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)

Studies of aural and other body tissues suggest that otosclerosis represents the local manifestation of a general disorder of connective tissue. In particular, collagen abnormalities have been described. We have undertaken a pilot study of the in vivo messenger RNA (mRNA) transcription for procollagenase (precursor of collagenase), as well as for stromelysin and tissue inhibitor of metalloprotease (TIMP), an activator and a specific inhibitor of tissue collagenase activity, respectively. Human skin from individuals with surgically confirmed otosclerosis was compared to skin from their family members (clinically positive and clinically negative) and from unrelated normal controls. Preliminary data indicate that on average there are significantly lower levels of mRNA production for stromelysin among individuals with otosclerosis as compared to all others tested. Similar trends were demonstrated for TIMP and procollagenase, although these did not achieve statistical significance. In addition to suggesting a pathogenetic mechanism for the development of the disease, these data could serve as the basis of possible confirmatory tests for early diagnosis of otosclerosis and as a method for evaluating the genotype of offspring of affected individuals prior to their age of clinical manifestation. This could translate into the application of prophylactic treatment regimens in the future. The proposed abnormalities also suggest candidate genes for otosclerosis.
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PMID:Aberration of the tissue collagenase system in association with otosclerosis. 144 74

In this study, we determined the effects of indomethacin and calcitonin on bone resorption in otosclerosis-like lesions in rats. Morphometric analysis showed that both indomethacin and calcitonin inhibited active otosclerosis-like lesions (bone resorption) and rats immunologically induced with type II collagen, and indomethacin had a much higher inhibitory effect than calcitonin. In in vitro studies we found that conditioned medium from splenic lymphocytes of rats immunized with type II collagen stimulated collagenase production by macrophages and fibroblasts. Collagenase is the major enzyme for degradation of the organic components of bone. Treatment of the immunized rats with indomethacin and calcitonin significantly reduced the stimulatory effect of the lymphocyte-conditioned medium on collagenase production. Indomethacin caused a greater reduction of the stimulatory effect of the lymphocytes on collagenase production than calcitonin. These findings are in agreement with results of the morphometric study. Results of the present study also suggest that cell-to-cell interaction plays an important role in collagenase production for degradation of organic components of bone resorption in otosclerotic lesions.
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PMID:Effects of indomethacin and calcitonin on bone absorption in type II collagen-induced otosclerosis-like lesions in rats. 217 35

The hypothesis that otosclerosis is a local manifestation of a clinically and genetically heterogeneous group of generalized connective tissue disorders was tested by quantitative biochemical techniques. In contrast to previous studies, no significant differences were found in individual glycosaminoglycans excreted in urine of control subjects and patients with otosclerosis. Moreover, no significant differences were detected in the rate of synthesis and secretion of glycosaminoglycans and collagen in skin fibroblast cultures of patients and controls. Preliminary results obtained with more sensitive and specific methods suggest a possible error in collagen metabolism. Polyacrylamide gel electrophoresis revealed slight differences in migration patterns of several collagenous proteins between patients and control subjects. In addition, collagenase was significantly increased in three of five patients.
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PMID:Otosclerosis: a local manifestation of a generalized connective tissue disorder? 282 43

The otosclerotic stapes footplate exhibits higher activities of cathepsin D and H and collagenase-like peptidase than those of normal cortical bone. The elevated enzyme activities of osteoblastic origin (Cl-peptidase and cathepsin D) emphasize the essential and probably primary role of the bone-forming cells, not only in bone formation, but in resorption as well. The highest activity of cathepsin D from among the measured enzymes highlights the adjuvant role of acidic glucosaminoglycans in the otosclerotic demineralization process. As the osteoblastic osteoid synthesis is known to be sharply reduced in otosclerotic bone remodelling, and the above data emphasize the role of proteolytic enzymes of osteoblastic origin too, indirectly, osteoblasts seem to be the otosclerosis signal-transducing cells.
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PMID:Proteolytic enzymes in otosclerosis. Significance of proteolytic enzymes in otosclerotic bone remodelling. 332 89

In adult guinea-pig stapes organ cultures, 3H (2,3)-proline incorporation into the collagenase-digestible protein (CDP) and non-collagen protein (NCP) fractions of the ossicles was measured and the percentage of collagen synthesis (PCS) was calculated. Prostaglandin E2 (PGE2), a potent stimulator of bone resorption, inhibited the PCS in low concentrations (5 and 25 microM), whereas it stimulated it in pharmacological concentrations (50 and 100 microM). Ipriflavon, an isoflavone derivative of therapeutical potential in otosclerosis, also reduced the PCS in 1, 10 and 50 microM concentrations. 50 microM Ipriflavon stimulated the PCS inhibited by 5 microM PGE2, but decreased the PGE2-induced PCS enhancement in vitro.
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PMID:Effect of flavonoid on PGE2-induced alterations in percentage collagen synthesis in ossicle organ cultures. 347 54

Localized bone resorption in the otic capsules of experimental rats was induced by immunization with type II collagen. The otospongiosis-like lesion showed enlarged vascular spaces that contained many fibroblasts and macrophages as well as occasional osteoclasts. A high level of acid phosphatase activity in the sera of immunized rats suggested that this enzyme is one of the important factors causing decalcification of the bony otic capsule, the first step of bone resorption. Immunofluorescent assay showed that collagenase and cyclooxygenase (prostaglandin synthetase) appeared within macrophages, fibroblasts, and osteoclasts in the bone resorption areas. These findings suggest that the collagenase and prostaglandin synthetase being produced by macrophages, fibroblasts, and osteoclasts are also involved in the processes of bone resorption in otospongiosis. Immunolocalization assay showed deposition of immunoglobulin and fibronectin on the bone matrix and vascular wall within the otospongiotic lesions. Chemotaxis studies showed that both anti-type II collagen serum and fibronectin might play a role as chemoattractants to recruit macrophages and fibroblasts to the bone resorption sites. In vitro studies also showed anti-type II collagen serum stimulates the fusion of macrophages to become multinucleated osteoclast-like cells. The antiserum also activate these cells to produce collagenase and prostaglandin synthetase. It is concluded that the chemotactic processes of macrophages and fibroblasts, the multinucleation of macrophages, and the activation of these cells may be basic processes causing bone resorption in otosclerosis. When sodium fluoride, an inhibitor of hydrolytic and proteolytic enzymes, was given to rats immunized with type II collagen, no obvious inhibition of bone resorption was seen in histologic sections.
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PMID:Bone resorption in experimental otosclerosis in rats. 350 79

Collagen autoimmunity has been suggested as one etiologic mechanism to otosclerosis. Although substantial studies relating this disease to collagen autoimmunity have been reported, a basic understanding of the pathogenic mechanism involved is lacking. Some otosclerosis patients have a high level of antibody to type II collagen. In addition, complement and antibody were deposited in the stapes from otosclerosis patients. Furthermore, the otic capsule and stapes have been found to contain type II collagen by immunohistologic studies and biochemical analysis. Otospongiosis-like lesions have also been produced in rats by immunizing them with type II collagen. This finding led us to postulate a hypothesis of an autoimmunity to type II collagen as an etiopathogenesis of this illness. Our initial hypothesis has been updated to incorporate new findings in the field of cell biology. The role of interleukin 1, osteoclasts, osteoblasts, bone resorption, and other factors such as minor collagens, calcitonin, vitamin D, parathyroid hormone, collagenase, and prostaglandins are incorporated in this updated hypothesis.
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PMID:Enchondral cartilage rests collagen-induced autoimmunity: a possible pathogenetic mechanism of otosclerosis. 350 78

The beneficial role of bioflavonoids in an otosclerosis-like bone-remodelling process can be implicated from its interference with bone resorption induced by prostaglandin E2 (PGE2) in cultured guinea pig ossicles. Ipriflavone (7-isopropoxy-isoflavon) and quercetin reduced PGE2-elevated collagenase-like peptidase (Cl-peptidase) activity and potentiated a PGE2-induced decrease in collagen synthesis. The fact that PGE2 effects are mediated through cyclic AMP in bone turnover and flavonoids act synergistically with PGE2 in collagen synthesis confirm a cyclic AMP phosphodiesterase inhibitory role of flavonoids. It has already been attempted to use Ipriflavone medical treatment of otosclerosis. Quercetin, which has a better than Ipriflavone water-solubility seems as promising as Ipriflavone in the control of the otosclerotic bone-remodelling disturbance.
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PMID:Flavonoids alter bone-remodelling in auditory ossicle organ cultures. 761 Aug 25