Matrix metalloproteinase-13
(MMP13, MMP-13)

Collagenase-3 (CLG3)
EC Number: ?

Gene: maps to 11q22.3. This gene is composed of 10 exons and 9 introns and spans over 12.5 kb. The overall organization of the gene is similar to that of other MMP genes clustered at chromosome 11q22, including MMP-1, MMP-7, and MMP-12 (macrophage metalloelastase), but is more distantly related to genes coding for MMP-11, MMP-2, and MMP-9, which map outside of this gene cluster. Nucleotide sequence analysis of about 1 kb of the 5'-flanking region of the collagenase-3 gene revealed the presence of a TATA box, an AP-1 motif, a PEA-3 consensus sequence, an osteoblast specific element (OSE-2), and a TGF-beta inhibitory element. DNA binding analysis with nuclear extracts from HeLa cells revealed the formation of specific complexes between collagenase-3 promoter sequences containing the AP-1 site and nuclear proteins. The presence of this AP-1 functional site, which is able to confer responsiveness to a variety of tumor promoters and oncogene products, amy contribute to explaining the high-level expression of collagenase-3 in breast carcinomas and degenerative joint diseases (Pendás A.M. et al., 1995, 1997).
mRNA: size: ? kb. Northern blot analysis of RNA from normal and pathological tissues demonstrated the existence in breast tumors of three different mRNA species, which seem to be the result of the utilization of different polyadenylation sites present in the 3'-noncoding region of the gene. By contrast, no collagenase-3 mRNA was detected either by Northern blot or RNA polymerase chain reaction analysis with RNA from other human tissues, including normal breast, mammary fibroadenomas, liver, placenta, ovary, uterus, prostate, and parotid gland (Freije J.M. et al., 1994). However, MMP13 was found to be expressed by chondrocytes in human osteoarthritic cartilage (Mitchell P.G. et al., 1996).
Protein: the cDNA encodes a polypeptide of 471 amino acids. The predicted protein sequence displays extensive similarity to the previously known MMPs and presents all the structural features characteristic of the members of this protein family, including the well conserved PRCGXPD motif, involved in the latency of the enzyme and the zinc-binding domain (HEXGHXXXXXHS). In addition, MMP-13 contains in its amino acid sequence several residues specific to the collagenase subfamily (Tyr-214, Asp-235, and Gly-237) and lacks the 9-residue insertion present in the stromelysins (Freije J.M. et al., 1994). MMP-13 is able to degrade fibrillar collagens. The expression of MMP-13 in osteoarthritic cartilage and its activity against type II collagen suggest that the enzyme plays a significant role in cartilage collagen degradation (Mitchell P.G. et al., 1996)
See also: structural and functional characteristics of MMPs

Cell lines:
- Coculture experiments using human fibrroblasts and MCF-7 breast cancer cells (BCC) revealed that conditioned medium from breast cancer cells stimulated the fibroblastic expression of MMP13 mRNA. In contrast, no stimulatory effect was observed when medium from fibroblast cells was added to breast cancer cells. These results strongly suggest that transcription of MMP13 in stromal cells is activated by diffusible factors released from epithelial breast cancer cells. A survey of a series of cytokines and growth factors known for their ability to induce MMP13 expression in human fibroblasts identified interleukin-1 alpha and interleukin-1 beta as potential candidates for inducing the expression of this MMP gene in breast carcinomas (Uría J.A. et al., 1997).

- MMP13 was found to be constitutively eexpressed in the MDA-MB-231 BCC line. Functional analysis of the MMP13 promoter showed that both the activator protein-1 (AP-1) site and the runt domain (RD) binding site were required for maximal constitutive expression of MMP13 in these cells. Determination of factors binding to those sites by Northern analysis and transient transfections identified the requirement of Fra-1, c-Jun, and Cbfa1 for basal MMP13 promoter activity in MDA-MB-231 BCC (Selvamurugan N. and Partridge N.C., 2000).

- Analysis of MMP expression by RT-PCR sshowed expression of MMP-1, MMP-3, and MMP-13 in highly invasive MDA-MB-231 BCC, but not in slightly invasive MCF-7, T-47D, and BT-20 cell lines. The extracellular secretion of MMP-1 and MMP-3 by MDA-MB 231 cells could be also shown by ELISA. TIMP-1 and TIMP-2 mRNAs were found in all cell lines, however, the extracellular secretion of both TIMPs was much higher in MDA-MB-231 cells than in the other cell lines. When the cells were cultured on Matrigel matrix, MMP-9 expression was induced in MDA-MB-231 cells only, as assessed by RT-PCR and zymography experiments. The invasive potential of MDA-MB-231 cells evaluated in vitro through Matrigel was significantly inhibited by the MMP inhibitor BB-2516 (Balduyck M et al., 2000).

Tumors:
- In breast carcinomas, MMP13 expressionn was found in stromal cells immediately adjacent to epithelial tumor cells but not by the tumor cells themselves; MMP13 expression was not found in the normal breast glandular epithelium (Uría J.A. et al., 1997).

- Expression of MMP-13 in stromal fibrobblast-like cells was found in all 21 invasive ductal carcinomas studied and in 4 of 9 invasive lobular carcinomas. In most carcinomas, expression of MMP-13 was limited to small stromal foci in the tumor area. Combined in situ hybridization and immunohistochemistry showed coexpression of alpha-smooth muscle actin immunoreactivity and MMP-13 mRNA in myofibroblasts. In contrast, cytokeratin-positive cancer cells, alpha-smooth muscle actin-positive vascular smooth muscle cells, CD68-positive macrophages, and CD31-positive endothelial cells were all MMP-13 mRNA negative. In situ hybridization for MMP-13 in 17 DCIS lesions revealed expression in 10 cases. Immunohistochemical analysis of all DCIS cases identified microinvasion in 8 of the 17 lesions. Seven of the eight lesions with microinvasion were MMP-13 positive. Further analysis showed that MMP-13 expression was often associated with the microinvasive events. This particular expression pattern was unique for MMP-13 among other MMPs analyzed, including MMP-2, -11, and -14 (Nielsen B.S. et al., 2001).

Balduyck M. et al. (2000) Specific expression of matrix metalloproteinases 1, 3, 9 and 13 associated with invasiveness of breast cancer cells in vitro. Clin. Exp. Metastasis 18, 171-178. (PubMed)
Freije J.M. et al. (1994) Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J. Biol. Chem. 269, 16766-16773. (PubMed)
Knauper V. et al. (1996) Biochemical characterization of human collagenase-3. J. Biol. Chem. 271, 1544-1550. (PubMed)
Mitchell P.G. et al. (1996) Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J. Clin. Invest. 97, 761-768. (PubMed)
Nielsen B.S. et al. (2001) Collagenase-3 expression in breast myofibroblasts as a molecular marker of transition of ductal carcinoma in situ lesions to invasive ductal carcinomas. Cancer Res. 61, 7091-7100. (PubMed)
Pendás A.M. et al. (1995) The human collagenase-3 (CLG3) gene is located on chromosome 11q22.3 clustered to other members of the matrix metalloproteinase gene family. Genomics 26, 615-618. (PubMed)
Pendás A.M. et al. (1997) Structural analysis and promoter characterization of the human collagenase-3 gene (MMP13). Genomics 40, 222-233. (PubMed)
Pendás A.M. et al. (2000) An overview of collagenase-3 expression in malignant tumors and analysis of its potential value as a target in antitumor therapies. Clin. Chim. Acta 291, 137-155 (Review). (PubMed)
Selvamurugan N. and Partridge N.C. (2000) Constitutive Expression and Regulation of Collagenase-3 in Human Breast Cancer Cells. Mol. Cell. Biol. Res. Commun. 3, 218-223. (PubMed)
Uría J.A. et al. (1997) Regulation of collagenase-3 expression in human breast carcinomas is mediated by stromal-epithelial cell interactions. Cancer Res. 57, 4882-4888. (PubMed)
Wernicke D. et al. (1996) Cloning of collagenase 3 from the synovial membrane and its expression in rheumatoid arthritis and osteoarthritis. J. Rheumatol. 23, 590-595. (PubMed)
Willmroth F. et al. (1998) A matrix metalloproteinase gene expressed in human T lymphocytes is identical with collagenase 3 from breast carcinomas. Immunobiology 198, 375-384. (PubMed)

Genome Database data (GDB Access Number: 373966)
GeneCard data (MMP13)
UniGene data (Hs.2936)
OMIM data (ID = 600108)
LocusLink data (LocusID = 4322)
Swiss-Prot (ID = P45452)


MMP1, MMP2, MMP3, MMP7, MMP9, MMP11, MMP14, MMP15, MMP16, MMP17, TIMP1, TIMP2, TIMP3, TIMP4

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