Alternative titles; symbols
HGNC Approved Gene Symbol: MMP10
Cytogenetic location: 11q22.2 Genomic coordinates (GRCh38): 11:102,770,502-102,780,628 (from NCBI)
MMP10 (EC 3.4.24.22) belongs to a family of matrix metalloproteinases (MMPs) with the combined capacity to degrade virtually all components of the extracellular matrix and basement membrane for tissue remodeling. MMP10 has a broad substrate specificity and can degrade fibronectin (FN1; 135600), laminin (see 150320), elastin (ELN; 130160), proteoglycan core protein (see 142461), gelatins, and several types of collagen (see 120150) (summary by Madlener and Werner, 1997).
Stromelysin (MMP3; 185250) is a metalloproteinase related to collagenase whose substrates include proteoglycans and fibronectin, but not type I collagen (see 120150). Muller et al. (1988) detected RNAs capable of hybridizing to a rat stromelysin cDNA in 11 of 69 human tumors tested. By molecular cloning of cDNAs to these RNAs, Muller et al. (1988) identified them as a mixture of stromelysin RNA and a 1.9-kb transcript of a related gene, stromelysin II. They also isolated cDNAs corresponding to a more distantly related human gene, PUMP1 (MMP7; 178990). The deduced stromelysin II protein contains 476 amino acids and has a putative N-terminal signal sequence. Comparison of the amino acid sequences of stromelysin II and PUMP1 with the sequences of stromelysin and collagenase (MMP1; 120353) showed significant similarities, with conservation of sequence motifs believed to have functional importance and metalloproteinase action.
Madlener and Werner (1997) cloned mouse Mmp10 from a wounded skin cDNA library. The deduced 476-amino acid protein contains an N-terminal signal sequence, followed by a propeptide region and an N-terminal catalytic domain. It also has 3 conserved histidines involved in coordinating the active-site zinc molecule. Mouse and human MMP10 share 76% amino acid identity. RNase protection assays revealed high Mmp10 expression in small intestine, much weaker expression in heart and lung, and no expression in other tissues examined.
By immunohistochemical analysis of human bone tissues, Bord et al. (1998) found distinct patterns of expression for SL1 (MMP3) and SL2. In situ zymography revealed that SL1 was secreted in the latent form, whereas SL2 was active. Latent SL1 was detected in extracellular matrix in fibrous tissue surrounding endochondral ossification in osteophytes, and adjacent to periosteum in fetal rib bone. Active SL1 was detected in osteocytes and the matrix surrounding osteocytic lacunae. In contrast, SL2 associated with cells at sites of resorption in areas of endochondral ossification and in resorptive cells at the chondroosseous junction. In fetal rib, active SL2, but not SL1, localized in chondrocytes of the growth plate. Vascular areas showed strong SL2 staining with some proteolytic activity. SL2, but not SL1, was strongly expressed in osteoclasts and most mononuclear cells within the marrow. At sites of bone formation, both SL1 and SL2 were expressed by osteoblasts, with SL1 also in osteoid. Bord et al. (1998) concluded that SL2 is secreted in an active form with associated degradation, whereas SL1 is produced in a matrix-bound proenzyme form that may act as a reservoir for later activation.
Using Western blot analysis, Madlener and Werner (1997) found that expression of Mmp10 was significantly upregulated in wounded mouse skin. Mouse Mmp10 was secreted from transfected COS cells and could be induced to undergo autocatalytic processing.
Nakamura et al. (1998) found that activated MMP10 purified from OSC-20 human oral squamous carcinoma cells could activate the proenzyme forms of MMP9 (120361) and, partially, MMP7, but not MMP2 (120360) and MMP3.
Using an in vitro migration assay, Krampert et al. (2004) showed that recombinant human ST2 enhanced migration of human keratinocytes in a dose-dependent manner. Transgenic mice expressing constitutively active mouse St2 in keratinocytes appeared grossly normal, had unaltered skin architecture, and appeared to exhibit normal wound closure. However, histologically, the tip of the migrating epithelium in wounds of transgenic mice appeared disorganized, with incorrect deposition of laminin-5 and proteolytic disappearance of the gamma-2 chain of laminin-5 (LAMC2; 150292). Wounds from transgenic mice had altered localization of beta-1 integrin (607153) and activated Fak (PTK2; 600758), and in many wounds with a strong phenotype, these changes were accompanied by reduced phosphorylation of Akt (see 164730) at the tip of the migrating epithelium and elevated apoptosis.
Chang et al. (2006) found that human umbilical vein endothelial cells in which HDAC7 (HDAC7A; 606542) expression was suppressed by RNA interference failed to adhere to each other. Microarray analysis showed that HDAC7 suppression led to dysregulation of numerous genes encoding extracellular matrix and adhesion proteins, including 6.5-fold upregulation of MMP10 and 8.6-fold downregulation of the MMP10 inhibitor, TIMP1 (305370). Chang et al. (2006) found that HDAC7 downregulated MMP10 by associating with MEF2 (see MEF2A; 600660), an MMP10 transcriptional activator. Hdac7 deletion in mice, which was embryonic lethal due to widespread vascular damage, resulted in dramatic upregulation of Mmp10 in the perivascular region and downregulation of Timp1 in endothelial cells.
Huntington disease (143100) is a dominantly inherited neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) tract in the huntingtin (HTT; 613004) protein. Neurodegeneration is thought to be due to proteolytic release of toxic peptide fragments from mutant huntingtin. By transfecting small interfering RNAs directed against 514 human proteases into polyQ HTT-expressing HEK293 cells, Miller et al. (2010) identified 11 proteases, including MMP10, MMP14 (600754), and MMP23B (603321), as putative polyQ HTT-processing proteases. Further characterization revealed that MMP10 was the only metalloprotease in this group that directly processed polyQ HTT; MMP14 and MMP23B appeared to cause polyQ HTT degradation indirectly. MMP10 cleaved polyQ HTT at a conserved site near the N terminus with the consensus sequence (S/T)xxGG(I/L). Both Mmp10 and Mmp14 were upregulated in mouse striatal cells expressing polyQ HTT, and knockdown of either Mmp10 or Mmp14 reduced cell death and caspase activation. Htt and Mmp10 colocalized in cells undergoing apoptosis.
Jung et al. (1990) mapped the MMP10 gene to chromosome 11q22.3-q23 by in situ hybridization. Pendas et al. (1996) isolated a 1.5-Mb YAC clone mapping to chromosome 11q22.3. Detailed analysis of this nonchimeric YAC clone ordered 7 MMP genes as follows: cen--MMP8 (120355)--MMP10--MMP1 (120353)--MMP3--MMP12 (601046)--MMP7--MMP13 (600108)--tel.
Bord, S., Horner, A., Hembry, R. M., Compston, J. E. Stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) expression in developing human bone: potential roles in skeletal development. Bone 23: 7-12, 1998. [PubMed: 9662124] [Full Text: https://doi.org/10.1016/s8756-3282(98)00064-7]
Chang, S., Young, B. D., Li, S., Qi, X., Richardson, J. A., Olson, E. N. Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10. Cell 126: 321-334, 2006. [PubMed: 16873063] [Full Text: https://doi.org/10.1016/j.cell.2006.05.040]
Jung, J. Y., Warter, S., Rumpler, Y. Localization of stromelysin 2 gene to the q22.3-23 region of chromosome 11 by in situ hybridization. Ann. Genet. 33: 21-23, 1990. [PubMed: 2369069]
Krampert, M., Bloch, W., Sasaki, T., Bugnon, P., Rulicke, T., Wolf, E., Aumailley, M., Parks, W. C., Werner, S. Activities of the matrix metalloproteinase stromelysin-2 (MMP-10) in matrix degradation and keratinocyte organization in wounded skin. Molec. Biol. Cell 15: 5242-5254, 2004. [PubMed: 15371548] [Full Text: https://doi.org/10.1091/mbc.e04-02-0109]
Madlener, M., Werner, S. cDNA cloning and expression of the gene encoding murine stromelysin-2 (MMP-10). Gene 202: 75-81, 1997. [PubMed: 9427548] [Full Text: https://doi.org/10.1016/s0378-1119(97)00456-3]
Miller, J. P., Holcomb, J., Al-Ramahi, I., de Haro, M., Gafni, J., Zhang, N., Kim, E., Sanhueza, M., Torcassi, C., Kwak, S., Botas, J., Hughes, R. E., Ellerby, L. M. Matrix metalloproteinases are modifiers of huntingtin proteolysis and toxicity in Huntington's disease. Neuron 67: 199-212, 2010. [PubMed: 20670829] [Full Text: https://doi.org/10.1016/j.neuron.2010.06.021]
Muller, D., Quantin, B., Gesnel, M.-C., Millon-Collard, R., Abecassis, J., Breathnach, R. The collagenase gene family in humans consists of at least four members. Biochem. J. 253: 187-192, 1988. [PubMed: 2844164] [Full Text: https://doi.org/10.1042/bj2530187]
Nakamura, H., Fujii, Y., Ohuchi, E., Yamamoto, E., Okada, Y. Activation of the precursor of human stromelysin 2 and its interactions with other matrix metalloproteinases. Europ. J. Biochem. 253: 67-75, 1998. [PubMed: 9578462] [Full Text: https://doi.org/10.1046/j.1432-1327.1998.2530067.x]
Pendas, A. M., Santamaria, I., Alvarez, M. V., Pritchard, M., Lopez-Otin, C. Fine physical mapping of the human matrix metalloproteinase genes clustered on chromosome 11q22.3. Genomics 37: 266-269, 1996. [PubMed: 8921407] [Full Text: https://doi.org/10.1006/geno.1996.0557]