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)

The matrix metalloproteinases (MMPs) collagenase, gelatinase and stromelysin, contribute to the destruction of articular cartilage which occurs during rheumatoid and osteoarthritis. Ro 31-4724, a substrate analogue containing a hydroxamic acid function, is a potent but non-selective inhibitor of all three MMPs (I50, collagenase = 10 nM), whereas Ro 31-7467, a phosphinic acid transition-state analogue, shows 14-fold and 12-fold selectivity for collagenase (I50 = 17 nM) over gelatinase and caseinase (stromelysin) respectively. The effects of these inhibitors on interleukin-1-induced bovine nasal cartilage degradation were examined. The hydroxamate Ro 31-4724 inhibits proteoglycan and collagen loss, whereas the phosphinic acid Ro 31-7467 selectively inhibits collagen breakdown in this model. This represents the first demonstration of potent and selective inhibition of IL1-induced cartilage degradation in vitro by MMP inhibitors. These results suggest that collagenase is responsible for collagen loss and that a different enzyme, possibly stromelysin, is responsible for proteoglycan degradation in this model.
...
PMID:Potent collagenase inhibitors prevent interleukin-1-induced cartilage degradation in vitro. 166 94

Arthritis was induced by injecting cationic amidated bovine serum albumin (aBSA) (pI approximately 9.2) into the knee joint of immunized guinea pigs and the mechanisms of articular cartilage destruction were studied morphologically and biochemically. Marked synovitis associated with polymorphonuclear leukocyte (PML) infiltration occurred within 1 day of the challenge. Articular cartilage infiltrated by PMLs was almost completely destroyed after 2 weeks. During the initial destructive process, proteoglycans were depleted from the cartilage and later collagen fibers disappeared. Granulation tissue growing in the inflamed synovium and bone marrow replaced the destroyed cartilage and joint cavity and formed fibrous scar tissue (fibrous ankylosis) by 8 weeks. Subsequently, the knee joints developed cartilagenous ankylosis by 12 weeks and finally bony ankylosis at 28 weeks. Autoradiography using 125I-aBSA and immunofluorescence studies for immunoglobulin (IgG) and complement (C3) demonstrated that the antigen is trapped in all zones of the articular cartilage and serves as a trigger for immune complex formation. Significantly increased neutral proteinase activities against substrates of proteoglycan subunits, [3H]carboxymethylated transferrin and L-pyroglutamyl-L-prolyl-L-valine-paranitroanilide were detected in homogenates of the synovium and cartilage from arthritic knee joints 1 and 2 weeks after induction. Inhibitor studies and pH curves suggested that the proteinase is leukocyte elastase. Measurable amounts of gelatinolytic activity, detected by activation with 4-aminophenylmercuric acetate and inhibited with EDTA, were also present in the same samples, but there was no detectable collagenase activity. The data on SDS-gelatin substrate gel showed that the proteinase is gelatinase derived from PMLs. These results suggest that in aBSA-induced arthritis, elastase and gelatinase from PMLs invading articular cartilage may play important roles in cartilage destruction.
...
PMID:Arthritis induced immunologically with cationic amidated bovine serum albumin in the guinea pig. A morphological and biochemical study on the destruction of articular cartilage. 167 78

Cytokines, interleukin-1 (IL-1), tumor necrosis factor alpha, and the neurotransmitter, substance P, have been implicated in the pathogenesis of arthritis because they stimulate synovial cells to secrete prostaglandin E2 and collagenase in vitro. We investigated in vivo changes in intraarticular substance P and the degradation of cartilage proteoglycan in response to intraarticular cytokine injections in rabbits. Twenty-four hours after a single injection of 10 ng, 30 ng, or 100 ng of recombinant human IL-1 alpha (rHuIL-1 alpha) per joint, the mean +/- SEM levels of substance P detected in the cell-free joint lavage fluid were 250 +/- 67 fmoles, 480 +/- 60 fmoles, and 530 +/- 130 fmoles (n = 4-5), respectively. The level of substance P in the contralateral knees injected with diluent was 58 +/- 8 fmoles (n = 12). The level of substance P had increased by 2 hours after IL-1 injection and remained elevated in the joint 48 hours after injection. Cytokine-induced proteoglycan depletion was also time- and dose-dependent. Proteoglycan concentrations in articular cartilage dissected from the weight-bearing condyles were calculated as the ratio of sulfated glycosaminoglycan measured using 1,9-dimethylmethylene blue: hydroxyproline. After 48 hours, 10 ng, 30 ng, or 100 ng of rHuIL-1 alpha per joint decreased proteoglycan levels by 9 +/- 4%, 14 +/- 4%, and 21 +/- 3% (n = 8), respectively. Likewise, the injection of recombinant human tumor necrosis factor alpha induced depletion of intraarticular substance P and cartilage proteoglycan.
...
PMID:Elevated substance P and accelerated cartilage degradation in rabbit knees injected with interleukin-1 and tumor necrosis factor. 169 99

Collagenase production by chondrocytes appears to play a major role in the development of osteoarthritis. Although the mechanisms regulating collagenase production by chondrocytes are not known, incubation of bovine chondrocytes in serum markedly decreases collagenase production. Since serum has been demonstrated to increase levels of phosphotyrosine (P-Tyr) in several cell types, we determined the effect of altering intracellular levels of P-Tyr on collagenase production. Both orthovanadate, a potent inhibitor of tyrosine phosphatases, and serum caused a marked increase in tyrosine phosphorylation. The increase in P-Tyr was associated with a decrease in the production of collagenase, suggesting that two processes may be linked. Orthovanadate caused an increase in P-Tyr in the absence of serum, suggesting that P-Tyr levels in resting chondrocytes are regulated through activity of both tyrosine kinases and phosphatases. Orthovanadate and serum induced a synergistic increase in P-Tyr levels, suggesting that serum functions through increasing kinase activity rather than decreasing phosphatase activity. In the absence of serum, concentrations of orthovanadate which maximally inhibited collagenase production primarily increased phosphorylation of a 36 kDa protein, suggesting that the phosphorylation of this protein may play a major role in regulating collagenase production. Orthovanadate had limited effects on chondrocyte proteoglycan synthesis, morphology or viability in the presence or absence of serum, suggesting that the decrease in collagenase production was not due to non-specific inhibition of protein synthesis or cellular toxicity. Inhibition of tyrosine phosphatases by orthovanadate or activation of tyrosine kinases by addition of serum correlated with the inhibition of collagenase production.
...
PMID:Inverse correlation between tyrosine phosphorylation and collagenase production in chondrocytes. 169 63

Rotary shadowing of zonular fibrils in human and bovine eyes revealed a "string of beads" configuration with multiple interconnecting filaments, identical to that recently reported in fibrils of unknown type within the vitreous. These 29 nm beaded fibrils were the only macrostructures present in zonular samples, showing ultrastructural features correlating with both the macro and microperiodicity of zonular fibrils in tissues. Interbead periodicity varied from 30-57 nm and interbead filaments appeared capable of stretching even further, possibly explaining the inherent elasticity of zonular fibrils. The junctions between outer filaments and beads were fibrillin-positive. Similar beaded fibrils were found in the human and bovine anterior vitreous along with type II and IX collagen fibrils, proteoglycan filaments and other unidentified fibrils. After collagenase and elastase digestion, bovine ligamentum nuchae showed type VI collagen fibrils and clumps of beaded fibrils like those in zonule and vitreous. This distribution indicates that the beaded fibril is the microfibril which constitutes the basic unit of the elastic system.
...
PMID:Rotary shadowing of elastic system microfibrils in the ocular zonule, vitreous, and ligamentum nuchae. 170 1

The mechanism of proteoglycan (GAG) loss from rat femoral articular cartilage (FHC) induced by recombinant human interleukin-1 beta (rhIL-1 beta) in vitro has been investigated. The metalloproteinase inhibitor 1,10-phenanthroline, the serine proteinase inhibitor N alpha-p-tosyl-l-lysine chloromethyl ketone (TLCK), the activator of latent metalloproteinase p-aminophenylmercuric acid (APMA), and an inhibitory metalloproteinase substrate analogue U27391 were tested for their ability to modulate rhIL-1 beta-induced GAG loss and GAG synthesis ([35S]O4 uptake) inhibition. As expected 1,10-phenanthroline inhibited GAG loss, however [35S]O4 incorporation was significantly reduced. TLCK was without effect, and APMA inhibited both parameters. U27391 reversed both the inhibition of [35S]O4 incorporation and GAG loss. It is concluded that the adverse effects on proteoglycan metabolism explain the inhibitory actions of 1,10-phenanthroline and APMA, whilst the action of TLCK may indicate that serine proteinases are not involved in the activation of latent metalloproteinase. U27391 exhibited chondroprotective activity and confirmed the induction of either metalloproteinases such as stromelysin or collagenase by rhIL-1 beta.
...
PMID:Investigation of the role of metalloproteinases in recombinant human interleukin-1 beta-induced degradation of rat femoral head cartilage. 179 2

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

The effects of tranexamic acid, an inhibitor of plasminogen activator, were evaluated in a rabbit model of osteoarthritis induced by section of the knee joint anterior cruciate ligament. Prophylactic treatment administered intramuscularly thrice weekly for 12 or 24 weeks significantly reduced cartilage destructive lesions, increased cartilage hypertrophy but did not prevent changes in cartilage water and proteoglycan content. A suppression of synovial membrane stromelysin and collagenase activity was found while phospholipase A2 activity was unaffected.
...
PMID:Study of an inhibitor of plasminogen activator (tranexamic acid) in the treatment of experimental osteoarthritis. 185 Dec 28

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

NG2 is a chondroitin sulfate proteoglycan previously found to be expressed by glial progenitor cells of the O2A lineage. We have examined the expression of NG2 in the developing rat limb by immunohistochemistry and northern blot analysis. Staining of embryonic day 14 (E14) rat limb bud sections with polyclonal and monoclonal anti-NG2 antibodies reveals reactivity in the precartilaginous mesenchymal condensation. The staining intensity increases with the differentiation of chondrocytes until E16. NG2 staining is not detected in the mature hypertrophic chondrocytes of E17 and postnatal day 3 (P3) limbs even after treatment of the sections with hyaluronidase or collagenase. Immuno-precipitations with anti-NG2 antibody using 125I-labeled limb cells in culture showed a 400 to 800 x 10(3) Mr proteoglycan species with a core protein size of 300 x 10(3) Mr, comparable to NG2 from O2A cells and neural cell lines. Northern blot analysis reveals the expression of an 8.9 kb mRNA in E16 limbs and at a lower level in P1 cartilage. The northern blot analyses also show that NG2 is distinct from the large aggregating proteoglycan of the cartilage. Our results indicate that in the developing limb cartilage, as in the differentiating oligodendrocytes, NG2 is present on immature cells in the process of differentiating, but its expression is downregulated as terminal differentiation of chondrocytes takes place.
...
PMID:The expression of NG2 proteoglycan in the developing rat limb. 187 62


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

---