Mutations in two matrix metalloproteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice

• Published in: Oncogene Vol. 23; no. 29; pp. 5041 - 5048
• Main Authors: JUNSEO OH, TAKAHASHI, Rei, ITOH, Takeshi, ITOHARA, Shigeyoshi, TAKAHASHI, Chiaki, NODA, Makoto, ADACHI, Eijiro, KONDO, Shunya, KURATOMI, Shinobu, NOMA, Akinori, ALEXANDER, David B, MOTODA, Hirotoshi, OKADA, Akiko, SEIKI, Motoharu
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 24-06-2004; Nature Publishing Group
• Subjects: Angiogenesis; Animals; Biological and medical sciences; Birth; Blood vessels; Blood Vessels - embryology; Blood Vessels - pathology; Cancer; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Central core disease; Embryogenesis; Enzymes; Extracellular matrix; Fundamental and applied biological sciences. Psychology; Gelatinase A; Genes, Lethal; Laboratories; Matrix metalloproteinase; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases - genetics; Metalloproteinase; Mice; Mice, Mutant Strains; Molecular and cellular biology; Muscle, Skeletal - embryology; Muscle, Skeletal - pathology; Mutation; Myoblasts; Myoblasts - pathology; Neovascularization, Pathologic; Pathology; Respiratory failure; University graduates; Japan; Enzyme; Rodentia; Metalloendopeptidases; Carcinogenesis; Myogenesis; Gelatinase A; Peptidases; Angiogenesis; Vertebrata; MT1-MMP; Mammalia; Gene; Mouse; MMP-2; Hydrolases; Mutation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207688

The matrix metalloproteinase (MMP) family (approximately 25 members in mammals) has been implicated in extracellular matrix remodeling associated with embryonic development, cancer formation and progression, and various other physiological and pathological events. Inactivating mutations in individual matrix metalloproteinase genes in mice described so far, however, are nonlethal at least up to the first few weeks after birth, suggesting functional redundancy among MMP family members. Here, we report that mice lacking two MMPs, MMP-2 (nonmembrane type) and MT1-MMP (membrane type), die immediately after birth with respiratory failure, abnormal blood vessels, and immature muscle fibers reminiscent of central core disease. In the absence of MMP-2 and MT1-MMP, myoblast fusion in vitro is also significantly retarded. These findings suggest functional overlap in mice between the two MMPs with distinct molecular natures.