Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

After intracardial injection of [1,2-3H]dehydroepiandrosterone ([3H]DHA) into female rats, [3H]DHA was found to accumulate and was metabolized in the preputial gland, but not in the diaphragm. The identified metabolites of [3H]DHA in the preputial gland were delta 4-androstenedione-3 alpha, 17 beta-diol. Cells were isolated from the preputial gland after treatment with trypsin and collagenase III, and centrifugation in Ficoll gradients. Activity of the enzyme complex delta 5-3 beta-hydroxysteroid dehydrogenase delta 4-5-isomerase (3 beta-HSD) responsible for transforming DHA into delta 4-androstenedione was found mainly in the 105,000 g pellet (microsomal fraction) of homogenates of the isolated cells. It used preferentially NAD over NADP as a coenzyme, with a pH optimum at 8.5. The apparent Km for DHA was 5.5 X 10(-5) M, and the Vmax was 1.72 nmol/min/mg microsomal protein. These findings indicate that DHA is preferentially taken up by the preputial gland where it undergoes metabolism to form more potent androgens, and suggest that DHA may have important androgenic influence on the preputial gland.
J Invest Dermatol 1984 Sep
PMID:delta 5-3 beta-Hydroxysteroid dehydrogenase delta 4-5-isomerase activity and metabolism of dehydroepiandrosterone in rat preputial gland. 623 67

A 10-yr-old female presented with cerebriform tumors covering the plantar surfaces of both feet. Histologically, the lesions consisted of thick collagen fibers and the content of collagen per surface area of skin was increased about 8-fold. Examination of the collagen by SDS-polyacrylamide gel electrophoresis, after limited pepsin proteolysis, showed that the lesions consisted almost exclusively of type I collagen, the predominant collagen type in human skin. Thus, a diagnosis of connective tissue nevi of the collagen type was made. Fibroblast cultures were established from the affected and normal-appearing areas of the skin, and examined for the rate of collagen synthesis, production of collagenase and growth kinetics of the cells. Cell cultures derived from the lesion and from control skin synthesized procollagen at the same rate and in a normal type I/type III procollagen ratio. However, the production of enzymatically active and immunologically detectable collagenase was reduced by 70-82% in the cultures derived from the lesion as compared to controls (p less than 0.005). Fibroblasts derived from the lesions also displayed a mean population doubling time of 1.17 +/- 0.08 days compared to 1.83 +/- 0.24 and 1.92 +/- 0.09 days for control cell strains and cells derived from normal skin of the patient, respectively (p less than 0.025). These results suggest that the excessive deposition of collagen in this case may have resulted from decreased local degradation of collagen. Enhanced proliferative capacity of the regional fibroblasts may have contributed to the accumulation of collagen in these lesions.
J Invest Dermatol 1982 Feb
PMID:Decreased collagenase production by regional fibroblasts cultured from skin of a patient with connective tissue nevi of the collagen type. 627 72

We studied the effects of two retinoids, naturally occurring all-trans-retinoic acid (retinoic acid) and the synthetic 4-hydroxyphenylretinamide (4-OH-PRT) on monolayer cultures of rabbit synovial fibroblasts and on explants of rabbit articular cartilage. Treatment of fibroblasts with phorbol myristate acetate (PMA; 10(-8) M) induced the synthesis and secretion of large amounts of collagenase: this was inhibited if the cells were treated with retinoic acid (10(-6) M) or dexamethasone (10(-7 M). Combined treatment with retinoic acid and the steroid prednisolone, at concentrations as low as 19(-10) M, gave an additive inhibition of collagenase production. Both retinoids inhibited collagenase production, but only 4-OH-PRT prevented the increase in prostaglandin E2 (PGE2) induced by PMA. Levels of plasminogen activator were also increased by treatment with PMA, and concomitant addition of either retinoid further enhanced this stimulation. Possible toxicity was assessed by measuring release of glycosaminoglycans (GAG) from explants of articular cartilage. Treatment with retinoic acid induced release of 80% of the total GAG, whereas treatment with 4-OH-PRT resulted in release of 40% of the total, a finding similar to that seen with untreated samples. 4-OH-PRT inhibited production of collagenase and PGE2 by rabbit synovial fibroblasts but was not toxic to articular cartilage.
J Am Acad Dermatol 1982 Apr
PMID:Effects of all-trans-retinoic acid (retinoic acid) and 4-hydroxyphenylretinamide on synovial cells and articular cartilage. 627 10

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.
J Am Acad Dermatol 1982 Apr
PMID:Inhibition of collagen degradative enzymes by retinoic acid in vitro. 627 11

Degradation of interstitial collagens probably takes place through different enzymatic mechanisms than degradation of basement membrane and pericellular collagens. Interstitial collagens are resorbed under pathological and physiological conditions by collagenases which function extracellularly and cleave polypeptide chains in the collagen triple helix at specific loci resulting in solubilization from the fibril. Production of collagenase in humans is ascribable to fibroblast-like cells which can be stimulated to synthesize new enzyme for release outside of the cell. In several inflammatory conditions, such as rheumatoid synovitis, modulation of collagenase production is mediated by interactions with surrounding inflammatory cells. Monocyte-macrophages produce a stimulatory factor, which has homologies with interleukin 1, which not only increases collagenase synthesis but also PGE2 synthesis. The PGE2 in turn has profound effects on cellular function. Production of the mononuclear cell factor is modulated by several interactions including T lymphocytes and T lymphocyte products, collagen of the extracellular matrix and the Fc portion of immunoglobulins. It is probable, from analogies with other stimulants such as phorbol myristate acetate, that the increase in collagen synthesis is controlled at the level of transcription. Further regulation of collagenase action outside of the cell is probably accomplished by proteolytic activation of a latent collagenase zymogen and interactions with inhibitory proteins also produced by cells in the local environment of the resorptive process.
J Invest Dermatol 1982 Jul
PMID:Collagenases and collagen degradation. 628 82

The regulatory mechanisms for collagenase synthesis in recessive dystrophic epidermolysis bullosa (RDEB) have been studied using messenger RNA (mRNA) harvested from normal and RDEB skin fibroblasts to direct protein synthesis in a rabbit reticulocyte lysate translation system. Fibroblast mRNA encoded the synthesis of approximately 60,000 and approximately 55,000 dalton forms of procollagenase in cell-free translation. In contrast to biosynthesis by intact cells, there was preferential translation of the approximately 60,000 dalton specie. For quantitative comparisons with mRNA from normal cells, mRNA was harvested from fibroblasts of 2 RDEB patents whose intact cells have been documented to have increased synthesis of collagenase. Although total translational activity was equal in normal and RDEB mRNA preparations, translatable collagenase mRNA was increased 3.5- to 10-fold, suggesting that the enhanced collagenase synthesis characteristic of RDEB is due to increased concentrations or preferential translation of collagenase mRNA.
J Invest Dermatol 1982 Sep
PMID:Enhanced cell-free translation of human skin collagenase in recessive dystrophic epidermolysis bullosa. 628 83

Microtubule-active agents affect the secretion of a variety of proteins, including collagenase. To gain insight into the mechanisms involved in this process, we examined the effects of colchicine on the synthesis, secretion, and activity of human skin collagenase. When added to monolayer cultures of human skin fibroblasts, 10(-6) M colchicine produced a mean 3-fold increase in trypsin-activatable collagenase in the culture medium. Stimulation was not observed with lumicolchicine. The enhanced accumulation of collagenase was dose-dependent with 10(-9), 10(-8), 10(-7), and 10(-6) M colchicine giving collagenase activities/mg protein that were 100 +/- 6%, 165 +/- 20%, 186 +/- 34%, and 297 +/- 62% of control, respectively. Although the effect on collagenase was seen under conditions independent of cellular growth (i.e., in serum-free medium), maximum stimulation occurred in subconfluent cultures. The colchicine-induced increase in activity was paralleled by an increase in immunoreactive enzyme protein, suggesting stimulation of enzyme synthesis. The catalytic efficiency of the enzyme (activity per unit immunoreactive protein) was unchanged, however, indicating that a structurally normal enzyme was being synthesized. To examine the process in more detail, the biosynthesis of 3H-labeled collagenase was quantitated in these cultures by specific immunoprecipitation. Although 10(-6) M colchicine produced no increase in total protein synthesis, an increased rate of collagenase synthesis was seen after only 1.5 hr. These data suggest that colchicine has a specific effect on the synthesis of collagenase and may be a useful probe for studying its regulation.
J Invest Dermatol 1982 Dec
PMID:Colchicine-induced modulation of collagenase in human skin fibroblast cultures. I. Stimulation of enzyme synthesis in normal cells. 629 9

The addition of colchicine to cultures of normal human skin fibroblasts produces a significant stimulation of collagenase. Because this finding implies a role for the microtubule system in the regulation of normal collagenase synthesis, we have used colchicine as a probe for aberrations in this enzyme in epidermolysis bullosa. In fibroblast cultures from the dominant simplex, dominant dystrophic, and recessive letalis forms of epidermolysis bullosa, 10(-6) M colchicine produced approximately a 2-fold increase in collagenase in the culture medium, a finding shown by biosynthetic studies to be attributable to enhanced synthesis of enzyme protein. In the case of typical recessive dystrophic epidermolysis bullosa, a disease characterized by excessive collagenase synthesis, the fibroblasts could also be stimulated to produce additional collagenase, despite having elevated baseline synthetic rates. In contrast, fibroblasts isolated from one recessive epidermolysis bullosa patient were resistant to the stimulatory effects of colchicine in concentrations up to 5 x 10(-6) M. In the absence of colchicine, collagenase synthesis in this patient's cells (termed REBc-) was 3-4 times that of normal controls, suggesting that the as yet undefined cellular function that is abrogated (or stimulated) by colchicine in normal cells may have been genetically impaired in these REBc- cells. Despite the resistance to colchicine, as manifested by the failure to stimulate collagenase, gross parameters of microtubular function, such as cell replication, were intact. Phenotypically, this patient had a form of epidermolysis bullosa intermediate between typical recessive dystrophic and recessive letalis forms of the disease. Although an experimentally induced blister was located in the lamina lucida, hypoplastic anchoring fibrils were also observed. These findings, in addition to the marked increase in collagenase synthesis, suggest the possibility that this patient may represent a compound heterozygote of two forms of epidermolysis bullosa and that colchicine may be useful in defining other such patients.
J Invest Dermatol 1982 Dec
PMID:Colchicine-induced modulation of collagenase in human skin fibroblast cultures. II. A probe for defective regulation in epidermolysis bullosa. 629 10

Hydrocortisone and dexamethasone prevent the appearance of gelatinase in serum-free explant cultures of normal human skin. Hydrocortisone inhibits maximally at 10(-6) M and dexamethasone at 10(-8) M in culture medium. Glucocorticoids at these concentrations do not cause a generalized decrease in protein synthesis; thus the effect on gelatinase shows specificity. The reduction in gelatinase activity caused by dexamethasone can be overcome in the presence of dexamethasone 21-mesylate, a glucocorticoid antagonist that binds irreversibly to the cytoplasmic steroid receptor. These data suggest that the enzymes of collagen degradation, collagenase and gelatinase, may be coregulated.
J Invest Dermatol 1983 Jun
PMID:Regulation of gelatinase in human skin organ cultures by glucocorticoids. 630 1

The enzyme activities of normal-looking skin and blister fluid from a patient with recessive dystrophic epidermolysis bullosa (RDEB) were measured. Of the hydrolytic enzymes measured, both collagenase and neutral protease activities were considerably increased in the skin and blister fluid samples compared with values found in normal control skin and in blister fluid from a patient with a burn. In addition, skin from a healthy person cultured with RDEB blister fluid showed dermal-epidermal separation. These findings suggest that collagenase and neutral protease may be involved in the formation of blisters in RDEB.
Br J Dermatol 1983 Jun
PMID:Increased neutral protease and collagenase activity in recessive dystrophic epidermolysis bullosa. 630 83


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