only inhibited IL-1beta-stimulated NF-kappaB activation in synoviocytes. No inhibition of IL-1beta-induced NO synthesis by chondrocytes was observed following NAC incubation, while synoviocytes did not release detectable levels of NO. NAC did not induce changes in MMP-1 protein expression in either IL-1beta-stimulated synoviocytes or chondrocytes. Thus, NAC decreases the synthesis of several catabolic mediators by osteoarthritic synoviocytes, whereas, it failed to produce the same effects in osteoarthritic chondrocytes. Our results suggest that NAC inhibits some oxygen-dependent mechanisms in synoviocytes but not in chondrocytes during osteoarthritis. Therefore, NAC might have a symptomatic effect on the synovium rather than a structural effect on the cartilage in osteoarthritis.
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PMID:Differential effects of the antioxidant n-acetylcysteine on the production of catabolic mediators in IL-1beta-stimulated human osteoarthritic synoviocytes and chondrocytes. 1976 84

Matrix metalloproteinase (MMP)-9 (gelatinase B) participates in a variety of diverse physiologic and pathologic processes. We recently characterized a cyclooxygenase-2 (COX-2)-->PGE(2)-->EP4 receptor axis that regulates macrophage MMP-9 expression. In the present studies, we determined whether MMPs, commonly found in inflamed and neoplastic tissues, regulate this prostanoid-EP receptor axis leading to enhanced MMP-9 expression. Results demonstrate that exposure of murine peritoneal macrophages and RAW264.7 macrophages to MMP-1 (collagenase-1) or MMP-3 (stromelysin-1) lead to a marked increase in COX-2 expression, PGE(2) secretion, and subsequent induction of MMP-9 expression. Proteinase-induced MMP-9 expression was blocked in macrophages preincubated with the selective COX-2 inhibitor celecoxib or transfected with COX-2 small interfering RNA (siRNA). Likewise, proteinase-induced MMP-9 was blocked in macrophages preincubated with the EP4 antagonist ONO-AE3-208 or transfected with EP4 siRNA. Exposure of macrophages to MMP-1 and MMP-3 triggered the rapid release of TNF-alpha, which was blocked by MMP inhibitors. Furthermore, both COX-2 and MMP-9 expression were inhibited in macrophages preincubated with anti-TNF-alpha IgG or transfected with TNF-alpha siRNA. Thus, proteinase-induced MMP-9 expression by macrophages is dependent on the release of TNF-alpha, induction of COX-2 expression, and PGE(2) engagement of EP4. The ability of MMP-1 and MMP-3 to regulate macrophage secretion of PGE(2) and expression of MMP-9 defines a nexus between MMPs and prostanoids that is likely to play a role in the pathogenesis of chronic inflammatory diseases and cancer. These data also suggest that this nexus is targetable utilizing anti-TNF-alpha therapies and/or selective EP4 antagonists.
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PMID:Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9: evidence for the role of TNF-alpha and cyclooxygenase-2. 1992 55


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