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)

Retinoic acid inhibits the enzyme collagenase by forming an inactive complex between the liganded nuclear retinoic acid receptors and c-Jun, a protein that is itself an activator of the collagenase gene.
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PMID:The molecular basis of the inhibition of collagenase by vitamin A. 133 26

Six patients underwent dermabrasion while on or having recently completed isotretinoin (Accutane) therapy. All patients developed keloids in atypical locations; the keloids eventually responded to topical or intralesional steroid therapy. Retinoids have a modulatory effect on connective tissue metabolism, including suppression of collagenase, which may enhance keloid formation. Dermabrasion should be delayed in those patients taking or recently on isotretinoin therapy.
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PMID:Atypical keloids after dermabrasion of patients taking isotretinoin. 301 52

Treatment of mouse fibroblast BALB/c 3T6 cells with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate or the antipromoter retinoic acid affects the release of several glycoproteins into the medium. The phorbol ester decreases the secretion of a 180-kd and 160-kd glycoprotein and increases the release of a 38-kd glycoprotein. In contrast, retinoic acid affects these glycoproteins in the opposite way. Moreover, retinoic acid enhances the level of a 55-kd and 60-kd glycoprotein. The 180-kd and 160-kd glycoproteins appear sensitive to collagenase and after pepsin treatment are converted to bands which comigrate with collagen alpha 1 (I) and alpha 2 (I). These glycoproteins are tentatively identified as being pro alpha 1 (I) and pro alpha 2 (I). The 38-kd glycoprotein appears to comigrate with the major excreted protein. Retinoic acid appears to reduce significantly the incorporation of mannose into secreted glycoproteins whereas treatment with the phorbol ester induces an enhancement in mannose incorporation. Our results indicate that both phorbol esters and retinoids alter the release of several glycoproteins from 3T6 mouse fibroblasts. These changes appear to relate to the influence of these compounds on the expression of the transformed phenotype of these cells.
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PMID:Retinoic acid and 12-O-tetradecanoylphorbol-13-acetate alter release of glycoproteins from mouse fibroblast BALB/C 3T6 cells. 391 54

The effects of a variety of retinoids on collagenase and gelatinase expression have been examined in skin fibroblast cultures derived from normal volunteers and from patients with the hereditary blistering disorder, recessive dystrophic epidermolysis bullosa. Both 13-cis- and all-trans-retinoic acid were effective inhibitors of collagenase production in both cell types. In the case of collagenase, the inhibition of collagenase activity was paralleled by a reduction in immunoreactive enzyme protein, suggesting that these retinoids act by inhibiting synthesis and/or secretion of the enzyme. Retinoic acid also inhibited production of the second enzyme in the collagen degradative pathway, gelatinase. In this case, the decrease in gelatinase activity was equal to or slightly greater than the achieved in collagenase expression. The observation that certain retinoids modulate the two crucial enzymes in the degradation of collagen in the skin suggests that they might be useful therapeutic agents in recessive dystrophic epidermolysis bullosa, a disease in which the pathogenesis of blistering is in part related to connective tissue destruction.
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PMID:Inhibition of collagen degradative enzymes by retinoic acid in vitro. 627 11

Blood vessel angiogenesis is an important component of chronic synovitis, and its regulation may be mediated through local production and effects of certain inflammatory cytokines, including interleukin-1 (IL-1). Retinoic acid (RA) can alter the progression of some inflammatory arthritic diseases, presumably through effects on fibroblast collagenase and PGE2 production. To explore alternate hypotheses, we examined the interaction of retinoic acid and IL-1 on endothelial cell (EC) function and found that RA directly affects and modifies the effects of IL-1 on EC proliferation, prostacyclin production, and plasminogen activator inhibitor capacity (PAI-1). With respect to EC proliferation, cis- and trans-retinoic acid and retinol induced a dose-dependent increase of [3H]TdR uptake by cultured ECs, independent of the effects of serum or eicosanoid production. This effect was blocked by IL-1. With respect to EC prostacyclin production, although retinoic acid alone had no effect, cis and trans-retinoic acid and retinol all induced a dose-dependent increase in IL-1-mediated prostacyclin production, which was most marked at higher concentrations (20 U/ml) of IL-1. This effect was mediated through effects independent of cyclooxygenase (COX) production. With respect to plasminogen activator inhibitor capacity, both IL-1 and retinoic acid stimulated EC PAI-1 synthesis, but the individual effects were additive, with RA augmenting the known IL-1 effects on EC PAI-1 production. The interaction between RA and IL-1 on the endothelium, described in this study, may play a role in the fashion through which retinoic acid alters the expression of synovitis in certain types of experimental inflammatory arthritis.
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PMID:Retinoic acid effects on endothelial cell function: interaction with interleukin 1. 802 Jan 93

Growth hormone (GH) exerts direct differentiative and proliferative effects on osteoblasts. We studied 125I-labeled human (h) GH binding to primary mouse osteoblasts derived from collagenase-treated 18-day fetal mouse calvaria. Scatchard analysis of the data revealed a single class of high affinity GH receptors (apparent Ka = 5.74 x 10(9) M-1) with 2200 sites per cell. Affinity crosslinking and SDS-PAGE electrophoresis showed two bands with apparent molecular masses of 120 and 70 kDa. Mouse osteoblasts express GH receptor mRNA with gene transcripts of 4.2 and 1.2 kb, at levels which reach approximately 1/6 of those in mouse liver and 1/3 of those in mouse muscle. Two populations of undifferentiated and diffentiated osteoblasts, obtained by sequential collagenase digestion of mouse calvaria, were used to study the relationship between osteoblastic phenotype and GH receptor expression. Although the affinity of the receptors in undifferentiated and differentiated cells was the same, the capacity was significantly higher (1.45 +/- 1.0% vs 2.39 +/- 0.9%, P = 0.03) in differentiated cells. This stresses the specific importance of the osteoblast as a target cell for GH. The differentiating potential of the vitamin A derivative retinoic acid was subsequently used experimentally to induce differentiation in the cells. Retinoic acid increased 125I-hGH binding to preosteoblasts (153%, P = 0.02). Together, these data demonstrate the presence of a high affinity GH receptor in mouse osteoblasts which is related to differentiation.
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PMID:Growth hormone binds to a single high affinity receptor site on mouse osteoblasts: modulation by retinoic acid and cell differentiation. 888 65

Collagenase-1 (matrix metalloproteinase-1 (MMP-1)) degrades the extracellular matrix and enhances the invasive phenotype of tumor cells. v-src activated MMP-1 transcription through a series of elements in the proximal promoter, including the E2BP (nt -172), polyoma virus enhancer A3 (PEA3) (nt -94), activator protein-1 (AP-1) (nt -72), and signal transducer and activator of transcription (STAT) (nt -57) consensus sites. Of these sites, PEA3 and STAT contributed specifically to induction by v-src, whereas the remaining elements were also involved in induction by the phorbol ester phorbol myristate acetate (PMA). However, in contrast to MMP-1 induction by PMA, an AP-1 site located at nt -186 did not contribute to v-src induction. These results suggest divergence of the tyrosine kinase- and protein kinase C-dependent pathways with respect to MMP-1 transcription. v-src induced MMP-1 through mitogen-activated protein kinases, with extracellular signal-regulated kinases playing a larger role than c-jun N-terminal kinase. Retinoic acid, which inhibits the progression of certain cancers, repressed v-src-induced MMP-1 transcription. Constitutive expression of retinoic acid receptors (RARs) alpha or beta, but not gamma, or of retinoid X receptor alpha, repressed v-src-induced collagenase-1 transcription. We concluded that oncogenic induction of MMP-1 by v-src depends on signaling pathways and cis-acting sequences that are distinct from those involved in phorbol ester activation. Furthermore, v-src induction of MMP-1 may, by acting in concert with other genes, enhance matrix degradation and tumor progression, and retinoic acid and RARs may antagonize this induction in an RAR type-specific manner.
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PMID:v-src activation of the collagenase-1 (matrix metalloproteinase-1) promoter through PEA3 and STAT: requirement of extracellular signal-regulated kinases and inhibition by retinoic acid receptors. 953 51

Retinoic acid (RetA) and interleukin-1alpha (IL-1) together can induce a reproducible release of proteoglycan fragments from bovine nasal cartilage in culture. However, release of collagen fragments with either agent alone is often variable. In this study over 70% of the total collagen was released from bovine nasal cartilage in culture by day 14 when RetA and IL-1 were combined. This release was accompanied by the appearance of collagenolytic activity in the culture medium that cleaved collagen specifically at the (1/4)/(3/4) position. Tissue inhibitor of metalloproteinases (TIMP) activity was present at day 7 but low or absent in media from resorbing tissue at day 14. The breakdown of cartilage collagen could be prevented by the addition of BB-94, a specific metalloproteinase inhibitor. These results suggest that RetA promotes the early release of TIMP from the tissue and that IL-1 stimulates pro-collagenase secretion which, when activated, exceeds the local concentration of TIMP. Thus in the later stages of culture collagen destruction occurs. Both MMP-1 and MMP-13 were detected and appear to be involved in IL-1 + RetA induced bovine cartilage destruction. However, for the first time, we also present evidence to suggest that MMP-13 is the predominant collagenase in this system.
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PMID:Retinoic acid combines with interleukin-1 to promote the degradation of collagen from bovine nasal cartilage: matrix metalloproteinases-1 and -13 are involved in cartilage collagen breakdown. 1099 43

Proteolytic degradation of extracellular matrix is thought to play an important role both in emphysema and in tissue development and repair. Retinoic acid has been suggested to modify tissue injury, and in an animal model of emphysema may induce alveolar repair. Since cytokines can induce matrix metalloproteinase (MMP) production in fibroblasts and neutrophil elastase (NE) can activate MMPs, we hypothesized that retinoic acid could attenuate collagen degradation by modifying MMP production and activation. To evaluate this, human lung fibroblasts were cast into native type I collagen gels and floated in medium containing cytomix (TNF-alpha, IL-1beta, and IFN-gamma) alone or in combination with NE in the presence and absence of retinoic acid (1 microM). After 5 d, cytomix with elastase induced significant degradation of the collagen gels assessed by quantifying total hydroxyproline (41.6 +/- 1.6 microg versus 3.3 +/- 1.5 microg, P < 0.01). Retinoic acid significantly inhibited this degradation (23.3 +/- 1.5 microg versus 3.3 +/- 1.5 microg, P < 0.01). Gelatin zymography and Western blot revealed that MMP-1, MMP-3, and MMP-9 were induced by cytomix and that co-exposure to NE resulted in increased production of activated forms of these enzymes. Retinoic acid attenuated the induction and activation of MMP-1 and MMP-3. The current study, therefore, suggests that in addition to stimulating anabolic effects, retinoic acid may modulate proteolytic processes thought to contribute to tissue destruction in emphysema.
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PMID:Retinoic acid attenuates cytokine-driven fibroblast degradation of extracellular matrix in three-dimensional culture. 1171 5

Adapalene is a new naphthoic acid derivative with strong retinoid agonistic pharmacological properties. We propose that adapalene might contribute to the wound repairing process as is detected with retinoids. In this controlled study, the effects of topical adapalene, tretinoin and collagenase on full-thickness wound healing were compared in an animal model. Thirty-two adult male Wistar-Albino rats were used in the study. Two circular, full-thickness wounds were made for each animal with a standard 8-mm punch biopsy, on both sides of the midline on the back. No treatment was given to Group I rats (n:8) which comprised the control group. Tretinoin cream (0.1%) was applied topically in Group II (n:8), adapalene gel (0.1%) in Group III (n:8), and collagenase ointment in Group IV (n:8) once daily. On day 7, the wounds were photographed to measure the wound surface area. The wounds on the left side of each animal were excised on day 7, for histopathologic and biochemical examination. The treatments were continued for the right side wounds up to 14 days when the same procedure was repeated. In Group II, a significant decrease in hydroxylproline (HP) levels was detected at day 7 (p = 0.018), and an increase at day 14 (p = 0.002) compared to the control group. HP results revealed no difference either in Group III nor in Group IV versus control at day 7 or 14. However, findings of improved healing were more prominent in Groups II and III than the other groups in histopathologic examination. In conclusion, tretinoin and adapalene contributed to the wound healing process resulting in an enhancement of collagen production, angiogenesis and granulation tissue formation.
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PMID:Comparison of the effects of tretinoin, adapalene and collagenase in an experimental model of wound healing. 1187 10


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