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

---

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

Evidence suggests that in the lower uterine segment at term an increased production of tumor necrosis factor (TNF) alpha and interleukin (IL)-1 beta induces an increase in the expression of adhesion molecules by the endothelium. The expression of endothelial-leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1 were found to increase from a cervical dilatation of 2-3 cm and reaches a maximum at cervical dilatation of more than 6 cm. Increased adhesiveness of the endothelium leads to extravasation of neutrophils into the cervical stroma. The chemotaxis and degranulation of these cells is triggered by a rise in the concentration of IL-8 found in the lower uterine segment when cervical dilatation progresses. A significant increase in stroma invasion by neutrophils with progressive cervical dilatation was observed. This finding coincides with a rise in the granulocytic matrix metalloproteinases (MMP)-8 and MMP-9 concentrations up to complete cervical dilatation. We found similar patterns of cytokine concentrations in the lower uterine segment of patients with preterm delivery: at 2-3 cm dilatation the concentrations of IL-1 beta, IL-6- und IL-8 were significantly higher than at less than 2 cm. Concomitantly, we also found an increase in MMP-8, MMP-9 and tissue inhibitor of metalloproteinases-1 concentrations from less than 2 cm to 2-3 cm cervical dilatation. These findings suggest that the changes in the lower uterine segment during preterm parturition seem to be similar to those at term and both resemble an inflammatory process.
...
PMID:The importance of extracellular matrix in the induction of preterm delivery. 1022 99

Lipoxins are a novel class of endogenous eicosanoid mediators that potently inhibit inflammatory events by signaling via specific receptors expressed on phagocytic cells. Animal models have shown that lipoxin A4 (LXA4) down-regulates inflammation in vivo. Here we demonstrate, for the first time, the expression of LXA4 receptors, and their up-regulation by IL-1 beta, in normal human synovial fibroblasts (SF). We examined whether exogenous LXA4 abrogated IL-1 beta stimulation of SF in vitro. IL-1 beta induced the synthesis of IL-6, IL-8, and matrix metalloproteinases (MMP)-1 and -3. At nanomolar concentrations, LXA4 inhibited these IL-1 beta responses with reduction of IL-6 and IL-8 synthesis, by 45 +/- 7% and 75 +/- 11%, respectively, and prevented IL-1 beta-induced MMP-3 synthesis without significantly affecting MMP-1 levels. Furthermore, LXA4 induced a 2-fold increase of tissue inhibitor of metalloproteinase (TIMP)-1 and a approximately 3-fold increase of TIMP-2 protein levels. LXA4 inhibitory responses were dose dependent and were abrogated by pretreatment with LXA4 receptor antiserum. LXA4-induced changes of IL-6 and TIMP were accompanied by parallel changes in mRNA levels. These results indicate that LXA4 in activated SF inhibits the synthesis of inflammatory cytokines and MMP and stimulates TIMP production in vitro. These findings suggest that LXA4 may be involved in a negative feedback loop opposing inflammatory cytokine-induced activation of SF.
...
PMID:Lipoxin A4 inhibits IL-1 beta-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases. 1067 6

Successful transplantation of autologous chondrocytes for repair of articular cartilage defects requires an undisturbed matrix-synthesis of the transplanted cells. This, in turn, is dependent on the composition of the synovial fluid (SF) of the respective joint. We addressed the question whether analysis of a patient's SF can predict the rate of matrix-synthesis of articular cartilage exposed to this SF in vitro. SF was obtained from 115 patients with disorders of the knee, including gonarthrosis (n = 44), meniscal tears (n = 10), rheumatoid arthritis (n = 53), and reactive arthritides (n = 8). In the SF, the following parameters were determined: Interleukin-1 beta, IL-6, IL-8, IL-1-RA, TNF alpha, Insulin-like growth-factor I (IGF-I), IGF-II, IGF-binding protein-2 (IGFBP-2), IGFBP-3 as well as total proteinase activity and total collagenase activity. To assess the effect of SF on the matrix synthesis of articular chondrocytes, bovine cartilage was incubated in the presence of SF, and the rate of proteoglycan synthesis subsequently determined. In some cases, a monoclonal antibody directed against IGF-I was added. SF from patients with OA or trauma, respectively, stimulated PG-synthesis of bovine cartilage more markedly than did SF from patients with rheumatic arthritides. On the average, 60 percent of the SF-induced increase of cartilage matrix synthesis could be titrated out by an anti-IGF-I-AB. The best predictor for the SF-effects on PG-synthesis of exposed cartilage was the proportion of free IGF-I (r = 0.573, p < 0.001, Spearman rank correlation) followed by the SF-concentrations of IGF-I (with a positive sign), IGFBP-3, IL-1 beta, and TNF alpha (all with a negative sign). According to our data, IGF-I is the most important anabolic factor in human SF with respect to cartilage PG-synthesis. The proportion of free IGF-I seems to be of special importance in this regard. Low SF-levels of free IGF-I could be identified as a possible risk-factor for a sub-optimal protoeglycan synthesis of chondrocytes exposed to this synovial milieu.
...
PMID:[Value of synovial analysis for prognosis of matrix synthesis of transplanted chondrocytes]. 1074 38

Inflammatory cytokines play a major role in cartilage destruction in diseases such as osteoarthritis and rheumatoid arthritis. Because physical therapies such as continuous passive motion yield beneficial effects on inflamed joints, we examined the intracellular mechanisms of mechanical strain-mediated actions in chondrocytes. By simulating the effects of continuous passive motion with cyclic tensile strain (CTS) on chondrocytes in vitro, we show that CTS is a potent antagonist of IL-1 beta actions and acts as both an anti-inflammatory and a reparative signal. Low magnitude CTS suppresses IL-1 beta-induced mRNA expression of multiple proteins involved in catabolic responses, such as inducible NO synthase, cyclo-oxygenase II, and collagenase. CTS also counteracts cartilage degradation by augmenting mRNA expression for tissue inhibitor of metalloproteases and collagen type II that are inhibited by IL-1 beta. Additionally, CTS augments the reparative process via hyperinduction of aggrecan mRNA expression and abrogation of IL-1 beta-induced suppression of proteoglycan synthesis. Nonetheless, the presence of an inflammatory signal is a prerequisite for the observed CTS actions, as exposure of chondrocytes to CTS alone has little effect on these parameters. Functional analysis suggests that CTS-mediated anti-inflammatory actions are not mediated by IL-1R down-regulation. Moreover, as an effective antagonist of IL-1 beta, the actions of CTS may involve disruption/regulation of signal transduction cascade of IL-1 beta upstream of mRNA transcription. These observations are the first to show that CTS directly acts as an anti-inflammatory signal on chondrocytes and provide a molecular basis for its actions.
...
PMID:Cyclic tensile strain acts as an antagonist of IL-1 beta actions in chondrocytes. 1086 Oct 84

Orthodontic treatment is based on the biologic principle that prolonged pressure on teeth results in remodeling of periodontal structures, allowing for tooth movement. Periodontal remodeling is a complex process regulated in part by prostaglandins and adversely affected by the use of nonsteroidal anti-inflammatory drugs. We investigated the effects of indomethacin on collagenase activity and procollagen synthesis in rat endothelial cell cultures. Cyclooxygenase inhibition resulted in exacerbation of IL-1 beta-mediated collagenase B (MMP-9) production and activity, as well as attenuation of type IV procollagen synthesis levels by endothelial cells in vitro. Hence, the use of over-the-counter nonsteroidal anti-inflammatory drugs during tooth movement may result in aberrant remodeling of periodontal vasculature and other structures, ultimately affecting orthodontic treatment efficacy. Further studies are needed to establish novel pain relievers that do not interfere with orthodontic processes.
...
PMID:Nonsteroidal anti-inflammatory drugs in orthodontic tooth movement: metalloproteinase activity and collagen synthesis by endothelial cells. 1093 62

Ultraviolet (UV) irradiation causes human skin aging and skin cancer through the activation of matrix metalloproteinases (MMPs) which are responsible for the degradation of collagen and tumor progression in human skin. The molecular mechanisms of UV-induced MMPs are yet to be defined. Our previous studies and others suggest that i) the transient activation of cell surface receptors and subsequent activation of MAP kinase cascade contributes to the transcriptional up-regulation of MMPs; and ii) UV-induced expression of pro-inflammatory cytokines such as IL-1 beta and TNF-alpha may also account for the expression of MMPs. However, signaling pathway through which cytokines induce MMP expression remains to be unraveled. In this study, we investigated the pathway that leads to the IL-1 beta-induced up-regulation of MMP-1 in human keratinocytes. IL-1 beta activated epidermal growth factor (EGF) receptor in cultured human keratinocytes in a time- and dose-dependent manner. IL-1 beta-induced EGF receptor tyrosine phosphorylation started at 5 min and peaked at 10 min and remained elevated up to 40 min post IL-1 beta treatment. EGF receptor kinase inhibitor PD153035 and AG1478 inhibited IL-1 beta-induced EGF receptor tyrosine phosphorylation. To test the effect of EGF receptor transactivation on downstream components, we examined the ERK activation by IL-1 beta. We found that IL-1 beta-induced ERK phosphorylation, PD153035 and MEK inhibitor PD98059 blocked IL-1 beta-induced ERK activity. Furthermore, both inhibitors also dramatically reduced IL-1 beta-induced expression of c-jun and c-fos mRNA which are required for up-regulation of MMPs. EGF receptor kinase inhibitor PD153035 and AG1478 and MEK inhibitor PD98059 also blocked IL-1 beta induction of MMP-1 in cultured human keratinocytes. Collectively, our data indicate that IL-1 beta-induced expression of MMP-1 is mediated by transactivation of EGF receptor and through ERK pathway in human keratinocytes.
...
PMID:Transmodulation of epidermal growth factor receptor mediates IL-1 beta-induced MMP-1 expression in cultured human keratinocytes. 1117 16

Until recently, osteoarthritis (OA) was classified as a mechanical wear-and-tear disorder of articular cartilage, for which only pain-modifying therapies such as nonaddictive analgesics were prescribed. Little scientific attention had been focused on the patient with OA, who typically was seen as a frail elderly person hobbling down the street with a cane. With the demographic change that is facing medical policy makers, musculoskeletal disability will decrease the quality of life of the elderly population. By way of analogy, the medical establishment viewed osteoporosis as a similar disease paradigm. However, because of huge commitments of funding and drug development effort, new drugs that reduce the frequency of fractures in postmenopausal women are available. OA and the area of cartilage biology will undoubtedly follow a similar course. Recently, new research identified interleukin 1-beta, collagenase and other matrix metalloproteinases, and signal transduction pathways as important pathobiologic targets in OA. Cartilage agonists such as recombinant human growth factors and gene therapy constructs that stimulate the chondrocyte are being studied in animal models and in humans. Orthopedic approaches, including cartilage regeneration and joint resurfacing techniques with or without biomaterials, are being developed. During the next decade, new efforts will modify the structure and function of the joint, which will be layered onto the drugs, devices, and strategies in use that reduce the pain and suffering in patients with this disease.
...
PMID:Innovative therapies in osteoarthritis. 1170 11

Excessive mechanical load induces harmful outcomes for joint diseases, such as osteoarthritis and rheumatoid arthritis, but physical stimuli at appropriate intensity are essential for growth and maintenance of bone and articular cartilage. Using a fibroblast-like synoviocyte cell line derived from a patient with rheumatoid arthritis, we examined the effects of gentle cyclic strain, focusing on the expression and activity of matrix metalloproteinase-1 (MMP-1) and MMP-13. Synovial cells were cultured on a collagen-coated agar block and exposed to 2% cyclic strain at 6 rev./min for 1 h. Expression of MMP-1 and MMP-13 was assayed using semi-quantitative and real-time PCR, as well as immunoblotting. Their activity was measured using spectrofluorometry and zymography. The results showed that the cyclic strain reduced the mRNA and protein levels of MMP-1 and MMP-13, and that both collagenase and gelatinase activity was decreased under the strain. The reduction in MMP activity by the cyclic strain was not achieved by the transcriptional inhibitor, actinomycin D. In the presence of proinflammatory cytokines, such as IL-1 beta and TNF-alpha, the strain reduced the cytokine-induced expression and activities of MMPs. Interestingly, the strain elevated the mRNA level of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. These results support a potential role of mechanical strain in down-regulating the cytokine-mediated proteolytic processes in synoviocytes.
...
PMID:Reduction of cytokine-induced expression and activity of MMP-1 and MMP-13 by mechanical strain in MH7A rheumatoid synovial cells. 1200 32

Overuse injuries and trauma in tendon often involve acute or chronic pain and eventual matrix destruction. Anti-inflammatory drugs have been used as a treatment, however, the cellular and molecular mechanisms of the destructive processes in tendon are not clearly understood. It is thought that an inflammatory event may be involved as an initiating factor. Mediators of the inflammatory response include cytokines released from macrophages and monocytes. Interleukin-1 beta (IL-1 beta) is a candidate proinflammatory cytokine that is active in connective tissues such as bone and cartilage. We hypothesized that tendon cells would express receptors and respond to IL-1 beta in an initial "molecular inflammation" cascade, that is, connective tissue cell expression of cytokines that induce matrix destructive enzymes. This cascade results in expression of matrix metalloproteinases (MMPs) and aggrecanases that may lead to matrix destruction. Normal human tendon cells from six patients were isolated, grown to quiescence and treated with human recombinant IL-1 beta in serum-free medium for 16 h. Total RNA was isolated and mRNA expression assessed by semiquantitative RT-PCR. IL-1 beta (1 nM) induced mRNAs for cyclooxygenase 2 (COX2), MMP-1, -3, -13 and aggrecanase-1 as well as IL-1 beta and IL-6, whereas mRNAs for COX1 and MMP-2 were expressed constitutively. The IL-1 beta-treated tendon cells released prostaglandin E(2) (PGE(2)) in the medium, suggesting that the inducible COX2 catalyzed this synthesis. Induction of PGE(2) was detectable at 10 pM IL-1 beta. IL-1 beta also stimulated MMP-1 and -3 protein secretion. Induction of MMP-1 and -3 was detectable at 10 pM IL-1 beta. Post-injury or after some other inciting events, exogenous IL-1 beta released upon bleeding or as leakage of local capillaries may drive a proinflammatory response at the connective tissue cell level. The resulting induction of COX2, MMP-1 and -3 may underscore a potential for nonlymphocyte-mediated cytokine production of MMPs that causes matrix destruction and a loss of tendon biomechanical properties. Endogenous IL-1 beta might contribute to the process through a positive feedback loop by stimulating expression and accumulation of MMPs in the tendon matrix.
...
PMID:IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells. 1256 57

The LG4 module of the laminin alpha 3 chain (alpha 3 LG4), a component of epithelial-specific laminin-5, has cell attachment activity and binds syndecan (Utani, A., Nomizu, M., Matsuura, H., Kato, K., Kobayashi, T., Takeda, U., Aota, S., Nielsen, P. K., and Shinkai, H. (2001) J. Biol. Chem. 276, 28779-28788). Here, we show that recombinant alpha 3 LG4 and a 19-mer synthetic peptide (A3G756) within alpha 3 LG4 active for syndecan binding increased the expression of matrix metalloproteinase-1 (MMP-1) in keratinocytes and fibroblasts. This induction was inhibited by heparin and required de novo synthesis of proteins. In keratinocytes, A3G756 up-regulated interleukin (IL)-1 beta and MMP-1 expression and an IL-1 receptor antagonist thoroughly inhibited A3G756-mediated induction of MMP-1. A3G756 also activated p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-related kinase (Erk). Studies with specific inhibitors of MAPKs showed that p38 MAPK activation was necessary for both IL-1 beta and MMP-1 induction, but Erk activation was required only for MMP-1 induction. In fibroblasts, IL-1 receptor antagonist did not block A3G756-mediated induction of MMP-1. These results indicated that induction of MMP-1 by alpha 3 LG4 is mediated through the IL-1 beta autocrine loop in keratinocytes but the mechanism of the induction in fibroblasts is different. Our study suggests that the laminin alpha 3 LG4 module may play an important role in tissue remodeling by inducing MMP-1 expression during wound healing.
...
PMID:Laminin alpha 3 LG4 module induces matrix metalloproteinase-1 through mitogen-activated protein kinase signaling. 1282 66


<< Previous 1 2 3 4 5 6 7 8 9 10

---