Disease relevance of MMP12

• Transgenic studies have shown that when MMP1 is over-expressed, pulmonary emphysema develops in mice, while MMP12 knockout mice do not develop pulmonary emphysema when exposed to cigarette smoke [1].
• Both recombinant HME expressed in Escherichia coli and native HME derived from human alveolar macrophage-conditioned media degraded insoluble elastin [2].
• On transcriptional assay by quantitative RT-PCR and real-time RT-PCR analysis to validate those molecules, both transcripts of MMP-10 and MMP-12 were significantly more upregulated in recurred stage IB lung cancer than in the non-recurred stage IB lung cancer (P=0.004) [3].
• The MMP-12 structure is an excellent template for the structure-based design of specific inhibitors for emphysema therapy and for the construction of mutants to clarify the role of this MMP [4].
• In contrast to other MMPs, overexpression of MMP-12 is associated with increased survival in colorectal cancer, presumably as a result of an inhibitory effect on angiogenesis [5].

Psychiatry related information on MMP12

• The study took place at a freestanding sleep disorders center in Atlanta, Georgia, and two HME providers in Buffalo, New York, and Boston, Massachusetts. The patients comprised 21 adults who had been previously diagnosed with obstructive sleep apnea; there were 7 stable CPAP users with at least 1 year on therapy and 14 new users [6].

High impact information on MMP12

• Purified macrophage elastase degraded glycoprotein and elastin components but had no effect on the collagens [7].
• Macrophage elastase apparently does not degrade human granulocyte elastase-alpha 1-proteinase inhibitor complexes or release active granulocyte elastase from these complexes [8].
• After degradation by macrophage elastase, alpha 1-proteinase inhibitor is no longer able to inhibit human granulocyte elastase, a serine proteinase implicated in the pathogenesis of emphysema [8].
• Limited proteolysis by macrophage elastase inactivates human alpha 1-proteinase inhibitor [8].
• In vitro, the fraction of MMP-12 sequestered by insoluble elastin was two- to fivefold greater than other elastases found in AAA tissue [9].

Chemical compound and disease context of MMP12

• Using data from a population-based case-control study conducted among Chinese women in Shanghai, we evaluated the association of breast cancer risk and survival with two common polymorphisms in the MMP12 gene: A-82G in the promoter region and A1082G in exon, resulting in an amino acid change of asparagine to serine [10].
• When HME was incorporated into RBC ghosts by reversible hemolysis, the degree of inhibition of sodium efflux was comparable to that found with ouabain outside the red cells and was always greater than the inhibition produced with HME outside cells [11].
• In this study, we report that the steroid extract 5alpha, 8alpha-epidioxycholest-6-ene-3beta-ol (MME) from Meretrix meretrix has the ability to inhibit growth of hepatoma cells and to induce G1-phase cell cycle arrest in two human hepatoma cell lines, HepG2 and Hep3B [12].
• METHODS: 45 critically ill patients undergoing mechanical ventilation were included in the study and allocated to receive one of three humidification techniques: 1) Bennett Cascade water-bath humidifier (Bennett group); 2) Fisher & Paykel servocontrolled humidifier (F & P group); 3) HME Hygrobac DAR (HME group) [13].

Biological context of MMP12

• However, haplotypes consisting of alleles from the MMP1 G-1607GG and MMP12 Asn357Ser polymorphisms were associated with rate of decline of lung function (P = 0.0007) [14].
• Conversely, the SW480 transformants showed up-regulation of MMP12 and MMP17 [15].
• In a Caucasian population, polymorphisms in the MMP1 and MMP12 genes, but not MMP9, have been suggested to be either causative factors in smoking-related lung injury or are in linkage disequilibrium with other causative polymorphisms [16].
• HME and MME were similar in their substrate specificity and showed a stronger preference for Leu/Ile than did the 92-kDa enzyme [17].
• The full-length HME cDNA spans 1.8 kilobases and contains an open reading frame of 1410 base pairs; the predicted molecular mass of the HME proenzyme is 54 kDa [2].

Anatomical context of MMP12

• Migration of monocytes/macrophages in vitro and in vivo is accompanied by MMP12-dependent tunnel formation and by neovascularization [18].
• Expression of MMP-12 by human macrophage cell lines was increased by stimulation with acetylated low-density lipoprotein, implying augmentation of MMP-12 production during foam cell formation [19].
• HME mRNA and protein were detected in human alveolar macrophages [2].
• The principal source of MMP-12 was macrophage foam cells (MFCs) that had infiltrated the atherosclerotic intima; this was demonstrated in both in vitro culture studies of MFCs purified from atherosclerotic lesions and immunohistochemical studies of aortic lesions [19].
• In the atherosclerotic lesions, MMP-12 was produced abundantly at both the mRNA and protein levels, whereas no expression was observed in the normal rabbit aortas [19].

Associations of MMP12 with chemical compounds

• Expression and localization of matrix metalloproteinase-12 in the aorta of cholesterol-fed rabbits: relationship to lesion development [19].
• Similar to murine macrophage metalloelastase, HME readily undergoes NH2- and COOH-terminal processing to a mature 22-kDa form [2].
• The catalytic domain of human recombinant MMP-12 has been crystallized in complex with the broad-specificity inhibitor batimastat (BB-94) [4].
• IL-1beta-induced MMP-12 activity and gene expression was down-regulated by the corticosteroid dexamethasone but up-regulated by the inflammatory cytokine tumour necrosis factor (TNF)-alpha through enhancing activator protein-1 activation by IL-1beta [20].
• INTRODUCTION: Matrix metalloproteinase 12 (MMP12) is a proteolytic enzyme responsible for cleavage of plasminogen to angiotensin, which has an angiostatic effect [10].

Enzymatic interactions of MMP12

• NH(2)-terminal amino acid sequencing revealed that MMP-12 cleaved TFPI at Lys(20)-Leu(21)(close to Kunitz I domain and producing a 35-kDa band), Arg(83)-Ile(84) (between Kunitz I and II domains), and Ser(174)-Thr(175) (between Kunitz II and III domains) [21].

Regulatory relationships of MMP12

• CONCLUSION: Our findings indicate that human airway smooth muscle cells express and secrete MMP-12 that is up-regulated by IL-1beta and TNF-alpha [20].
• In HaCaTs and epithelial MCF-10f cells, MMP-12 mRNA was induced by transforming growth factor-beta1 (TGF-beta1) and tumour necrosis factor-alpha (TNF-alpha) as measured by quantitative RT-PCR (TaqMan) [22].
• Elevated MMP-12 protein levels in induced sputum from patients with COPD [23].
• Tenascin-C stimulates glioma cell invasion through matrix metalloproteinase-12 [24].
• MMP-12 was also demonstrated in the tumors by western blotting and it was expressed in the same regions as MMP-13 mRNA [25].

Other interactions of MMP12

• Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII [26].
• Our results suggest that the abnormal production of tropoelastin and fibrillin by heat in human skin and that their degradation by various MMP, such as MMP-12, may contribute to the accumulation of elastotic material in photoaged skin [27].
• MMP-7 (matrilysin) and MMP-12 (metalloelastase) were not found in either IPM or vitreous [28].
• In MFS, decreased MMP-2 (76+/-7; P<0.05 versus control), increased MMP-12 (161+/-27% versus control; P<0.05), and increased MT1-MMP (248+/-64% versus 91+/-21 non-MFS and control; P<0.05) were observed [29].
• RESULTS: We provide evidence that MMP-12 mRNA and protein are expressed by in-situ human airway smooth muscle cells obtained from bronchial biopsies of normal volunteers, and of patients with asthma, COPD and chronic cough [20].

Analytical, diagnostic and therapeutic context of MMP12

• Endpoint RT-PCR with densitometry gave consistent results with the cDNA array findings for all three genes selected for study (CTSF, MMP11 and MMP12) [30].
• MMP-12 protein expression and secretion from cultured primary airway smooth muscle cells was further analysed by Western blot [20].
• MMP-12 protein localization in bronchial tissue sections was detected by immunohistochemistry [20].
• The pro-inflammatory cytokine, interleukin (IL)-1beta, induced a >100-fold increase in MMP-12 gene expression and a >10-fold enhancement in MMP-12 activity of primary airway smooth muscle cell cultures [20].
• By in situ hybridization, expression of MMP-12 mRNA was detected in 28/33 vulvar SCC samples in CD-68-positive macrophages, while 10 samples had positive cancer cells [22].

References