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)

Doxycycline, a member of the tetracycline family, has been shown to reduce a type X collagen epitope as detected by immunohistochemistry with a monoclonal antibody in an avian explant culture system (). It was also shown to decrease collagenase and gelatinase activities and thus matrix degradation. This study investigates the effect of doxycycline on type X collagen synthesis in monolayer cultures of hypertrophic chondrocytes. Protein synthesis was evaluated by radioisotopic labeling during doxycycline, tetracycline, or minocycline treatment. Radiolabeled proteins were analyzed by gel electrophoresis, and total collagen was quantitated by hydroxyproline analysis. Additionally, the synthesis of type X collagen was measured by immunoprecipitation. Doxycycline was found to inhibit type X production more effectively than either of the other tetracyclines at comparable dose levels. Furthermore, type X collagen was inhibited more than other collagens, non-collagenous proteins and proteoglycans, with maximal inhibition at 80 microg/ml and an IC50 of 7 microg/ml. This inhibition by doxycycline was specific for type X collagen at 10 microg/ml, and the pattern was distinct from cycloheximide, a recognized inhibitor of protein translation. This suppression of type X collagen could not be overcome by excess extracellular calcium, conditions that have been demonstrated to induce synthesis of this protein (2).
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PMID:Doxycycline inhibits type X collagen synthesis in avian hypertrophic chondrocyte cultures. 882 32

Diabetes produces extensive alterations of collagen metabolism including enhanced gingival collagenase activity. However, the mechanism for this enhanced enzyme activity is unclear. Collagenase is secreted from cells in a latent form and plasmin has been proposed as an important in vivo activator of procollagenase. Plasmin is converted from its precursor, plasminogen, by the proteolytic action of a serine proteinase, plasminogen activator (PA). The current study was therefore undertaken to determine the effect of diabetes on gingival PA activity in the rat. Since doxycycline is a potent collagenase inhibitor, the effect of doxycycline on gingival PA activity was also investigated. Eighteen male, Sprague-Dawley rats were made diabetic by streptozotocin injection (7 mg/100 g). Control rats (N = 8) were sham-treated. Doxycycline (5 mg/day/rat) was administered to 9 of the 18 diabetic rats by gavage on a daily basis. The other 9 diabetic rats were administered with saline. After 3 weeks, blood and gingival tissue were collected from each rat for the determination of glucose level and gingival PA activity. The tissues were then minced and extracted with 5 mM sodium phosphate containing 1% Triton X-100. PA assay was performed using chromatogenic substrate to determine PA activity in the extracts. Gingival PA activity in the diabetic rats was significantly reduced compared to the control (13.5 +/- 1.6 vs. 36.0 +/- 3.3 microunits/100 micrograms protein, P < 0.01). Doxycycline administration to diabetic rats had no effect on the already reduced gingival PA activity (10.4 +/- 3.5 in doxycycline-treated rats vs. 13.5 +/- 1.6 mu units/100 micrograms protein in untreated diabetic rats). PA activities in gingival tissues from the diabetic, nondiabetic control and doxycycline-treated diabetic groups were also demonstrated on zymographs as lytic bands. Regarding the well-known fact that gingival collagenase activity is enhanced during diabetes, our results did not support the notion that this biochemical alteration is attributed to increased activation of procollagenase by PA.
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PMID:Plasminogen activator activity is decreased in rat gingiva during diabetes. 886 12

The collagenolytic activity and its sensitivity to doxycycline inhibition in tracheal aspirates (TA) of horses with chronic obstructive pulmonary disease (COPD) was analyzed with SDS-PA gel electrophoresis (SDS-PAGE), using Type 1 collagen as the substrate. Both autoactive and total collagenase activities were significantly higher in TAs of horses with symptomatic COPD than in TAs of healthy horses. Doxycycline inhibition studies suggest that most of the TA collagenase is of the neutrophil type (MMP-8), but some is derived from other cells such as fibroblasts and monocyte/macrophages (MMP-1) and bacteria (bacterial collagenases). Drugs inhibiting collagenases in the respiratory tract might be worth a trial in the treatment of COPD in horses.
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PMID:Collagenolytic activity and its sensitivity to doxycycline inhibition in tracheal aspirates of horses with chronic obstructive pulmonary disease. 912 42

Collagenase and gelatinase are matrix metalloproteinases (MMPs) which play an important role in tissue destruction in arthritic joints. Studies have demonstrated that tetracyclines can inhibit MMPs and prevent tissue destruction independent of their antimicrobial activity. The purpose of this pilot study is to assess the potential therapeutic role of Doxycycline in patients with advanced osteoarthritis of the temporomandibular joint (TMJ). This ongoing investigation includes patients with a diagnosis of osteoarthritis of the TMJ based on clinical and diagnostic imaging findings, symptoms (localized TMJ pain, limited mobility, dysfunction) for a minimum of 36 months, and failure of previous non-surgical and surgical modalities to alleviate the symptoms. A synovial fluid sample is collected by a saline injection and aspiration technique, followed by diagnostic arthroscopy. Patients are placed on Doxycycline 50 mg BID for three months and then undergo repeat diagnostic arthroscopy and synovial fluid collection. The samples are stored at -80 degrees C. Collagenase activity is determined by a combination of SDS-polyacrylamide gel electrophoresis and fluorography and calculated based on the percentage of collagen alpha chains that are degraded into alphaA breakdown products. Three patients have completed the three-month course of Doxycycline thus far, and 5 joints with osteoarthritis have been analyzed. All patients were female (mean age = 35, mean duration of symptoms = 132 months) and had undergone previous bilateral arthroscopies. One patient had undergone unilateral arthroplasty. The mean collagenase activity showed 55% collagen lysis prior to Doxycycline treatment and 19% after three months of therapy. The mean gelatinase activity was 28% prior to Doxycycline treatment and 7% after three months of therapy. The mean interincisal opening was 33 mm initially and 41 mm after three months of Doxycycline. Subjectively, two of the three patients reported significant improvement in their overall symptoms, which they had not experienced over the previous three years. One patient did not experience any change in symptoms, in spite of a marked reduction in collagenase activity from 86.4% to 9.6%. Because of the very small numbers of patients enrolled in this pilot study so far, no statistically significant differences could be appreciated. However, the dramatic reduction in collagenase activity in these patients, with a long history of TMJ symptoms from osteoarthritis, suggests the potential promising role of Doxycycline in the management of osteoarthritis, and further investigation is warranted.
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PMID:The potential role of doxycycline in the treatment of osteoarthritis of the temporomandibular joint. 997 22

Doxycycline is a commonly used broad-spectrum antibiotic. Recently, it has been shown that it also inhibits the activity of mammalian collagenases and gelatinases, an activity unrelated to its antimicrobial efficacy. In this study, we show that doxycycline not only inhibits MMP-8 and MMP-9 (gelatinase B) activity, but also the synthesis of MMPs in human endothelial cells. Doxycycline (50 microM) completely inhibited the phorbol-12-myristate-13-acetate (PMA)-mediated induction of MMP-8 and MMP-9, as measured by Western blotting and gelatin zymography, respectively. The inhibition was also observed at the mRNA level. No effect was observed on the expression of MMP-2 and of the MMP inhibitors TIMP-1 and TIMP-2. Chemically modified tetracyclines (CMTs) showed an inhibition similar to that of doxycycline, albeit less efficient. These observations demonstrate that endothelial cells display a specific regulation of MMPs, which may have implications for the pharmaceutical interaction in angiogenesis and angiogenesis-related diseases.
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PMID:Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells. 997 33

The objective was to assess the effect of doxycycline treatment on a magnetic resonance imaging (MRI) biomarker of cartilage volume loss, and on matrix metalloproteinase (MMP) activity in a guinea pig osteoarthritis model. Guinea pigs (9 months old) were dosed with vehicle or doxycycline, 0.6, 3.0 mg/kg/day for 66 days. Fat-suppressed 3D gradient-echo MRI of the left knee was acquired pre- and post dosing. Change in medial tibial plateau (MTP) cartilage volume (MT.VC) was determined using image analysis. At termination, MTP cartilage was removed from knees and proteolytic MMP activity determined using a fluorescent peptide substrate assay. Vehicle-treated animals lost 20.5% (95% CI mean 25.6-15.1) MT.VC. The doxycycline (0.6 mg/kg/day) group lost 8.6% (P < 0.05, 95% CI 20.6 to -5.3) whilst the 3.0 mg/kg/day group lost 10.0% (P < 0.05, 95% CI 13.9-6.0%). Endogenous levels of active MMPs were below limits of detection in all samples. However, doxycycline treatment ablated amino phenyl mercuric acid activated MMP-13 and MMP-8 levels, reduced MMP-9 levels by 65% and MMP-1 levels by 24%. Doxycycline treatment resulted in partial protection from MT.VC loss and was associated with complete reduction in MMP-13 and MMP-8, and partial reduction in MMP-9 activity. These data imply a role of MMPs in cartilage degeneration but incomplete protection suggests that additional doxycycline insensitive mechanisms are important in this model. The protective effect of doxycycline correlates with the clinical finding of lessened joint space narrowing, strengthens the utility of this animal model in identifying disease-modifying osteoarthritic drugs and supports the use of MRI biomarkers of cartilage loss.
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PMID:Evaluation of a magnetic resonance biomarker of osteoarthritis disease progression: doxycycline slows tibial cartilage loss in the Dunkin Hartley guinea pig. 1933 56


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