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)

In inflammatory granuloma, synovial sclerosis or inflammation and in Dupuytren's contracture, the neocollagen contains chains and/or transverse links that are characteristic of rapidly growing immature tissues. In arthrosis, a conversion of collagen synthesis towards a cutaneous type may occur. The destruction of cartilage in rheumatoid arthritis is brought about by a specific collagenase that originates from the inflamed synovial membrane. Finally, certain forms of osteoporosis may be due to alterations of the osseous collagen which impair the mechanism of calcification.
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PMID:[Biochemistry of collagen and locomotor apparatus. Hereditary diseases of the connective tissue and rheumatic diseases (3)]. 19 5

The Freund's adjuvant-injected rat shares a number of features with the arthritis patient, viz the presence of a proliferative synovitis, joint swelling, and cartilage and bone erosion. Naproxen, a prostaglandin synthetase inhibitor which is an effective antiinflammatory agent in laboratory animals and humans, was evaluated as an inhibitor of connective tissue destruction in this model by use of radiologic and histopathologic analyses. Sixteen days after rats were injected with Freund's complete adjuvant, marked joint swelling was noted. On day 17, vehicle or naproxen, 7 mg/kg/day, was administered orally. Twenty-eight days later vehicle-treated animals demonstrated the following pathologic changes in their hindpaws; swelling, cartilage loss, large amounts of pannus within the joint spaces, osteoporosis, bone erosions, periosteal new bone formation, heterotopic ossification, and bony ankylosis. Rats treated 28 days with naproxen had significantly milder disease than the vehicle controls. The incidence of severe juxtaarticular bone destruction was 10/10 in the vehicle controls versus 2/10 of the drug-treated group (P less than 0.01). A comparable reduction in cartilage erosion, incidence of pannus, and new bone formation was noted in the drug-treated group. These effects may relate to an inhibition of prostaglandin biosynthesis; prostaglandins have been shown to: 1) stimulate collagenase secretion from macrophages, 2) stimulate bone resorption in vivo and in vitro, and 3) diminish proteoglycan synthesis in cartilage.
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PMID:Effects of naproxen on connective tissue changes in the adjuvant arthritic rat. 51 18

Matrix metalloproteinases are an important group of zinc enzymes responsible for degradation of the extracellular matrix components such as collagen and proteoglycans in normal embryogenesis and remodeling and in many disease processes such as arthritis, cancer, periodontitis, and osteoporosis. A matrixin family is defined, comprising at least seven members that range in size from Mr 28,000 to 92,000 and are related in gene sequence to collagenase. All family members are secreted as zymogens that lose peptides of about 10,000 daltons upon activation. Latency is due to a conserved cysteine that binds to zinc at the active center. Latency is overcome by physical (chaotropic agents), chemical (HOCl, mercurials), and enzymatic (trypsin, plasmin) treatments that separate the cysteine residue from the zinc. Expression of the metalloproteinases is switched on by a variety of agents acting through regulatory elements of the gene, particularly the AP-1 binding site. A family of protein inhibitors of Mr 28,500 or less binds strongly and stoichiometrically in noncovalent fashion to inhibit members of the family. The serum protein alpha 2-macroglobulin and relatives are also strongly inhibitory.
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PMID:Matrix metalloproteinases and their inhibitors in connective tissue remodeling. 185 Jul 5

The efficacy of sodium fluoride therapy for osteoporosis remains controversial. Evidence from clinical studies and from animals receiving fluoride has suggested that fluoride might act on bone to increase osteoblast numbers and matrix synthesis. In order to examine the hypothesis that fluoride has a direct mitogenic or anabolic action on the osteoblast, we tested the effect of fluoride on first passage human osteoblastic bone cells grown from collagenase-treated trabecular bone fragments. Under a variety of culture conditions, including both medium supplementation with serum and with a chemically defined medium, fluoride in doses ranging from 10(-6) to 10(-3) M did not alter cell proliferation as measured either by thymidine incorporation or by direct cell counting. Furthermore, exposure to fluoride under conditions of low serum supplementation did not alter either the total protein synthesis of the cells or their biosynthetic profile. These data suggest that fluoride does not act in vitro upon differentiated osteoblastic bone cells derived from adult human patients.
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PMID:Sodium fluoride does not increase human bone cell proliferation or protein synthesis in vitro. 173 78

Collagenase etching has been used to show the microstructure of bone from patients suffering from primary osteoporosis. Both polished and unpolished surfaces of trabecular bone from femoral heads were treated with collagenase solution before study in the scanning electron microscope. The polished surfaces show the mineral component of this bone as small rounded units approximately 10-20 nm across, which aggregate to form a continuous phase of contiguous spheroidal particles approximately 100 nm across. Lamellations are clearly seen to be due to the removal of collagen fibres up to approximately 200 nm across, fibres in adjacent lamellae being arranged approximately perpendicular to each other. The unpolished surfaces also show small rounded units, which aggregate into rods of mineral approximately 100 nm across. Although these rods form a connected system, they are loosely packed, compatible with their being interspersed with the collagen fibres in vivo. This model for the detailed microstructure of bone is consistent with specimens from a number of other sources and shows no features unique to osteoporosis.
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PMID:Osteoporotic bone microstructure by collagenase etching. 254 70

Using EDTA extraction and collagenase digestion, cancellous bone of the femoral heads from 10 normal and 9 osteoporotic subjects were analyzed for their contents of collagen, sialoprotein, proteoglycan and carbohydrate. The percentage of extracted matrix proteins of the osteoporotic bone in EDTA was significantly decreased, as was the collagenase-resistant fraction (p less than 0.05). The sialic acid level in osteoporotic bone matrix was lower than in controls (p less than 0.05). The alterations found in bone matrix constituents in osteoporotic bone relative to controls suggest that in osteoporosis and fractures, not only bone mass changes, but also bone quality changes play a role in bone strength.
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PMID:Studies on EDTA extracts and collagenase digests from osteoporotic cancellous bone of the femoral head. 282 Jun 17

Estrogens play a crucial role in the development of postmenopausal osteoporosis. However, the mechanism by which estrogens exert their effects on bone is unknown. To examine possible direct effects of 17 beta-estradiol on bone-forming cells, we used pure rat osteoblast-like cells in vitro as a model. Osteoblast-like cells prepared from calvaria of newborn rats were cultured serum-free in methylcellulose-containing medium for 21 days. Osteoblast-like cells proliferate selectively into clonally derived cell clusters of spherical morphology. 17 beta-Estradiol at concentrations of 0.1 nM and 1 nM enhanced osteoblast-like cell proliferation by 41% and 68% above vehicle-treated controls. The biologically inactive stereoisomer 17 alpha-estradiol (same concentrations) had no effect. Moreover, the antiestrogen tamoxifen abolished the stimulation of osteoblast-like cell proliferation by 17 beta-estradiol. After 21 days of culture, RNA was prepared and analyzed in a dot-hybridization assay for the abundance of pro alpha 1(I) collagen mRNA. Steady-state mRNA levels were increased in cultures treated with 17 beta-estradiol in a dose-dependent manner with maximal stimulation at 1 nM and 10 nM. At the same concentrations, the percentage of synthesized protein (labeled by [3H]proline pulse) that was digestible by collagenase was increased, indicating that 17 beta-estradiol acts at pretranslational levels to enhance synthesis of bone collagen. These data show that the osteoblast is a direct target for 17 beta-estradiol.
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PMID:Enhanced osteoblast proliferation and collagen gene expression by estradiol. 335 79

Osteoporosis is a slowly progressing disease resulting from an imbalance between bone accretion and degradation. As interstitial collagenase is a key enzyme in the degradation of bone matrix, we investigated a possible relationship between the collagenase gene and osteoporosis. Analysis of an amplified genomic DNA fragment from -524 to +52 by denaturing gradient gel electrophoresis and sequencing allowed us to detect three dimorphic sites upstream of base -300, one of them leading to a BanI restriction site. None of the sites could be directly associated with osteoporosis. The allele frequencies of the three dimorphic sites were estimated. The interallelic ratios were high, thus providing new useful genetic markers for linkage analysis. When comparing these ratios in osteoporotic and nonosteoporotic subjects, no significant differences could be observed.
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PMID:Investigation of the relationship between osteoporosis and the collagenase gene by means of polymorphism of the 5'upstream region of this gene. 779 53

Osteoporosis, especially the juxtaarticular osteoporosis of involved joints, is a characteristic manifestation of rheumatoid arthritis (RA). Histomorphometric studies suggest the existence of increased bone turnover in RA: impaired bone formation and hightened osteoclasic bone resorption. Recent studies show that important mediators in the pathogenesis of RA such as prostaglandin E, interleukin 1 (IL1) or tumor necrosis factor (TNF) alpha also play important roles in bone remodelling. Prostaglandin E2 promotes maturation of osteoclasts from hematopoietic precursor cells. IL1 inhibits collagen synthesis in osteoblasts. IL1 enhances collagenase and stromelysin gene expression and stimulates osteoclastic bone resorption. TNF alpha inhibits bone collagen synthesis and causes osteoclastic bone resorption. TNF alpha, and possibly IL1, enhances collagenase and stromelysin gene expression by stimulating the AP-1 promoter sites of the genes. Constitutive expression of c-fos induces joint destruction without lymphocyte infiltration in antigen-induced arthritis in mice, and supports cell growth of human rheumatoid synovial cells, possibly acting on the AP-1 sites. Furthermore, constitutive c-fos expression decreases collagen synthesis in osteoblasts and increases the mediator secretion from osteoblasts thereby stimulating osteoclastic bone resorption. These findings suggest that signal transduction through AP-1 transcriptional regulation sites may play an important role in the pathogenesis of joint destruction and osteoporosis in RA.
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PMID:Osteoporosis in rheumatoid arthritis: a molecular biological aspect of connective tissue gene activation. 780 9

Mechanical stimulation of bone tissue by physical activity stimulates bone formation in normal bone and may attenuate bone loss of osteoporotic patients. However, altered responsiveness of osteoblasts in osteoporotic bone to mechanical stimuli may contribute to osteoporotic bone involution. The purpose of the present study was to investigate whether osteoblasts from osteoporotic patients and normal donors show differences in proliferation and TGF beta production in responses to cyclic strain. Human osteoblasts isolated from collagenase-treated bone explants of 10 osteoporotic patients (average age 70 +/- 6 yr) and 8 normal donors (average age 54 +/- 10 yr) were plated into elastic rectangular silicone dishes. Subconfluent cultures were stimulated by cyclic strain (1%, 1 Hz) in electromechanical cell stretching apparatus at three consecutive days for each 30 min. The cultures were assayed for proliferation, alkaline phosphatase activity and TGF beta release in each three parallel cultures. In all experiments, osteoblasts grown in the same elastic dishes but without mechanical stimulation served as controls. Significant differences between stimulated cultures and unstimulated controls were determined by a paired two-tailed Wilcoxon test. In comparison to the unstimulated controls, osteoblasts from normal donors significantly increased proliferation (p = 0.025) and TGF beta secretion (p = 0.009) into the conditioned culture medium. In contrast, osteoblasts from osteoporotic donors failed to increase both proliferation (p > 0.05) and TGF beta release (p > 0.05) in response to cyclic strain. Alkaline phosphatase activity was not significantly affected (p > 0.05) in normal as well as osteoporotic bone derived osteoblasts. These findings suggest a different responsiveness to 1% cyclic strain of osteoblasts isolated from normal and osteoporotic bone that could be influenced by both the disease of osteoporosis and the higher average age of the osteoporotic patient group. While osteoblasts from osteoporotic donors failed to increase proliferation and TGF beta release under the chosen mechanical strain regimen that stimulated both parameters in normal osteoblasts, it is possible that some other strain regimen would provide more effective stimulation of osteoporotic cells.
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PMID:Human osteoblasts from younger normal and osteoporotic donors show differences in proliferation and TGF beta-release in response to cyclic strain. 866 81


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