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)

Substrate specificity studies of collagenase extracted from human rheumatoid synovium suggest that synovial pannus tissue overlying articular cartilage may not be particularly active in degradation of cartilage type II collagen, which, considering the poor inherent healing capacity of the articular hyaline cartilage, may exert a protective function against inadvertant tissue damage. Rheumatoid synovial tissue was also used to establish synovial fibroblast cell lines. Treatment of these cells in monolayer cultures with IL-1 leads to collagenase gene activation, increased collagenase production and an almost complete autoactivation of secreted collagenase. Interleukin-1 also activated stromelysin gene suggesting this as a possible mechanism effecting autoactivation. Latent human fibroblast and macrophage collagenase purified from culture medium were efficiently activated by phenylmercuric chloride but also by gold thioglucose, gold sodium thiomalate and HCIO. These new observations support the Cys73 switch activation mechanism. In contrast to neutrophil collagenase, the activation by gold(I) compounds and HCIO was associated with a change in the apparent molecular weight of the fibroblast procollagenase. In addition, gold(I) compounds rendered collagenase more susceptible to thermal denaturation. Thus the fibroblast-type interstitial collagenase, probably derived from fibroblast- and macrophage-like synoviocytes, seems to provide the predominant collagenolytic potential in human rheumatoid synovial tissue. Furthermore, the conditions in synovitis tissue may be such as to favor at least initial activation of collagenase synthesized and secreted in situ.
...
PMID:Substrate specificity and activation mechanisms of collagenase from human rheumatoid synovium. 166 9

Aminophenyl mercuric acetate (APMA)-activated collagenase (C) (60 U/ml) obtained from in vitro cultures of human skin fibroblasts or recombinant interleukin-1 beta (IL-1 beta) (200 U/ml) was infused continuously for 7 days into the rabbit knee synovial space by means of an implanted Alzet osmotic pump. In stability studies in vitro, activated C or IL-1 incubated for 7 days at 37 degrees C, showed no significant loss of biological activity. Alterations in knee cartilage morphology and proteoglycan (PG) content were determined histologically, and the incidence of cartilage damage calculated. C or IL-1 vehicles infused for 7 days, caused no damage. Incidences of damage for C or IL-1 (n = 8-9), respectively, were as follows: loss PG: 88% and 100%; chondrocyte disorganization and loss, 50% and 78%, fissures and or fraying, 25% and 78%; and convergence of inflammatory cells, 25% and 66%. These results confirm the important role of C and IL-1 in cartilage damage.
...
PMID:Rapid induction of early osteoarthritic-like lesions in the rabbit knee by continuous intra-articular infusion of mammalian collagenase or interleukin-1. 166 94

The effects of potential anti-osteoarthritic compounds both on the direct inhibition of collagenase and neutral protease activities and on IL-1 induced release of neutral proteases from rabbit articular chondrocytes were investigated. WY-46,135 ((+)-N-[[[(5-chloro-2-benzothiazolyl)thio]phenyl]acetyl]-L- cysteine) directly inhibited collagenase activity (IC50 = 15.4 microM). This inhibition was reversible upon dialysis. WY-46,135 also directly inhibited neutral protease activity (IC50 = 16.8 microM) but did not significantly block bacterial collagenase activity at a concentration of 80 microM. In contrast, WY-48,989 (4-[[2-(7-chloro-2-phenyl-2H-pyrazolo[4,3-c]quinolin-4- yl)ethyl]amino]benzonitrile) did not directly inhibit either collagenase (10 microM) or neutral protease (100 microM) activity. Both WY-48,989 and WY-46,135 inhibited IL-1 stimulated release of neutral proteases (IC50 = 3 microM). The activities of these compounds represents two potential approaches for the treatment of osteoarthritis. WY-46,135 combines direct metalloprotease inhibitory activity with the inhibition of IL-1 stimulated neutral protease release from articular chondrocytes while WY-48,989 selectively inhibits the IL-1 induced release of metalloproteases.
...
PMID:Inhibition of interleukin-1 (IL-1) induced neutral proteases from rabbit articular chondrocytes by WY-46,135 and WY-48,989. 166 95

Mediators released from injured human skin that initiate the inflammatory response have not been adequately identified. Organ culture of full-thickness skin explants enables us to do so, because injury to the skin can be made in vitro, eliminating the rapid leakage of serum and infiltration of leukocytes that occur in vivo. In our studies, the military vesicant sulfur mustard (SM) (10 microliters of a 0.01 to 1.0% dilution) was topically applied to injure the epidermis of the explant. Then, the explants were cultured in small Petri dishes, usually for 18 h at 36 degrees C, and the organ-culture fluids were assayed for various inflammatory mediators. We found that the culture fluids from SM-exposed and control explants contained similar amounts of angiotensin-converting enzyme, trypsin-like and chymotrypsin-like proteases, acid phosphatase, beta-glucuronidase, beta-galactosidase, lysozyme, deoxyribonuclease, ribonuclease, interleukin 1, and lactic dehydrogenase. However, the culture fluids from SM-exposed explants contained increased amounts of histamine and plasminogen-activating activity, and often prostaglandin E2, when compared to culture fluids from control explants. After 3 to 4 d in culture, full-thickness human skin explants, when exposed to 0.2% SM (but not when exposed to 1.0% SM), sometimes showed separation of the epidermis and increased collagenase activity (i.e., hydroxyproline release). Thus, histamine (from local mast cells), and prostaglandin E2 and plasminogen-activating activity (probably from both mast cells and epidermal cells) are apparently involved in early mediation of the inflammatory response.
...
PMID:Mediators, initiating the inflammatory response, released in organ culture by full-thickness human skin explants exposed to the irritant, sulfur mustard. 171 Jun 39

Eicosanoids, lymphokines, and free radicals are known to participate in the pathogenesis of inflammation. Tumour necrosis factor (TNF), interleukin-1 and 6 (IL-1 and IL-6) and colony stimulating factor -1 (CSF-1) are secreted mainly by activated macrophages, whereas T-cells secrete IL-2, IL-3, IL-4 and interferon-gamma (IFN-gamma). In addition, activated macrophages and lymphocytes can also produce eicosanoids and free radicals which have potent pro-inflammatory actions. Eicosanoids, lymphokines, and free radicals can modulate the immune response, cell proliferation, stimulate collagenase and proteases secretion and induce bone resorption; events which are known to be associated with various collagen vascular diseases. On the other hand transforming growth factor-beta (TGF-beta) produced by synovial tissue, platelets and lymphocytes can inhibit collagenase production, suppress T-cell and NK-cell proliferation and activation and block free radical generation and seems to be of benefit in rheumatoid arthritis. Drugs such as cyclosporine, 1,25,dihydroxycholecalciferol and pentoxyfylline can block lymphokine and TNF production and thus, may inhibit the inflammatory process. Essential fatty acids, the precursors of eicosanoids, are suppressors of T-cell proliferation, IL-1, IL-2 and TNF production and have been shown to be of benefit in rheumatoid arthritis, systemic lupus erythematosus and glomerulonephritis. Thus, the interactions between essential fatty acids, eicosanoids, lymphokines, TGF-beta and free radicals suggest that new therapeutic strategies can be devised to modify the course of collagen vascular diseases.
...
PMID:Interaction(s) between essential fatty acids, eicosanoids, cytokines, growth factors and free radicals: relevance to new therapeutic strategies in rheumatoid arthritis and other collagen vascular diseases. 172 26

Recombinant human interleukin-1 alpha (IL-1 alpha) and recombinant human IL-1 beta stimulate matrix proteoglycan degradation and inhibit glycosaminoglycan synthesis in bovine nasal cartilage explants. A 17-kd human recombinant IL-1 receptor antagonist protein (IRAP) caused a concentration-dependent (0.2-200 ng/ml) suppression of the effects of IL-1 alpha and IL-1 beta in cartilage organ cultures. IRAP inhibited the binding of radiolabeled IL-1 alpha to rabbit articular chondrocytes. Matrix metalloproteinase (collagenase, gelatinase, and stromelysin) and prostanoid production by IL-1-activated rabbit articular chondrocytes was also suppressed by IRAP. These results could have potential significance in the development of a new antiarthritis therapy based on an IRAP.
...
PMID:Biologic effects of an interleukin-1 receptor antagonist protein on interleukin-1-stimulated cartilage erosion and chondrocyte responsiveness. 182 16

Glucocorticoids play an important role in the therapy of arthritic diseases. We sought, firstly, to identify, characterize and localize glucocorticoid receptors (GR) in normal human chondrocytes and, secondly, to determine whether glucocorticoid suppression of human recombinant interleukin-1 beta (rhIL-1 beta)-stimulated metalloproteases (MPs) synthesis by chondrocytes requires GR occupancy. Radioligand binding studies with cultured chondrocytes revealed the presence of high affinity-low capacity [3H]dexamethasone (DEX) binding sites with the following kinetic parameters: Kd = 12.5 +/- 1.4 nmol/L, Nmax = 57,560 +/- 3,960 sites per cell. Competition studies indicated that the DEX binding site was glucocorticoid specific and the competitive hierarchy established was: DEX greater than RU-26988 greater than RU-486 greater than cortisol greater than progesterone much greater than testosterone greater than estradiol-17 beta. Immunocytochemical studies using a specific anti-human GR antiserum identified immunoreactive material primarily in the cytoplasm with cells cultured in the absence of glucocorticoids. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis-Western immunoblotting analysis of chondrocyte cytosol detected the presence of a macromolecular species comigrating with a standard protein possessing a molecular weight of 94 kilodalton. rhIL-1 beta provoked the synthesis and secretion of the MPs stromelysin and collagenase from human chondrocytes in a saturable, coordinate, and dose-dependent fashion. DEX and cortisol inhibited the cytokine-stimulated MP synthesis in similar dose-dependent fashions: DEX, IC50 for stromelysin and collagenase suppression was 1.12 X 10(-8) mol/L and 1.26 X 10(-9) mol/L, respectively and the IC50 for cortisol was 6.3 X 10(-7) mol/L and 4.9 X 10(-8) mol/L, respectively. rhIL-1 beta failed to stimulate metalloprotease synthesis and release from chondrocytes pretreated with 10 nmol/L DEX, even after 20 days of incubation. The antiglucocorticoid, RU-486 completely reversed the DEX induced suppression of MP synthesis at 10(-7) mol/L. RU-486 alone had no effect on MP synthesis. We believe there is a biochemical rationale for the therapeutic efficacy of glucocorticoid administration in the management of arthritic diseases such as osteoarthritis and rheumatoid arthritis, and cytokines such as IL-1 are likely to be involved in the increase in MP synthesis.
...
PMID:Glucocorticoid receptor mediated inhibition of interleukin-1 stimulated neutral metalloprotease synthesis in normal human chondrocytes. 184 71

We report that nucleic acid sequence analysis of a full-length cDNA clone for a rabbit serum amyloid A (SAA)-like protein has identified this protein as more closely related to SAA3 than to SAA1. SAA3 induced collagenase synthesis in rabbit synovial fibroblasts, and immune IgG raised against this SAA protein abrogated the induction. Using antisera to immunoprecipitate biosynthetically labeled 3H-SAA and 3H-collagenase from culture medium, we compared the levels of SAA and collagenase synthesized by cultures of rabbit fibroblasts at early passage (passages 3-6) with those synthesized by late passage cells (passage 16). Comparatively high levels of both proteins were produced constitutively by fibroblasts at low passage. With increasing passage, levels of both proteins drop so that by passage 16, constitutive production of SAA and collagenase was only approximately 15-20% that of passage 3 cells. Cells at low passage could be readily stimulated with phorbol myristate acetate (PMA) or interleukin 1 (IL-1) to synthesize increased amounts of both SAA and collagenase. In passage 5 cells treated with PMA, we detected increased SAA mRNA by 1.5 h and collagenase mRNA by 5 h. However, older passage cells were more refractory to stimulation and required longer induction times. We suggest that SAA3 may be expressed by fibroblasts at sites of acute inflammation or injury, and that elevated levels of SAA3 may signify "activated" fibroblasts which are already producing increased amounts of collagenase constitutively and which are predisposed to further stimulation.
...
PMID:Serum amyloid A (SAA3) produced by rabbit synovial fibroblasts treated with phorbol esters or interleukin 1 induces synthesis of collagenase and is neutralized with specific antiserum. 184 44

Degradation of cartilage matrix macromolecules depends on the increase of metalloprotease activity. It has been suggested that interleukin 1 (IL-1) contributes to cartilage break-down by modulating the synthesis of the elements favoring an activation of these metalloenzymes. We analyzed the effect of IL-1 on the synthesis of collagenase, stromelysin, and tissue inhibitor of metalloproteases (TIMP) in human cartilage explants and culture chondrocytes, as well as its effect on the secretion of plasminogen activators (t-PA, u-PA) and inhibitors (PAI-1, PAI-2) in cartilage explants. Messenger RNA levels of collagenase and TIMP were also analyzed following chondrocyte incubation in the presence or absence of IL-1. We demonstrate that IL-1 stimulates the secretion of metalloproteases and t-PA in a dose dependent manner. At a relatively low concentration (5 pg/ml), IL-1 induced collagenase and stromelysin synthesis in parallel with a decline in TIMP secretion. While IL-1 induced collagenase gene expression, no change in the TIMP mRNA level was noted. The increase in t-PA synthesis was accompanied by a decreased PAI-1 level, while the PAI-2 level remained unchanged. u-PA could not be detected in the culture medium. This study gives insight into the ways that the synthesis, activation and inhibition of metalloproteases are modulated by IL-1. These results support the importance of IL-1 in the etiology of cartilage degeneration.
...
PMID:In vitro effects of interleukin 1 on the synthesis of metalloproteases, TIMP, plasminogen activators and inhibitors in human articular cartilage. 185 Dec 31

The presence of T cells and antibodies reactive with heat-shock proteins (hsps) in the joints of patients with rheumatoid arthritis may indicate a role of hsps in this disease. In the present study we examined whether increased temperature and interleukin 1 (IL 1), both of which are elevated in arthritic joints, induced the expression of two hsp70 genes in bovine chondrocyte cultures. We found that heat shock resulted in increased expression of constitutive and inducible hsp70 mRNA species. IL 1 and phorbol 12-myristate 13-acetate (PMA) also induced an increase in the constitutive hsp70 mRNA species, but without affecting the expression of the inducible hsp70 gene. The increase induced by IL 1 was observed only after 3 h, whereas increases induced by PMA were observed within 1 h. For all treatments, the hsp70 mRNA decreased by 24 h. Heat treatment of chondrocytes did not affect levels of collagenase and caseinase activity in the medium, nor did it alter proteoglycan synthesis by these cells.
...
PMID:Interleukin 1 induces the expression of a heat-shock gene in chondrocytes. 185 60


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

---