TABLE 1

MMP knockout mice phenotypes

MMPPhenotype of MMP Knockout MouseImpact on Biologic FunctionsReferences
Mmp1a−/−No obvious abnormalities and both males and females were fertile.↓Lung tumor growth and angiogenesis using LLC1 lung cancer cell line.(Fanjul-Fernández et al., 2013, 2018; Foley et al., 2014)
Mmp1b−/−N/AN/AN/A
Mmp2−/−Both males and females were fertile. Smaller at birth and ∼15% slower growth rate. Litters from heterozygous crosses yielded ∼85% fewer than expected homozygous Mmp2−/− pups.↑Susceptibility to dextran-sulfate-induced colitis, ↑protection and ↓reduction in hepatocyte apoptosis in TNFα-induced hepatitis, ↑severity of antibody-induced arthritis, ↓white matter sparing and ↓serotonergic fibers in spinal-cord lesions, ↑cardiac allograft survival, delay of neovascularization, ↓atherosclerotic plaques, ↓numbers and proliferation of osteoblasts and osteoclasts, ↑apoptosis.(Itoh et al., 1997, 2002; Wielockx et al., 2001; Campbell et al., 2005; Samolov et al., 2005; Garg et al., 2006; Hsu et al., 2006; Kuzuya et al., 2006; Martignetti et al., 2014)
Mmp3−/−No obvious abnormalities and both males and females were fertile.↑Protection and ↓reduction in hepatocyte apoptosis in TNFα-induced hepatitis, ↓immune-complex-induced lung injury and ↓neutrophils, ↑myocardial scar volume post injury, ↓skin-contact hypersensitivity, delayed clearance of bacteria and appearance of CD4+ T lymphocytes into intestinal lamina propria, ↓production of macrophage chemoattractant in disc hernia in vitro.(Mudgett et al., 1998; Wang et al., 1999; Haro et al., 2000a; Warner et al., 2001; Wielockx et al., 2001; Li et al., 2004; Mukherjee et al., 2005)
Mmp7−/−No obvious abnormalities and both males and females were fertile. Normal lifespan.↓Release of TNFα from peritoneal macrophage in vitro, ↓transepithelial neutrophil migration in bleomycin-induced lung injury, ↓reepithelization postinjury in trachea, ↓processing of alpha-defensin resulting in ↓innate immunity, ↑corneal neovascularization after injury, ↓epithelial cell apoptosis linked with ↓Fas ligand processing, protected from LPS-induced intestinal permeability and lethality.(Wilson et al., 1997; Dunsmore et al., 1998; Powell et al., 1999; Wilson, 1999; Haro et al., 2000b; Li et al., 2002; Kure et al., 2003; Vandenbroucke et al., 2014)
Mmp8−/−Normal development, fertile, and no reduction in survival.↑Incidence of skin tumors, ↓inflammatory cell apoptosis but ↑neutrophils in BAL in an asthma model, ↑protection in TNFα-induced hepatitis and impaired leukocyte influx, ↓neutrophil infiltration toward LPS, ↓mortality and hypothermia in sepsis and renal ischemia/reperfusion.(Balbín et al., 2003; Gueders et al., 2005; Van Lint et al., 2005; Tester et al., 2007; Vandenbroucke et al., 2012; Fortelny et al., 2014)
Mmp9−/−No gross phenotypic abnormalities, fertile, and normal lifespan. However, they have abnormal development of growth plates in long bones.↑Protection and ↓reduction in hepatocyte apoptosis in TNFα-induced hepatitis, ↓severity of antibody-induced arthritis, ↓cardiac allograft survival, ↓immune-complex-induced lung injury, prolonged skin-contact hypersensitivity, ↓alveolar bronchiolization after bleomycin treatment, ↑bronchoalveolar lavage cell recruitment post allergic challenge, impaired neutrophil infiltration and ↑ early vascular permeability in a model of zymosan peritonitis, ↓resistance against Escherichia coli peritonitis due to ↓leukocyte recruitment, ↓dextran-sulfate-induced colitis, ↑bacterial-induced arthritis but ↓bacterial clearance, ↑brain hemorrhage and injury, ↓remyelination after spinal cord trauma, spontaneous deficient myelination of corpus callosum with fewer oligodendrocytes, ↓experimental autoimmune encephalomyelitis in young mice, ↓vessel formation in an ischemic limb model, ↓left-ventricle dilation and fibrosis post pressure overload, ↓capillary branching post ischemic insult, ↑myocardial injury and foci of infection when infected with coxsackievirus B3.(Vu et al., 1998; Dubois et al., 1999; Wang et al., 1999; Betsuyaku et al., 2000; Wielockx et al., 2001; Warner et al., 2001; Itoh et al., 2002; Larsen et al., 2003, 2006; McMillan et al., 2004; Johnson et al., 2004; Tang et al., 2004; Campbell et al., 2005; Heissig et al., 2005; Heymans et al., 2005; Castaneda et al., 2005; Kolaczkowska et al., 2006; Renckens et al., 2006; Calander et al., 2006; Cheung et al., 2008)
Mmp10−/−No overt defects in fertility, litter size, gross appearance, organ structure, or tissue histology.Muscles displayed impaired recruitment of endothelial cells, reduced levels of extracellular matrix proteins, diminished collagen deposition, and decreased fiber size muscles displayed impaired recruitment of endothelial cells, reduced levels of extracellular matrix proteins, diminished collagen deposition, and decreased fiber size, muscles display ↓recruitment of endothelial cells, ↓ECM proteins, ↓fiber size, delayed fibrinolysis, ↑collagen deposition in skin wounds, ↑infiltration of macrophages during acute infection.(Kassim et al., 2007; Orbe et al., 2011; Bobadilla et al., 2014; Rohani et al., 2015; McMahan et al., 2016)
Mmp11−/−Viable, fertile, no behavior differences with wild type littermates.↑Neointima formation after vascular injury, ↓7,12-dimethylbenzanthracene-induced tumorigenesis, ↑subcutaneous (SC) and gonadal (GON) fat deposits, adipogenesis, adipocyte membrane alteration, ↑dysregulation of metabolism.(Masson et al., 1998; Lijnen et al., 1999, 2002; Andarawewa et al., 2005; Dali-Youcef et al., 2016)
Mmp12−/−Normal embryonic and postnatal development in the absence of inflammatory stress. Resting hematopoiesis and myelomonocytic development are normal. Mmp12−/− mice have a 40% reduction in litter sizes likely due to placental abnormalities.↓Migration and invasion in macrophages, resistance against cigarette-smoke-induced emphysema, unable to process chemokines and cytokines like IFNα and IFNγ resulting in exacerbation of acute and chronic inflammation, unable to resolve bacterial and virus infections, reduced phagocytosis and hemolysis capacity, dysregulated complement activation, ↓macrophage infiltration in ligament-injury repair, spontaneous deficient myelination of corpus callosum with fewer oligodendrocytes, ↑experimental autoimmune encephalomyelitis severity.(Shipley et al., 1996; Hautamaki et al., 1997; Weaver et al., 2005; Larsen et al., 2006; Dean et al., 2008; Houghton et al., 2009; Bellac et al., 2014; Marchant et al., 2014; Dufour et al., 2018; Mallia-Milanes et al., 2018)
Mmp13−/−No gross phenotypic abnormalities, fertile, and normal lifespan.Spontaneous abnormal growth plate and ↑trabecular bone.(Inada et al., 2004; Stickens et al., 2004)
Mmp14−/−/
Mt1-mmp−/−		Viable but display severe runting, wasting and ↑mortality. Death occurs between 50 and 90 days after birth.Craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues, ↓lung alveolar surface area, retarded lung alveolar development, ↓neovessel formation, poorly differentiated kidney tubular epithelia, lack of molar tooth eruption and root formation, defects in dentin formation and mineralization, ↓metabolic homeostasis, ↓regulation of adipocyte fate determination in the developing mammary gland.(Holmbeck et al., 1999, 2003; Chun et al., 2004; Koshikawa et al., 2004; Atkinson et al., 2005; Irie et al., 2005; Feinberg et al., 2016; Mori et al., 2016; Xu et al., 2016; Mai et al., 2017)
Mmp15−/−/
Mt2-mmp−/−		Viable, fertile, and live through adulthood.↑Positive regulators of brown or induced brown (beige) adipocytes production.(Feinberg et al., 2016)
Mmp16−/−/
Mt3-mmp−/−		Viable, fertile, but displayed retarded growth of the skeleton compared with wild types or heterozygous littermates.↓Viability of mesenchymal cells in skeletal tissues.(Shi et al., 2008)
Mmp17−/−/
Mt4-mmp−/−		No apparent defects in growth, fertility, and life span.↑Protection from Il1β-mediated GAG release into synovial fluid in a model of joint inflammation; ↑predisposition to aortic aneurysms; plays a role in embryonic development, brain formation, angiogenesis and limb development.(Rikimaru et al., 2007; Clements et al., 2011; Martín-Alonso et al., 2015; Blanco et al., 2017)
Mmp19−/−Viable, fertile, and no apparent phenotype under homeostasis.↑Body weight under high-fat diet, adipocytes hypertrophy,
↓susceptibility to develop skin tumors induced by a model of chemical carcinogens; in a model of contact hypersensitivity, impaired T cell-mediated immune reaction characterized by minimal influx of inflammatory cells, low proliferation of keratinocytes, ↓activated CD8+ T cells in lymph nodes; after an allergen challenge, ↑eosinophilic inflammation and ↑ tenascin protein, ↑lung fibrotic response to bleomycin, ↑protection against hepatic fibrosis, ↑susceptibility to colitis in a dextran sulfate sodium-induced colitis model.		(Pendás et al., 2004; Beck et al., 2008; Gueders et al., 2010; Jirouskova et al., 2012; Yu et al., 2012; Jara et al., 2015; Brauer et al., 2016)
Mmp20−/−Severe tooth defects but mice were viable and had no fertility issues.Hypomineralization of mantle dentin, defects in processing amelogenin, altered enamel protein, and associated rod pattern.(Caterina et al., 2002; Beniash et al., 2006)
Mmp21−/−N/AN/AN/A
Mmp23−/−N/AN/AN/A
Mmp24−/−/
Mt5-mmp−/−		Normal appearance, fertile, and have normal lifespan.Unable to develop neuropathic pain with mechanical allodynia after a sciatic nerve injury; ↓nerve-fiber sprouting and neural invasion; ↑sensitivity to noxious thermal stimuli under basal conditions; unable to develop thermal hyperalgesia under inflammatory conditions; protected against amyloid pathology, cognitive decline, and inflammation.(Komori et al., 2004; Folgueras et al., 2009; Baranger et al., 2016)
Mmp25−/−/
Mt6-mmp−/−		Viable, fertile, and no apparent phenotype under homeostasis.Defective innate immune response via a low sensitivity to bacterial LPS, hypergammaglobulinemia, ↓secretion of proinflammatory molecules, impaired NF-κB activation.(Soria-Valles et al., 2016)
Mmp26−/−N/AN/AN/A
Mmp27−/−N/AN/AN/A
Mmp28−/−Viable, fertile, and no apparent phenotype under homeostasis.↑Macrophage recruitment, ↑macrophage migration, and ↑bacterial clearance into the lung in Pseudomonas aeruginosa–treated mice; ↓macrophage polarization, ↓collagen deposition, and few myofibroblasts.(Manicone et al., 2009, 2017; Ma et al., 2013; Gharib et al., 2014)