Disease relevance of Mmp13

• Collagenase 3 (MMP-13) is a recently identified member of the matrix metalloproteinase (MMP) gene family that is expressed at high levels in diverse human carcinomas and in articular cartilage from arthritic patients [1].
• Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis [2].
• After BDL for 3 weeks liver fibrosis was suppressed in MMP-13-deficient mice versus WT animals [2].
• These experiments have shown that in addition to collagenase, gelatinases A and B are likely to play a significant role in bone resorption [3].
• Collagenase-3 (MMP-13) was produced at low levels by melanoma cells whatever the cell culture conditions [4].
• Resolution of CCl(4)-induced fibrosis was retarded in MMP13-deficient mice [5].
• Chondrocyte hypertrophy is not regulated by MMP-13 activity in this model and does not in itself lead to cartilage erosion [6].

High impact information on Mmp13

• A pericellular collagenase directs the 3-dimensional development of white adipose tissue [7].
• Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema [8].
• This pathology is strikingly similar to the morphological changes observed in human emphysema and therefore implicates interstitial collagenase as a possible etiological agent in the disease process [8].
• We demonstrate that c-Jun and Jun-B nevertheless differ markedly in their ability to activate AP-1 responsive genes. c-Jun is an efficient activator of the c-jun and collagenase promoters, which contain a single TRE; Jun-B is not [9].
• In intact cells, the active site of the 16S acetylcholinesterase is protected by a membrane-impermeable inhibitor, and this form of the enzyme can be removed by treatment of the cells with collagenase [10].

Chemical compound and disease context of Mmp13

• After 3 days of ischemia, MMP-2 activity and MMP-3 and MMP-13 protein levels were increased in untreated and aminoguanidine-treated diabetic mice when compared with controls (P < 0.05) [11].
• Here we show that interstitial collagenase has an essential role in initiating bone resorption, distinct from that of the cysteine proteinases [12].
• Tumor necrosis factor receptor deficiency alters matrix metalloproteinase 13/tissue inhibitor of metalloproteinase 1 expression in murine silicosis [13].
• These results suggest that inhibition of metastasis due to treatment with OA and DHA might be due to depressed type-IV collagenase activity [14].
• Collagenase production was maximal in granulomas obtained from liver of mice 8 weeks postinfection and was inhibited by Actinomycin D or cycloheximide, and enhanced by lymphocyte factor(s) or heparin [15].

Biological context of Mmp13

• The severity of the Mmp13- null growth plate phenotype increased until about 5 weeks and completely resolved by 12 weeks of age [16].
• On the basis of these transcriptional regulation studies, together with the potent proteolytic activity of collagenase 3 on diverse collagenous and noncollagenous bone and cartilage components, we proposed that this enzyme may play a key role in the process of bone formation and remodeling [1].
• Upregulation of fibrogenic markers, for example, transforming growth factor beta1 (TGF-beta1), was also significantly suppressed in livers of MMP-13-deficient mice versus in WT mice [2].
• In Gadd45beta(-/-) mouse embryos, defective mineralization and decreased bone growth accompanied deficient Mmp-13 and Col10a1 gene expression in the hypertrophic zone [17].
• During wound healing, MMP-13 and TNFalpha were stimulated to an even higher level, suggesting they are regulated by multiple factors [18].

Anatomical context of Mmp13

• Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification [19].
• Conditional inactivation of Mmp13 in chondrocytes and osteoblasts showed that increases in trabecular bone occur independently of the improper cartilage ECM degradation caused by Mmp13 deficiency in late hypertrophic chondrocytes [16].
• This protein is present on the surface of several types of human tumor cells in vitro and in vivo and stimulates production of interstitial collagenase in human fibroblasts [20].
• Matrix metalloproteinase (MMP) 13 (collagenase 3) is poised to play a crucial role in bone formation and remodeling because of its expression both in terminal hypertrophic chondrocytes in the growth plate and in osteoblasts [16].
• Compared with those in WT animals, serum ALT and the number of hepatic neutrophils were reduced in MMP-13-deficient mice [2].

Associations of Mmp13 with chemical compounds

• Ascorbic acid induces collagenase-1 in human periodontal ligament cells but not in MC3T3-E1 osteoblast-like cells: potential association between collagenase expression and changes in alkaline phosphatase phenotype [21].
• The addition of protein synthesis inhibitor, cycloheximide (CHX), partially inhibits the induction of type X collagen and MMP-13 mRNA by RA [22].
• We have used tetracycline-regulated transcription in conjunction with a cartilage-specific promoter to target a constitutively active human MMP-13 to the hyaline cartilages and joints of transgenic mice [23].
• We have found that all-trans retinoic acid (RA), which usually downregulates MMPs, strongly induces collagenase-3 expression in cultures of embryonic metatarsal cartilage rudiments and in chondrocytic cells [24].
• Cycloheximide and actinomycin D did not inhibit the MMP-13 and c-fos mRNA expression, suggesting that such expression does not require de novo protein synthesis and not change their stabilities [25].

Physical interactions of Mmp13

• Collagenase was found within some cells of the primary tumour and also bound to the extracellular matrix at discrete sites [26].
• Furthermore, AP-1 binding and collagenase mRNA accumulation were completely suppressed by SP600125 [27].
• Properties of prolactin receptors were measured by monitoring [125I]prolactin binding to specific receptor sites on collagenase-dissociated mammary epithelial cells of virgin, pregnant and lactating mice [28].
• Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization [29].
• Electrophoretic mobility shift assays showed that bZip Jun homodimers and bZip Jun/Fos heterodimers bind a collagenase-like TRE (CTGACTCAT) with dissociation constants of respectively 1.4 x 10(-7) M and 5 x 10(-8) M [30].

Enzymatic interactions of Mmp13

• Type IV collagenase plays an important role in tumor invasion and metastasis through cleaving type IV collagen in the basement membrane and extracellular matrix [31].

Co-localisations of Mmp13

• Stromelysin was also co-localized with collagenase in some tumour cells [26].
• Stromelysin-2 co-localizes with collagenase-1 and may facilitate cell migration over non-collagenous matrices of the dermis [32].

Regulatory relationships of Mmp13

• Increased expression of the mRNA of inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) was significantly suppressed in livers of MMP-13-deficient mice [2].
• Mmp-9 deficiency enhances collagenase-induced intracerebral hemorrhage and brain injury in mutant mice [33].
• The messenger RNA for these MMPs as well as collagenase-3 and the tissue inhibitors of metalloproteinases were also expressed during uterine involution, as determined by Northern analysis and in situ hybridization [34].
• MMP-13 expression was restricted to chondrocytes of the lower zone of hypertrophic cartilage also expressing collagen type X. In osteoblasts involved in endochondral and intramembranous ossification Itm2a was not present [35].
• Our data are the first to demonstrate that deletion of CyC-AP can abolish fibronectin fragment-induced MMP-13 expression through an unknown mechanism [18].

Other interactions of Mmp13

• Whereas MMP-13 was transiently expressed mainly in the cells clustering in the periportal areas, MMP-9 expression and enzymatic activity were detected over the resolution process in several different kinds of cells located in the portal areas and along the fibrous septa [36].
• Like in man and rat, the expressions of collagenase I, stromelysin-1, and stromelysin-2 are regulated by the tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate and by UV irradiation, but not by cAMP [37].
• The sites of induced collagenase I expression correlate with the sites of Fos-induced long-term cellular alterations in transgenic mice including bone remodeling and T cell development [37].
• The expression of MMP-13 and DDR-2 protein and the amount of degraded type II collagen were higher in the knee joints of Col9a1(-/-) mice than in their wild-type littermates at the age of 6 months [38].
• Both AP-1 and Cbfa1-like factors are required for the induction of interstitial collagenase by parathyroid hormone [39].

Analytical, diagnostic and therapeutic context of Mmp13

• We determined the expression pattern of the matrix metalloproteinase interstitial collagenase (MMP-1) during mouse embryo development using in situ hybridization and immunohistochemistry [40].
• A corneal fibroblast bioassay that tests for mediators of collagenase synthesis, detected a stimulatory substance whose activity was greatly reduced in the presence of interleukin-1 receptor antagonist protein [41].
• Selection for traits such as loss of growth inhibitory responses, acquisition of increased adhesiveness, increased local immunosuppression, and enhanced motility and collagenase activities likely contribute to cancer progression and may be regulated through the action of growth factors [42].
• The MMP-13 protein and mRNA expression were determined by Western blotting and reverse transcriptase-PCR, respectively [25].
• Surface labeling of SMCs with biotin followed by immunoprecipitation revealed that a proportion of active collagenase-1, expressed in response to FGF-2, was bound to the plasma membrane [43].

References