B6-hMMP7 Mice

Catalog Number: I001180

Strain Name: C57BL/6JCya-Mmp7em1(hMMP7)/Cya

Genetic Background: C57BL/6JCya

 

Strain Description

MMP7 encodes matrix metalloproteinase-7 (MMP-7), also known as matrilysin, a member of the matrix metalloproteinase family that plays a crucial role in the degradation and remodeling of extracellular matrix (ECM) components [1]. MMP7 is primarily expressed in epithelial tissues of the gastrointestinal tract, lungs, and reproductive system. Cytokines, growth factors, hypoxia, and inflammatory signals regulate its expression. MMP7 is secreted as a zymogen and activated by other proteases or autolytic cleavage. Activated MMP7 can degrade ECM components such as collagen, proteoglycans, elastin, and fibronectin, and can also activate antimicrobial peptides (e.g., defensins) and process cytokines [2]. Functionally, MMP7 involves various physiological and pathological processes, including ECM remodeling, immune regulation, wound healing, and tumor progression. It is notably significant in tumor invasion and metastasis, where it promotes cancer cell migration by degrading matrix barriers and accelerates tumor growth by regulating angiogenesis and immune evasion [2-3]. MMP7 is associated with several diseases, including cancers (e.g., colorectal, gastric, pancreatic, and lung cancers, with high expression often correlated with poor prognosis), inflammatory diseases (e.g., inflammatory bowel disease, chronic obstructive pulmonary disease, and asthma), fibrotic diseases (e.g., idiopathic pulmonary fibrosis), and cardiovascular diseases (e.g., atherosclerosis and aneurysms) [3-5]. Hence, MMP7 is an important therapeutic target for various diseases. However, clinical trials targeting MMP7 face challenges in efficacy and safety. Broad-spectrum MMP inhibitors (e.g., Marimastat and Batimastat) have limited efficacy due to low specificity and adverse effects like musculoskeletal pain. Recent research focuses on selective MMP7-targeted inhibitory therapies, including small molecule inhibitors, monoclonal antibodies, peptide inhibitors, small interfering RNA (siRNA), and antisense oligonucleotides (ASO) [5-8]. MMP7 plays dual roles in maintaining physiological homeostasis and mediating pathological processes (particularly in cancer and fibrosis), making it a promising yet challenging therapeutic target.

B6-hMMP7 mice, a humanized model expressing human MMP7 protein, were generated by integrating the human MMP7 coding sequence (CDS) and the 3' untranslated region (UTR) into the mouse Mmp7 gene locus. These mice can be used for research on various cancers, inflammatory diseases, fibrotic diseases, and cardiovascular diseases, as well as for the development and preclinical pharmacodynamic evaluation of MMP7-targeted drugs.

Strain Strategy

 


Figure 1. Gene editing strategy of B6-hMMP7 mice. The ATG start codon and part of intron 1 of the mouse Mmp7 gene were replaced with the "Kozak-Human MMP7 CDS-3'UTR of Human MMP7-WPRE-BGH pA" gene expression cassette.

Applications

  • Development, screening, and preclinical pharmacodynamic evaluation of MMP7-targeted drugs.
  • Research on the occurrence and prognosis of cancers such as colorectal, gastric, pancreatic, and lung cancers.
  • Studies on inflammatory diseases like inflammatory bowel disease, chronic obstructive pulmonary disease, and asthma.
  • Research on fibrotic diseases such as idiopathic pulmonary fibrosis.
  • Studies on cardiovascular diseases like atherosclerosis and aneurysms.

 

References
[1]Wozniak J, Floege J, Ostendorf T, Ludwig A. Key metalloproteinase-mediated pathways in the kidney. Nat Rev Nephrol. 2021 Aug;17(8):513-527.
[2]Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001;17:463-516.
[3]de Almeida LGN, Thode H, Eslambolchi Y, Chopra S, Young D, Gill S, Devel L, Dufour A. Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology. Pharmacol Rev. 2022 Jul;74(3):712-768.
[4]Liao HY, Da CM, Liao B, Zhang HH. Roles of matrix metalloproteinase-7 (MMP-7) in cancer. Clin Biochem. 2021 Jun;92:9-18.
[5]Craig VJ, Zhang L, Hagood JS, Owen CA. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 2015 Nov;53(5):585-600.
[6]Liu G, Philp AM, Corte T, Travis MA, Schilter H, Hansbro NG, Burns CJ, Eapen MS, Sohal SS, Burgess JK, Hansbro PM. Therapeutic targets in lung tissue remodelling and fibrosis. Pharmacol Ther. 2021 Sep;225:107839.
[7]Cathcart J, Pulkoski-Gross A, Cao J. Targeting Matrix Metalloproteinases in Cancer: Bringing New Life to Old Ideas. Genes Dis. 2015 Mar 1;2(`1):26-34.
[8]Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF, Martinez-Avila N, Martinez-Fierro ML. The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int J Mol Sci. 2020 Dec 20;21(24):9739.