Disease relevance of MMP13

• Human collagenase-3 (MMP13) is a recently identified member of the matrix metalloproteinase (MMP) family that is expressed in breast carcinomas and in articular cartilage from arthritic patients [1].
• MMP13 expression was observed in 44% of MPNST but was absent in neurofibromas [2].
• The overall expression of MMP-13 in these cells in the synovial stroma was high in rheumatoid arthritis (86 +/- 12%) compared with osteoarthritis (17 +/- 5%) patient samples (P = 0.0027) [3].
• The cDNA of a novel matrix metalloproteinase, collagenase-3 (MMP-13) has been isolated from a breast tumor library (Freije, J. M. P., Dicz-Itza, I., Balbin, M., Sanchez, L. M., Blasco, R., Tolivia, J., and López-Otin, C. (1994) J. Biol. Chem. 269, 16766-16773), and a potential role in tumor progression has been proposed for this enzyme [4].
• Although the significance of these findings is currently unknown, they suggest that in addition to the effect of cytokines activation, the gene expression of hMMP13 could be dysregulated during the disease progression of rheumatoid arthritis (or cancer) associated with p53 inactivation [5].

High impact information on MMP13

• We show that a missense mutation of MMP13 causes the Missouri type of human spondyloepimetaphyseal dysplasia (SEMD(MO)), an autosomal dominant disorder characterized by defective growth and modeling of vertebrae and long bones [6].
• Histological evaluation of joint sections revealed no difference in the extent of synovial inflammation, its cellular composition (except for the lack of osteoclasts), and the expression of matrix metalloprotein-ase-3 (MMP-3) and MMP-13 [7].
• These data suggest that collagenase(s) produced by chondrocytes is (are) involved in the cleavage and denaturation of type II collagen in articular cartilage, that this is increased in OA, and that MMP-13 may play a significant role in this process [8].
• Experiments with intact type II collagen as well as a synthetic peptide suggested that MMP-13 cleaved type II collagen at the same bond as MMP-1, but this was then followed by a secondary cleavage that removed three amino acids from the 1/4 fragment amino terminus [9].
• Degenerate reverse transcription polymerase chain reaction experiments, Northern blot analysis, and direct immunodetection have now provided evidence that collagenase-3 (MMP-13), an enzyme recently cloned from human breast carcinoma, is expressed by chondrocytes in human osteoarthritic cartilage [9].

Chemical compound and disease context of MMP13

• CONCLUSIONS: Histamine exposure increased both MMP-13 and MMP-3 production by HAC in vitro, thereby suggesting a pathophysiological role in the chondrocytic phenotype associated with degenerative changes in osteoarthritis [10].
• In contrast, the remarkably elevated MMP-13 mRNA expression in the keloid group was significantly suppressed, with the peak suppression at 12 h after addition of tretinoin, while MMP-13 mRNA expression in the control group was not significantly changed [11].
• Effect of estrogen on the expression of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 and tissue inhibitor of metalloproternase-1 in osteoarthritis chondrocytes [12].
• Alpha v beta 6 integrin down-regulates the MMP-13 expression in oral squamous cell carcinoma cells [13].
• Licofelone, a novel dual inhibitor of cyclo-oxygenases (COX) and 5-lipoxygenase (5-LOX), can modulate MMP-13 production in human osteoarthritis chondrocytes [14].

Biological context of MMP13

• Also, forkhead, CD10, and MMP13 increased up to day 7 and decreased thereafter, suggesting roles in an intermediate stage of chondrogenesis [15].
• In-vitro transfection experiments with reporter gene constructs and electrophoretic mobility-shift assays showed that the MMP13 polymorphism was a functional variant [16].
• The genotype for one of the MMP13 polymorphisms was associated with fibrous plaque (P=0.024) in black males [16].
• The gene expression levels of collagen degrading MMPs, i.e. MMP8, MMP13 and MMP14 were similar in subcutaneous and supra-epicardial disks [17].
• A dramatic up-regulation of MMP-13 by inflammatory cytokines such as interleukin (IL)-1beta or by fibronectin fragments has been observed in chondrocytes [18].

Anatomical context of MMP13

• MMP13 promoter polymorphism is associated with atherosclerosis in the abdominal aorta of young black males [16].
• Expression of mRNAs encoding for growth factors, ECM molecules, and MMP13 in mono-cultures and co-cultures of human periodontal ligament fibroblasts and alveolar bone cells [19].
• Additionally, we have shown that in cartilage the median level of steady-state mRNA for MMP13 is approximately 20-fold higher than MMP28 and approximately 1,500-fold higher than ADAMTS16, with expression of this latter gene approximately 150-fold higher in synovium than cartilage [20].
• RESULTS: MMP-13 was detected in fibroblast- and macrophage-like mononuclear cells in the synovial lining and stroma and in vascular endothelial cells [3].
• Our data provide direct evidence for the role of MMP-13 as a potent invasion proteinase, which alone can enhance the ability of malignant cells to penetrate through both basement membrane and fibrillar collagen [21].

Associations of MMP13 with chemical compounds

• RESULTS: The glucocorticoids, dexamethasone, triamcinolone, and prednisolone, markedly decreased MMP1, MMP3, MMP13, TIMPI, and ferritin steady-state mRNA levels [22].
• Finally, in contrast to MMP-1 and MMP-8, MMP-13 was found to be relatively resistant to the inhibitory effects of doxycycline and clodronate in vitro [3].
• The enhanced invasion capacity of MMP-13 expressing HT-1080 cells was dependent on MMP activity, as it was blocked by MMP inhibitor Batimastat (BB-94) and tissue inhibitor of metalloproteinases-3 (TIMP-3) [21].
• Retinoic acid and oncostatin M combine to promote cartilage degradation via matrix metalloproteinase-13 expression in bovine but not human chondrocytes [23].
• NF-kappaB inhibitor, pyrrolidine dithiocarbamate yielded 83-84% reduction of MMP-3 and 38-55% for MMP-13 in human chondrocytes [24].
• ChIP assays revealed that TNFalpha treatment enhanced the binding of C/EBPbeta to the MMP-13 promoter [25].

Physical interactions of MMP13

• Reconstituted MMP-13/alpha 2M complex was unable to degrade collagen (MW 300,000) in contrast to the low-molecular-weight fluorogenic substrate (MW < 1500) [26].

Enzymatic interactions of MMP13

• The results show that MMP-13 cleaves aggrecan in the IGD at the same site (..PEN314-FFG..) identified for other members of the MMP family, and also at a novel site ..VKP384-VFE.. not previously observed for other proteinases [27].
• We showed, for the first time, that MMP-13 can degrade members from two classes of the SLRP family, and identified the site at which biglycan is cleaved by MMP-13 [28].

Regulatory relationships of MMP13

• Treatment with p38 kinase inhibitors (SB203580 and SB242235) strongly inhibited cytokine-induced MMP-13 expression in a dose-dependent fashion while having a somewhat weaker inhibitory effect on MMP-1 expression [29].
• Adenoviral delivery of p53 gene suppresses expression of collagenase-3 (MMP-13) in squamous carcinoma cells [30].
• Inhibitory effects of insulin-like growth factor-1 and osteogenic protein-1 on fibronectin fragment- and interleukin-1beta-stimulated matrix metalloproteinase-13 expression in human chondrocytes [18].
• Overexpression of Runx2 robustly stimulated the transcriptional activation of MMP-13 but had no effect on MMP-1 expression [29].
• Tumor necrosis factor-alpha (TNF-alpha) and PMA also upregulated MMP-13 expression but these agents were not as effective as IL-1alpha [31].

Other interactions of MMP13

• Adenovirus-mediated expression of dominant negative p38alpha and c-Jun potently inhibited induction of MMP-13 expression in gingival fibroblasts by TGF-beta1 [32].
• MMP-13 (P = 0.009) and IL-6 (P = 0.03) levels were significantly lower in encapsulating tenosynovium compared with wrist joint synovium [33].
• OSM potentiated IL-1beta-induced MMP-1 and MMP-13 expression in normal human cartilage/RASF cocultures, resulting in a significant increase in the MMP:TIMP ratio [34].
• A similar temporal profile was not observed for MMP-2 and MMP-13 [35].
• The frequency ranged from 1% for MMP-3 to 28% for MMP-13 [36].

Analytical, diagnostic and therapeutic context of MMP13

• In addition to the 3'-untranslated region of the matrix metalloproteinases-13 (MMP13) gene, the differential expression of an alternatively spliced transcript of the RNA-binding protein TIAR in human cell cultures is also critical for this post-transcriptional regulation [37].
• Immunohistochemistry using antibodies for MMP13 showed that MMP13 is expressed in all layers of the aorta [16].
• MMP-1 and MMP-13 gene expression and protein synthesis were investigated using Northern blotting and enzyme-linked immunosorbent assays [38].
• Expression of MMP-1 and MMP-13 was assayed using semi-quantitative and real-time PCR, as well as immunoblotting [39].
• Western blotting was performed to confirm the mRNA changes demonstrated in collagenase-3 (MMP-13) [40].

References