Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mechanical disturbance is directly implicated in the development of osteoarthritis (OA) but the precise mode for degenerative changes is still largely unknown because of the complexity of the biomechanical and biochemical milieu in the articular joint. To investigate the effects of tensile strain on articular cartilage, cyclic equibiaxial tensile strain (CTS, 0.5 Hz, 10% strain) was applied to monolayer cultures of porcine articular chondrocytes by using a Flexercell strain unit. Overproduction of proinflammatory mediators and imbalanced expression of anabolic and catabolic genes were induced. The cellular secretion of nitric oxide (NO) and prostaglandin E(2) (PGE(2)), as well as the mRNA level of cyclooxygenase-2 (COX-2) were up-regulated in response to mechanical stimuli. Additionally, CTS resulted in an initial peak of anabolic response at 3 h of stretch with respect to the expression of type II collagen and aggrecan. After 12 h of CTS, the expression for these two cartilage-specific matrix proteins fell to control levels. A distinct catabolic response developed after 24 h of stretch with an increase in matrix metalloproteinase-1 (MMP-1). Interestingly, a parallel increase in transforming growth factor (TGF) beta3 was associated with the anabolic changes while an increase in expression of TGF beta1, the predominant isoform of the TGF family, appeared at 24 h. The expression at 24 h of MMP-1, an enzyme that degrades interstitial collagens as well as other cartilage matrix proteins and TGF beta1, may signify a shift towards matrix remodeling and potentially a change in matrix composition as a consequence of continuous CTS.
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PMID:Cyclic equibiaxial tensile strain induces both anabolic and catabolic responses in articular chondrocytes. 1791 98

An in vivo rabbit animal model for the tendinopathy, epicondylitis, was used to examine the effects of repetitive load on the expression of various genes associated with matrix remodeling. Following 80 h of cumulative load, tissue from the distal and proximal regions of the flexor digitorum profundus tendon was collected. Quantitative RT-PCR was used to asses mRNA levels of collagenase-1 (MMP-1), stromelysin (MMP-3), vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF), cyclooxygenase-2 (COX-2), interleukin-1beta (IL-1beta), type III collagen (COL-III) and fibronectin (FBRN). No significant differences in expression levels were found between loaded and unloaded limbs at either region of the tendon. The findings were unexpected as the same model has already demonstrated an increase in the density of cells staining for VEGF and CTGF. Different regulatory mechanisms between mRNA and protein expression or localized changes missed due to homogenization of the tissue samples, may explain the discrepancy in findings.
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PMID:Evaluation of gene expression through qRT-PCR in cyclically loaded tendons: an in vivo model. 1792 37

The aim of this study was to clarify the anti-inflammatory mechanism of apigenin. Apigenin inhibited the collagenase activity involved in rheumatoid arthritis (RA) and suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) production in a dose dependent manner in RAW 264.7 macrophage cells. Pretreatment with apigenin also attenuated LPS-induced cyclooxygenase-2 (COX-2) expression. In addition, apigenin profoundly reduced the tumor necrosis factor-alpha (TNF-alpha)-induced adhesion of monocytes to HUVEC monolayer. Apigenin significantly suppressed the TNF-alpha-stimulated upregulation of vascular cellular adhesion molecule-1 (VCAM-1)-, intracellular adhesion molecule-1 (ICAM-1)-, and E-selectin-mRNA to the basal levels. Taken together, these results suggest that apigenin has significant anti-inflammatory activity that involves blocking NO-mediated COX-2 expression and monocyte adherence. These results further suggest that apigenin may be useful for therapeutic management of inflammatory diseases.
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PMID:Anti-inflammatory mechanisms of apigenin: inhibition of cyclooxygenase-2 expression, adhesion of monocytes to human umbilical vein endothelial cells, and expression of cellular adhesion molecules. 1803 11

Squamous cell carcinoma (SCC) of the tongue is the most common cancer in the oral cavity and has a high mortality rate. A total of 90 mobile tongue SCC samples were analysed for Bryne's malignancy scores, microvascular density, and thickness of the SCC sections. In addition, the staining pattern of cyclooxygenase-2, alphavbeta6 integrin, the laminin-5 gamma2-chain, and matrix metalloproteinases (MMPs) -2, -7, -8, -9, -20, and -28 were analysed. The expression of MMP-8 (collagenase-2) was positively associated with improved survival of the patients and the tendency was particularly prominent in females. No sufficient evidence for a correlation with the clinical outcome was found for any other immunohistological marker. To test the protective role of MMP-8 in tongue carcinogenesis, MMP-8 knockout mice were used. MMP-8 deficient female mice developed tongue SCCs at a significantly higher incidence than wild-type mice exposed to carcinogen 4-Nitroquinoline-N-oxide. Consistently, oestrogen-induced MMP-8 expression in cultured HSC-3 tongue carcinoma cells, and MMP-8 cleaved oestrogen receptor (ER) alpha and beta. According to these data, we propose that, contrary to the role of most proteases produced by human carcinomas, MMP-8 has a protective, probably oestrogen-related role in the growth of mobile tongue SCCs.
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PMID:Collagenase-2 (matrix metalloproteinase-8) plays a protective role in tongue cancer. 1825 13

Cancer-related mortality is caused in a large part by the metastasis of primary tumor. Each cancer has a particular way of spreading cancerous cells. Recently, genetic and pharmacological analysis identified the set of genes, such as epidermal growth factor receptor ligand epiregulin (EREG), cyclooxygenase-2 (COX2) and matrix metalloproteinases 1 and 2 (MMP-1 and MMP-2) that have been found to be associated with metastasis of breast cancer to lung. Inhibition of EGFR and COX2 could minimize lung metastasis of breast cancer in a clinical setting. In this review, we summarized the current knowledge on EREG, COX2, MMP-1 and MMP-2 in tumor development and metastasis.
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PMID:Genes controlling spread of breast cancer to lung "gang of 4". 1856 69

Adipose tissue-derived mesenchymal stem cells (AD-MSCs), which can differentiate into several lineages, have immunomodulatory properties similar to those of bone marrow-derived MSCs. However, the specific mechanism by which the immunomodulatory effect of MSCs occurs is not clear. In this study, we isolated canine AD-MSCs (cAD-MSCs) and induced their development into adipocyte, osteocyte, and neuron-like cells. We then investigated their phenotype and cytokine expression to determine whether they were able to exert an immunomodulatory effect and what the underlying mechanisms of this effect were. cAD-MSCs expressed CD44, CD90, and MHC class I and were also partially positive for the expression of CD34; however, they did not express CD14 and CD45. In addition, they expressed the mRNA of transforming growth factor beta (TGF-beta), IL-6, IL-8, CCL2, CCL5, vascular endothelial growth factor, hepatocyte growth factor (HGF), tissue inhibitor metalloproteinase-1/2, and cyclooxygenase-2 but not that of IL-10. Further, leukocyte proliferation induced by mitogens was suppressed when they were cocultured with irradiated cAD-MSCs, as well as with culture supernatants of cAD-MSCs alone. Moreover, TNF-alpha production significantly decreased, whereas TGF-beta, IL-6, and interferon-gamma production significantly increased in cAD-MSCs that were cocultured with leukocytes. Finally, immonomodulatory factors of MSCs, such as TGF-beta, HGF, prostaglandin E2 (PGE2), and indoleamine 2, 3 dioxygenase (IDO), increased significantly in cAD-MSCs that were cocultured with leukocytes; however, the production of PGE2 and IDO showed different kinetics, and leukocyte proliferation was effectively restored by PGE2 and IDO inhibitors. Taken together, these results indicate that the immunomodulatory effects of cAD-MSCs are associated with soluble factors (TGF-beta, HGF, PGE2, and IDO). Therefore, it is suggested that cAD-MSCs have a potential therapeutic use in the treatment of immune-mediated disease.
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PMID:Soluble factors-mediated immunomodulatory effects of canine adipose tissue-derived mesenchymal stem cells. 1871 42

The tumor microenvironment is heterogeneous for the expansion and infiltration by myeloid derived suppressor cells (MDSCs) which has been hypothesized to be dependent on tumor burden. We report a relationships between tumor size, MDSCs and T-cells; using four murine mammary tumors to assess tumor growth, infiltration and gene expression. Our analysis of cellular infiltration into tumors and gene expression used collagenase dissociated tumors and density gradient isolation of non-parenchymal cells (NPCs). The frequency of splenic and peripheral blood (PB) MDSCs was tumor dependent resulting in a significantly increased number of MDSCs. The MDSC frequency inversely correlated with the frequency of CD3+ lymphocytes in the spleen, independent of the tumor studied and directly correlated with tumor burden. Tumor growth up-regulated cyclooxygenase-2 (COX-2), vascular endothelial growth factor-A (VEGF-A), granulocyte (G-) and granulocyte-monocyte-colony stimulating factor (GM-CSF), arginase-1 (ARG-1), and nitric oxide synthase-2 (NOS-2) transcription in the tumor and spleens (not VEGF-A). The frequency of splenic MDSCs directly correlated with splenic COX-2, NOS-2, and ARG-1 message levels, while COX-2 and NOS-2 transcript levels inversely correlated with splenic CD3+ cell frequency. COX-2 mRNA levels also directly correlated with the ARG-1 and NOS-2 transcript levels from tumor-infiltrating leukocytic cells, supporting prostaglandin E2 as a regulator of ARG-1 and NOS-2 transcription. In summary, MDSC numbers in the spleen and tumor microenvironment are tumor dependent, directly correlating with tumor size and inversely correlating with T-cell number. MDSCs are also directly associated with VEGF-A and G-CSF transcript levels suggesting multiple mechanisms for MDSC regulation and COX-2, NOS-2 and ARG-1 supporting multiple mechanisms of T-cell suppression.
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PMID:Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells. 1936 67

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

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

Chronic inflammation, which is characterized by the proliferation of granulation tissues, is known to be regulated by angiogenesis. Recent results suggest that bone marrow-derived (BM-derived) hematopoietic cells regulate angiogenesis in vivo. We previously reported that the angiogenesis occurring during chronic inflammation is enhanced in response to the endogenous prostaglandins (PGs) derived from an inducible cyclooxygenase-2 (COX-2). In the present study, we examined the role of BM-derived cells expressing an E-type PG receptor subtype, EP3, in sponge-induced angiogenesis. The replacement of wild-type (WT) BM with BM cells (BMCs) from green fluorescent protein (GFP) transgenic mice revealed that the formation of granulation tissue around the sponge implants developed via the recruitment of BMCs. This recruitment was enhanced by topical injections of vascular endothelial growth factor (VEGF)-A, and a VEGF-dependent increase in the recruitment of BMCs was inhibited by a COX-2 inhibitor, celecoxib. FACS analysis of the granulation tissues after treatment with collagenase revealed that the Mac-1-positive macrophage fraction was enhanced by topical injections of VEGF-A, and that this increased recruitment of Mac-1-positive BMCs was inhibited by celecoxib. Selective knockdown of EP3 performed by BM transplantation with BMCs isolated from EP3 knockout (EP3) mice reduced sponge-induced angiogenesis, as estimated by mean vascular number and CD31 expression in the granulation tissues. This reduction in angiogenesis in EP3(-/-) BM chimeric mice was accompanied by reductions in the recruitment of BMCs, especially of Mac-1-positive cells and Gr-1-positive cells. These results indicate that the recruited bone marrow cells that express the EP3 receptor have a significant role in enhancing angiogenesis during chronic proliferative inflammation.
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PMID:Recruited bone marrow cells expressing the EP3 prostaglandin E receptor subtype enhance angiogenesis during chronic inflammation. 2001 9


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