ライフサイエンスコーパス: MMP-12

1 igh affinity and selectivity of RXP470.1 for MMP-12.

2 a(1) is a potent stimulator of Bax, Bid, and MMP-12.

3 s with NOE contacts unique to inhibitor-free MMP-12.

4 CCR2 on podocytes may underlie induction of MMP-12.

5 4 > MMP-15 > MMP-11 and -17 > MMP-1 and -3 > MMP-12.

6 -1, -11, -15, -16, and -19 > MMP-3 and 17, > MMP-12.

7 GBM due to MMP dysregulation, in particular, MMP-12.

8 trix metalloproteinase-3 (MMP-3), MMP-9, and MMP-12.

9 increased levels of mRNA encoding MMP-3 and MMP-12.

10 ing sCD14 in a process mediated by MMP-9 and MMP-12.

11 with markedly increased levels of MMP-9 and MMP-12.

12 14 by IL-13 was diminished in the absence of MMP-12.

13 arkedly decreased in the absence of MMP-9 or MMP-12.

14 of MMP-9, but not by isolated deficiency of MMP-12.

15 ng RSV infection and suppressed the level of MMP-12.

16 bitor, RXP470.1 to target the active form of MMP-12.

17 using MMP408, a pharmacological inhibitor of MMP-12.

18 s the active form of the catalytic domain of MMP-12.

19 tive probe would therefore not have detected MMP-12.

20 ted that macrophages were the sole source of MMP-12.

21 2 (76+/-7; P<0.05 versus control), increased MMP-12 (161+/-27% versus control; P<0.05), and increased

22 osatellite > or =24 CA repeat allele and the MMP-12-82 GG polymorphisms were associated with invasive

23 8%), MMP-8 (75+/-11%), MMP-9 (69+/-14%), and MMP-12 (85+/-15%) were decreased compared with control (

24 dence implicates macrophage metalloelastase (MMP-12), a macrophage-derived elastinolytic protease in

25 is mechanism operates in vivo, we focused on MMP-12, a macrophage-specific MMP known to mediate emphy

26 reducing pathological angiogenesis, lack of MMP-12 accelerated revascularization of avascular retina

27 delineating the signaling pathway regulating MMP-12 activation, potential therapeutic strategies that

28 Accordingly, molecular imaging of the MMP-12 active form can inform of the pathogenic process

29 ition in which the hydrogen bonding with the MMP-12 active site is less favorable in phosphinic inhib

30 r establishes multiple interactions with the MMP-12 active site, with its long P(1)' side chain filli

31 esis of COPD and might suggest that blocking MMP-12 activity in patients with COPD could prevent the

32 ein, the oxidant-deficient cells had greater MMP-12 activity than wild-type macrophages.

33 monstrate that plasmin and thrombin regulate MMP-12 activity through distinct mechanisms: post-transl

34 , a broad spectrum MMP inhibitor that blocks MMP-12 activity, results in largely restored GBM ultrast

35 transcripts upregulated (arginase-1, IL-1Ra, MMP-12, ADAM8, VEGF, and Clec-7a).

36 o groups are equivalent; thus, it seems that MMP-12 affects lung tumor growth, and not metastasis for

37 Specific knockdown of MMP-12 after focal cerebral ischemia offers neuroprotect

38 The hemopexin domains of MMP-12 and -9 each increased k(cat)/K(m) toward this sub

39 raphy and NMR spectra, prevents autolysis of MMP-12 and allows us to determine its NMR structure with

40 liferator-activated receptor gamma inhibited MMP-12 and Api-6 promoter activities.

41 Transcriptional activities of the MMP-12 and Api-6 promoters were stimulated by Spi-C or M

42 -1 and MMP-3 map to similar locations across MMP-12 and encompass the internal conformational adjustm

43 combined a favorable affinity profile toward MMP-12 and faster blood clearance.

44 oproteinases (MMPs), selective inhibitors of MMP-12 and MMP-13 are available and may be appropriate f

45 In contrast, macrophage expression of MMP-12 and MMP-13 is not altered by LXR ligands.

46 the approach for two distinct MMP proteases, MMP-12 and MT1-MMP (or MMP-14).

47 esponse to methacholine; and upregulation of MMP-12 and PAR2 expression.

48 2, respectively, to investigate the roles of MMP-12 and PAR2 in PCFs mediating airway diseases.

49 SLLRY-NH2 were the selective antagonists for MMP-12 and PAR2, respectively, to investigate the roles

50 two elastase-like activities consistent with MMP-12 and possibly MMP-7.

51 MMP-3, MMP-12, and MMP-13 levels also correlated with mean PD o

52 re noted between MMP-2, MMP-3, MMP-8, MMP-9, MMP-12, and MMP-13 levels and percentage of sites with P

53 MMP-1, MMP-8, MMP-9, MMP-12, and MMP-13 levels were reduced significantly up

54 levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-12, and MMP-13 were assessed using fluorometric kits

55 ession of MMP-14, while MMP-2, MMP-3, MMP-7, MMP-12, and MMP-13 were not induced by this peptide.

56 CD68, MMP-12, and MMP-13 were significantly higher in CC10-IL-

57 ssion of matrix matalloproteinase-1 (MMP-1), MMP-12, and MMP-9.

58 ression were observed with exodus-1 (CCL20), MMP-12, and RhoA.

59 s occurred at least partially via modulating MMP-12, and the activation of PAR2 might be related to P

60 increased levels of beta interferon, MMP-3, MMP-12, and TIMP-1 mRNA.

61 Many of these MC/Mph produced MMP-12- and TIMP-1-dependent tunnels coupled with acquis

62 alloelastase or matrix metalloproteinase-12 (MMP-12) appears to exacerbate atherosclerosis, emphysema

63 results showed a predominant upregulation of MMP-12 (approximately 47, 58, 143, and 265 folds on days

64 hat MMP-9, MMP-3, and MMP-7 but not MMP-2 or MMP-12 are needed for resistance.

65 metalloproteinase (MMP)-1, MMP-3, MMP-10 and MMP-12, are key players in the development of ulcers in

66 MMP-12 association with diverse cell membranes may targe

67 Both interfaces mediate MMP-12 association with vesicles and cell membranes.

68 Significantly, loss of MMP-12 attenuated retinal capillary dropout in early OIR

69 MMP-12 binds plasma membranes and is internalized to hyd

70 ons beside the active site, TIMP-2-inhibited MMP-12 binds vesicles and cells, suggesting compensatory

71 d intense synergistic increases in MMP-3 and MMP-12 but not in MMP-9.

72 thesis was not required for early release of MMP-12 but was required for later secretion of activated

73 ease of matrix metalloproteinase (MMP)-9 and MMP-12 by neutrophils and alveolar resident cells.

74 In conclusion, the active form of MMP-12 can be detected by optical imaging using RXP470.1

75 How does the MMP-12 catalytic domain achieve this specificity?

76 Supporting this observation, MMP-12 caused the release of sCD14 from RAW 264.7 cells

77 Thus, MMP-12/CCR2 inhibitors may provide a novel and effective

78 terminal amino acid sequencing revealed that MMP-12 cleaved TFPI at Lys(20)-Leu(21)(close to Kunitz I

79 dy we found that macrophage metalloelastase, MMP-12 cleaves, in vitro, apolipoprotein(a) (apo(a)) in

80 The higher stability of MMP-3 relative to MMP-12 coincides with the former's considerably lower pr

81 d never smokers), we measured induced sputum MMP-12 concentrations (ELISA) and enzyme activity (fluor

82 computed tomography (CT) and induced sputum MMP-12 concentrations and activity in patients with asth

83 Sputum MMP-12 concentrations and activity in patients with COPD

84 The influence of disease severity on sputum MMP-12 concentrations and activity is not known.

85 o values, is directly associated with sputum MMP-12 concentrations and activity.

86 Sputum MMP-12 concentrations are greater in patients with COPD

87 ociation between disease severity and sputum MMP-12 concentrations or activity.

88 12(-/-)/SP-D-/- mice demonstrating MMP-9 and MMP-12 contribute to proteolytic shedding of CD14.

89 MMP-9 inhibiting neutrophil accumulation and MMP-12 contributing to the accumulation of eosinophils a

90 a model in which trophoblasts and VSMCs use MMP-12 cooperatively to degrade elastin during vascular

91 In contrast, a deficiency in MMP-12 decreased the recovery of leukocytes, eosinophils

92 tion in the number of T cells in the injured MMP-12-deficient animals as compared to controls, levels

93 mulated pulmonary fibrosis is ameliorated in MMP-12-deficient animals.

94 s and other proinflammatory cytokines in the MMP-12-deficient mice may underlie the decrease in leuko

95 Using MMP-12-deficient mice we found a significant reduction i

96 onchoalveolar lavage fluid of CRA-challenged MMP-12-deficient mice, relative to CRA-challenged contro

97 e in lungs of wild-type, MMP-9-deficient, or MMP-12-deficient mice.

98 and -14 is mediated at least partially by an MMP-12-dependent pathway.

99 nsit via a mechanism that is neither NE- nor MMP-12-dependent.

100 that mice deficient in macrophage elastase (MMP-12) develop significantly more gross Lewis lung carc

101 Here we demonstrate the binding of MMP-12 directly to bilayers and cellular membranes using

102 For example, metalloelastase (MMP-12) displays higher apparent affinity for fEln-100,

103 d buried fibrous layers were reduced in apoE/MMP-12 double knockouts compared with controls, and doub

104 poE)/MMP-3, apoE/MMP-7, apoE/MMP-9, and apoE/MMP-12 double knockouts with their age-, strain-, and se

105 This new probe can detect the active form of MMP-12 down to a threshold of 1 fmol.

106 s 2.8 kcal/mol higher folding stability than MMP-12(E219A).

107 The regulation of MMP-12 elastin degradation was defined mechanistically u

108 However, the signaling pathway regulating MMP-12 expression and its potential role in human chondr

109 The inhibition of MMP-12 expression by TGF-beta1 suggests that TGF-beta1,

110 ments with CTB-conditioned medium stimulated MMP-12 expression in medial VSMCs.

111 nce, little is known about the regulation of MMP-12 expression in the context of atherosclerosis.

112 MMP-12 expression is induced in human chondrocytes durin

113 MMP-12 expression was localized to neurons, oligodendroc

114 We find that MMP-12 expression was upregulated in OIR, accompanied by

115 dly upregulates matrix metalloproteinase 12 (MMP-12) expression and its activity in human chondrosarc

116 ere we show that macrophage metalloelastase (MMP-12) expression is >40-fold induced in glomeruli from

117 In contrast, metalloelastase (MMP-12) expression is absent in these samples.

118 ative stress, or matrix metallopeptidase 12 (MMP-12) expression.

119 3) and metalloprotease (macrophage elastase, MMP-12) families.

120 The alpha1(V) THP protected MMP-12 from the NMR line broadening effects of Gd .EDTA

121 spectrum MMP inhibitor that does not inhibit MMP-12, had no effect.

122 Increased expression and production of MMP-12 have been found in the lung of human COPD patient

123 Increased expression and production of MMP-12 have been observed in the lungs of asthmatic pati

124 gelatinase (MMP-9) and macrophage elastase (MMP-12) have been implicated in this disease, but it is

125 Compared to crystal structures of MMP-12, helix B (hB) at the active site is unexpectedly

126 While binding of TIMP-2 to MMP-12 hinders membrane interactions beside the active s

127 tivated, Bax-mediated pathway and downstream MMP-12 in a variety of fibrogenic settings.

128 ively high affinity, as well as embedding of MMP-12 in damaged elastin fibrils in vivo.

129 However, little is known about the role of MMP-12 in retinal pathophysiology.

130 These data define a role for MMP-12 in suppressing the growth of lung metastases and

131 highlights the possible pathological role of MMP-12 in the context of ischemic stroke.

132 also suppressed the expression of MMP-3 and MMP-12 in the heart of mdx mice.

133 This finding supports a role for MMP-12 in the pathogenesis of COPD and might suggest tha

134 aradigm elastase macrophage metalloelastase (MMP-12) in its turnover during fibrosis.

135 shown an important role of metalloelastase (MMP-12) in the pathogenesis of acute and chronic lung in

136 s, the compound was orally efficacious in an MMP-12 induced ear-swelling inflammation model in the mo

137 induction, as demonstrated by the absence of MMP-12 induction in plasminogen(Plg)-treated urokinase-t

138 Using competition assays with a selective MMP-12 inhibitor as well as MMP-12 knock-out mice, one o

139 27 was identified as a potent and selective MMP-12 inhibitor possessing good physicochemical propert

140 y of fluorescent probes based on a selective MMP-12 inhibitor, RXP470.1 to target the active form of

141 MMP408 (14), a potent and selective MMP-12 inhibitor, was derived from a potent matrix metal

142 The crystal structure of MMP-12/inhibitor complex (1.15 A) reveals that the inhib

143 electivity toward MMP-12 similar to the best MMP-12 inhibitors reported to date.

144 group (ZBG), we have carried out a study on MMP-12 inhibitors with a common peptidic core but differ

145 Taken together, we conclude that MMP-12 is a key regulator of macrophage infiltration and

146 The presence of MMP-12 is associated with decreased tumor-associated mic

147 MMP-12 is expressed by both interstitial and endovascula

148 Taken together, MMP-12 is induced by several factors implicated in ather

149 dicate that the binding of this inhibitor to MMP-12 is mostly entropy driven (DeltaG degrees = -13.1

150 Like other members of MMP family, MMP-12 is produced as a proenzyme, mainly by macrophages

151 MMP-12 is solely macrophage derived in this model, being

152 Human metalloelastase (MMP-12) is a macrophage-specific MMP with broad substrat

153 alloelastase (matrix metalloproteinase-12 or MMP-12) is unique among MMPs in exerting high proteolyti

154 with a selective MMP-12 inhibitor as well as MMP-12 knock-out mice, one of these proteins was identif

155 uced from 62.87+/-4.13 to 34.67+/-5.39 after MMP-12 knockdown compared to untreated MCAO subjected ra

156 ons of MCAO-subjected rats was reduced after MMP-12 knockdown in addition to the reduced protein expr

157 in the extent of apoptosis was noticed after MMP-12 knockdown.

158 P-9 was reduced in ischemic rat brains after MMP-12 knockdown.

159 is in oxygen-induced retinopathy (OIR) using MMP-12 knockout (KO) mice.

160 defined mechanistically using CD11b-DTR and MMP-12 knockout mice.

161 Compared to wildtype mice, MMP-12 KO mice had decreased levels of adhesion molecule

162 MMP-9 and MMP-12 levels were also elevated, but only MMP-12 showed

163 1 (collagenase-1), MMP-9 (gelatinase B), and MMP-12 (macrophage elastase) cleaved TFPI into several f

164 analysis and immunocytochemistry implicated MMP-12 (macrophage metalloelastase) as a key mediator of

165 Thus, factors influencing the expression of MMP-12 may have a modulating action on the biology of Lp

166 leaved SLPI and incubation with SP-A reduced MMP-12-mediated SLPI cleavage.

167 Previous investigations have suggested that MMP-12 (metalloelastase) may be an important mediator in

168 elastin accumulation and higher fibrosis in MMP-12(-/-) mice compared with WT.

169 Exposure of CCl(4) in MMP-12(-/-) mice led to a similar degree of overall fibr

170 t in the urine of the animals except for the MMP-12(-/-) mice.

171 NE -/- mice but was virtually absent in the MMP-12(-/-) mice.

172 determine if human macrophage elastase (HME; MMP-12) might participate in this disease.

173 levels of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MPO, and TIMP-1 using multianalyte bead-based en

174 ling with propagermanium blocks induction of MMP-12 mRNA and prevents GBM damage.

175 Immunosuppression increased both MMP-3 and MMP-12 mRNA levels in CNS resident cells, suggesting tha

176 n was restricted to CNS resident astrocytes, MMP-12 mRNA was expressed by both inflammatory cells and

177 human peripheral blood-derived macrophages, MMP-12 mRNA was markedly up-regulated by several pro-ath

178 a1) inhibited cytokine-mediated induction of MMP-12 mRNA, protein, and enzymatic activity.

179 retion was not accompanied by an increase in MMP-12 mRNA, we examined post-translational mechanisms.

180 ection induced increased levels of MMP-3 and MMP-12 mRNAs as well as that of tissue inhibitor of matr

181 o apo(a) cleavage, we injected intravenously MMP-12(-/-), NE -/- mice and litter mates, all of the sa

182 ubtly perturbed amide NMR chemical shifts of MMP-12 not only in the active site cleft but also at rem

183 lytic domain of matrix metalloproteinase-12 (MMP-12 or macrophage metalloelastase) primed for catalys

184 Macrophage elastase (MMP-12 or MME) proved to be the most efficient angiostat

185 Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosa

186 Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosarcoma cell

187 ls in vitro, which are blocked by inhibiting MMP-12, PI3-K, p38 or JNK activity.

188 Finally, they demonstrate that Bax, Bid, and MMP-12 play similar roles in bleomycin-induced fibrosis,

189 MMP-12 plays a significant role in airway inflammation a

190 These studies indicate that MMP-12 plays an important proinflammatory role in the de

191 ide evidence that, in the mouse strain used, MMP-12 plays an important role in the generation of F1 f

192 nostaining localized MMP-12 probe binding to MMP-12 positive areas and F4/80 positive macrophages in

193 Co-immunostaining localized MMP-12 probe binding to MMP-12 positive areas and F4/80

194 stance after RSV infection through mediating MMP-12 production via PAR2, indicating that the inhibiti

195 on of PAR2 might be related to PCF-modulated MMP-12 production.

196 Analyses of MMP-12 promoter through transient transfections and elec

197 MMP-12 protein levels were only modestly changed and in

198 Since increased MMP-12 protein secretion was not accompanied by an incre

199 s: post-translational secretion of preformed MMP-12 protein, induction of protein secretion that is p

200 pe macrophages produced equivalent levels of MMP-12 protein, the oxidant-deficient cells had greater

201 lastase activity; these cells also expressed MMP-12 protein.

202 ion of activated murine macrophage elastase (MMP-12) protein.

203 Moreover, the inhibition of MMP-12 reduced the total number of cells and macrophages

204 Macrophage-derived MMP-12 regulates elastin degradation even in progressive

205 importantly, we show that serine proteinase MMP-12 regulation in macrophages occurs via the protein

206 AR-1-activating peptides were able to induce MMP-12 release.

207 inhibitor toward matrix metalloprotease-12 (MMP-12) remain elusive.

208 eolytic cleavage by MMP-1, MMP-7, MMP-9, and MMP-12 resulted in considerable loss of TFPI activity.

209 Inhibition of MMP-12 secretion by hirudin and pertussis toxin demonstr

210 In vitro, the fraction of MMP-12 sequestered by insoluble elastin was two- to five

211 d MMP-12 levels were also elevated, but only MMP-12 showed synergism.

212 NE and MMP-12 showed the greatest activity toward the gamma2 ch

213 MMP-12 shRNA expressing plasmid formulation was administ

214 Moreover, a specific inhibitor of MMP-12 significantly reduced CTB- and HASMC-mediated ela

215 Transcriptional inactivation of MMP-12 significantly reduced the infarct size.

216 ides displays potency and selectivity toward MMP-12 similar to the best MMP-12 inhibitors reported to

217 seen in all of the MMP-1, MMP-3, MMP-8, and MMP-12 SNPs and in four of five MMP-9 polymorphisms test

218 of specificity of interactions, to evaluate MMP-12 specificity without a structure of a complex.

219 MMP-12 supports lesion expansion and destabilization.

220 The greater activity of MMP-12 than MMP-3 toward substrates from protein fibrils

221 viors associated with the higher activity of MMP-12 than MMP-3, using nuclear magnetic resonance to m

222 Why is MMP-12 the more active protease?

223 , and apoptosis; that TGF-beta(1) stimulates MMP-12, TIMP-1, and cathepsins and inhibits MMP-9 and p2

224 unoblots were used to evaluate MMP-3, MMP-9, MMP-12, TNF-alpha, IL-1alpha, IL-1beta, IL-6, TNF recept

225 owed the concentration of the active form of MMP-12 to be around 1 fmol/mul in BALf from nanoparticle

226 /- mice was dependent upon the activation of MMP-12 via an MMP-9-dependent mechanism.

227 (VEGF) B and D, which in turn transactivate MMP-12 via PI3-K, p38 and JNK signaling pathways.

228 ged and in coimmunoprecipitation experiments MMP-12 was bound in greater quantities to its inhibitor

229 eover, the inhibitory effect of TGF-beta1 on MMP-12 was dependent on Smad3.

230 eas mice deficient in both NADPH oxidase and MMP-12 were protected from spontaneous emphysema.

231 gs and activation of matrix metalloelastase (MMP-12) were found in mice with a hemorrhage phenotype.

232 ge elastase (matrix metalloproteinase-12, or MMP-12) were previously shown to be protected from the d

233 flammatory protein-1 (MIP-1alpha), MIP-2 and MMP-12, were decreased in macrophages isolated from macF

234 genes MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and MMP-12 with bladder cancer risk in 560 Caucasian patient

235 tromelysin (MMP-3), and macrophage elastase (MMP-12) without significantly increasing the production