Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System Homozygote x Homozygote         (Female x Male) Species laboratory mouse Generation N10F?+N1F9 (04-DEC-07)   Donating Investigator Steven Shapiro,   University of Pittsburgh

Description
Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Homozygous females have reduced litter sizes. No gene product (mRNA or protein) is detected by Northern or Western blot analysis of peritoneal macrophages and fluid. Casein substrate gel zymographic analysis of thioglycollate-stimulated cultured macrophages and peritoneal fluid reveals there is no lytic activity. In whole lung extracts, no elastase activity was detected by zymography. Immunohistochemistry of lung tissue does not detect macrophage elastase. Macrophages from homozygous mice are unable to penetrate artificial basement membrane matrix. Addition of plasminogen to cultured macrophages does not increase elastase activity. When challenged with chronic exposure to cigarette smoke, mutant mice do not develop emphysema. IL-13 induced tissue inflammation is reduced in homozygotes. This mutant mouse strain may be useful in studies of wound repair and extracellular matrix remodeling.

Development
A targeting vector containing a neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter was used to disrupt most of exon 2 of the targeted gene. The construct was electroporated into 129X1/SvJ derived RW4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts.

Control Information

	Control
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Mmp12^tm1Sds/Mmp12^tm1Sds

        B6.129X1-Mmp12^tm1Sds

• homeostasis/metabolism phenotype
• decreased sensitivity to xenobiotics (MGI Ref ID J:86599)
  • mice fail to develop emphysema following a 6 month exposure to cigarette smoke unlike wild-type mice
  • following a 6 month exposure to cigarette smoke, mice exhibit fewer macrophages in bronchoalveolar lavage samples compared to wild-type mice

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Mmp12^tm1Sds/Mmp12^tm1Sds

        involves: 129X1/SvJ

• immune system phenotype
• abnormal macrophage physiology (MGI Ref ID J:32902)
  • macrophages have impaired capacity to degrade elastin and cannot penetrate reconstituted basement membranes in vitro and in vivo
• reproductive system phenotype
• decreased litter size (MGI Ref ID J:32902)
  • have litter sizes only 60% that of wildtype
• nervous system phenotype
• abnormal myelination (MGI Ref ID J:105765)
  • exhibit decreased myelination in the corpus callosum at P7 and P10, but not at P14, as evidenced by decreased MBP expression
• abnormal oligodendrocyte morphology (MGI Ref ID J:105765)
  • exhibit a decrease in the number of mature oligondendrocytes at P10, however no differences in oligodendrocyte precursor cell numbers

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Mmp12^tm1Sds related

Immunology and Inflammation Research
Inflammation

Metabolism Research
Enzyme Deficiency

Genes & Alleles

Gene & Allele Information

Allele Symbol		Mmp12tm1Sds
Allele Name		targeted mutation 1, Steven D Shapiro
Allele Type		Targeted (knock-out)
Common Name(s)		MME-; MMP-12-; Mmp12-;
Mutation Made By		Emily Heiss,   Brigham and Women's Hospital
Strain of Origin		129X1/SvJ
ES Cell Line Name		RW-4
ES Cell Line Strain		129X1/SvJ
Gene Symbol and Name		Mmp12, matrix metallopeptidase 12
Chromosome		9
Gene Common Name(s)		AV378681; HME; MGC138506; MME; Mmel; expressed sequence AV378681; macrophage elastase; macrophage metalloelastase;
Molecular Note		The gene was disrupted by replacement of the majority of exon 2 with a PGK-neo cassette via homologous recombination. Gene transcription and protein production was absent in homozygous mutant animals as demonstrated by Northern and Western blot analysis of peritoneal macrophages and peritoneal fluid. [MGI Ref ID J:32902]

Genotyping

Genotyping Information

Genotyping Protocols

Mmp12^tm1Sds, SEP PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Shipley JM; Wesselschmidt RL; Kobayashi DK; Ley TJ; Shapiro SD. 1996. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc Natl Acad Sci U S A 93(9):3942-6. [PubMed: 8632994]  [MGI Ref ID J:32902]

Additional References

Carmeliet P; Moons L; Lijnen R; Baes M; Lemaitre V; Tipping P; Drew A; Eeckhout Y; Shapiro S; Lupu F; Collen D. 1997. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet 17(4):439-44. [PubMed: 9398846]  [MGI Ref ID J:44387]

Hautamaki RD; Kobayashi DK; Senior RM; Shapiro SD. 1997. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277(5334):2002-4. [PubMed: 9302297]  [MGI Ref ID J:43130]

Mmp12^tm1Sds related

Carmeliet P; Moons L; Lijnen R; Baes M; Lemaitre V; Tipping P; Drew A; Eeckhout Y; Shapiro S; Lupu F; Collen D. 1997. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet 17(4):439-44. [PubMed: 9398846]  [MGI Ref ID J:44387]

Churg A; Dai J; Zay K; Karsan A; Hendricks R; Yee C; Martin R; MacKenzie R; Xie C; Zhang L; Shapiro S; Wright JL. 2001. Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects. Lab Invest 81(8):1119-31. [PubMed: 11502863]  [MGI Ref ID J:71105]

Churg A; Zay K; Shay S; Xie C; Shapiro SD; Hendricks R; Wright JL. 2002. Acute cigarette smoke-induced connective tissue breakdown requires both neutrophils and macrophage metalloelastase in mice. Am J Respir Cell Mol Biol 27(3):368-74. [PubMed: 12204900]  [MGI Ref ID J:113625]

Dean RA; Cox JH; Bellac CL; Doucet A; Starr AE; Overall CM. 2008. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx. Blood 112(8):3455-64. [PubMed: 18660381]  [MGI Ref ID J:140224]

Denis M; Cormier Y; Fournier M; Tardif J; Laviolette M. 1991. Tumor necrosis factor plays an essential role in determining hypersensitivity pneumonitis in a mouse model. Am J Respir Cell Mol Biol 5(5):477-83. [PubMed: 1931076]  [MGI Ref ID J:11522]

Edelstein C; Shapiro SD; Klezovitch O; Scanu AM. 1999. Macrophage metalloelastase, MMP-12, cleaves human apolipoprotein(a) in the linker region between kringles IV-4 and IV-5. Potential relevance to lipoprotein(a) biology. J Biol Chem 274(15):10019-23. [PubMed: 10187779]  [MGI Ref ID J:115221]

Hautamaki RD; Kobayashi DK; Senior RM; Shapiro SD. 1997. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277(5334):2002-4. [PubMed: 9302297]  [MGI Ref ID J:43130]

Heymans S; Luttun A; Nuyens D; Theilmeier G; Creemers E; Moons L; Dyspersin GD; Cleutjens JP; Shipley M; Angellilo A; Levi M; Nube O; Baker A; Keshet E; Lupu F; Herbert JM; Smits JF; Shapiro SD; Baes M; Borgers M; Collen D; Daemen MJ; Carmeliet P. 1999. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med 5(10):1135-42. [PubMed: 10502816]  [MGI Ref ID J:124004]

Houghton AM; Grisolano JL; Baumann ML; Kobayashi DK; Hautamaki RD; Nehring LC; Cornelius LA; Shapiro SD. 2006. Macrophage elastase (matrix metalloproteinase-12) suppresses growth of lung metastases. Cancer Res 66(12):6149-55. [PubMed: 16778188]  [MGI Ref ID J:110107]

Johnson JL; George SJ; Newby AC; Jackson CL. 2005. Divergent effects of matrix metalloproteinases 3, 7, 9, and 12 on atherosclerotic plaque stability in mouse brachiocephalic arteries. Proc Natl Acad Sci U S A 102(43):15575-80. [PubMed: 16221765]  [MGI Ref ID J:102482]

Kang HR; Cho SJ; Lee CG; Homer RJ; Elias JA. 2007. Transforming growth factor (TGF)-beta1 stimulates pulmonary fibrosis and inflammation via a Bax-dependent, bid-activated pathway that involves matrix metalloproteinase-12. J Biol Chem 282(10):7723-32. [PubMed: 17209037]  [MGI Ref ID J:120886]

Kassim SY; Fu X; Liles WC; Shapiro SD; Parks WC; Heinecke JW. 2005. NADPH oxidase restrains the matrix metalloproteinase activity of macrophages. J Biol Chem 280(34):30201-5. [PubMed: 15983040]  [MGI Ref ID J:101039]

Lanone S; Zheng T; Zhu Z; Liu W; Lee CG; Ma B; Chen Q; Homer RJ; Wang J; Rabach LA; Rabach ME; Shipley JM; Shapiro SD; Senior RM; Elias JA. 2002. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling. J Clin Invest 110(4):463-74. [PubMed: 12189240]  [MGI Ref ID J:78575]

Larsen PH; DaSilva AG; Conant K; Yong VW. 2006. Myelin formation during development of the CNS is delayed in matrix metalloproteinase-9 and -12 null mice. J Neurosci 26(8):2207-14. [PubMed: 16495447]  [MGI Ref ID J:105765]

Lee MM; Yoon BJ; Osiewicz K; Preston M; Bundy B; van Heeckeren AM; Werb Z; Soloway PD. 2005. Tissue inhibitor of metalloproteinase 1 regulates resistance to infection. Infect Immun 73(1):661-5. [PubMed: 15618213]  [MGI Ref ID J:94836]

Marsland BJ; Kurrer M; Reissmann R; Harris NL; Kopf M. 2008. Nippostrongylus brasiliensis infection leads to the development of emphysema associated with the induction of alternatively activated macrophages. Eur J Immunol 38(2):479-88. [PubMed: 18203142]  [MGI Ref ID J:131355]

Matute-Bello G; Wurfel MM; Lee JS; Park DR; Frevert CW; Madtes DK; Shapiro SD; Martin TR. 2007. Essential role of MMP-12 in Fas-induced lung fibrosis. Am J Respir Cell Mol Biol 37(2):210-21. [PubMed: 17446527]  [MGI Ref ID J:138494]

Morris DG; Huang X; Kaminski N; Wang Y; Shapiro SD; Dolganov G; Glick A; Sheppard D. 2003. Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema. Nature 422(6928):169-73. [PubMed: 12634787]  [MGI Ref ID J:89578]

Pouladi MA; Robbins CS; Swirski FK; Cundall M; McKenzie AN; Jordana M; Shapiro SD; Stampfli MR. 2004. Interleukin-13-dependent expression of matrix metalloproteinase-12 is required for the development of airway eosinophilia in mice. Am J Respir Cell Mol Biol 30(1):84-90. [PubMed: 12842850]  [MGI Ref ID J:95132]

Pyo R; Lee JK; Shipley JM; Curci JA; Mao D; Ziporin SJ; Ennis TL; Shapiro SD; Senior RM; Thompson RW. 2000. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms [see comments] J Clin Invest 105(11):1641-9. [PubMed: 10841523]  [MGI Ref ID J:62760]

Senft AP; Korfhagen TR; Whitsett JA; Shapiro SD; LeVine AM. 2005. Surfactant protein-D regulates soluble CD14 through matrix metalloproteinase-12. J Immunol 174(8):4953-9. [PubMed: 15814723]  [MGI Ref ID J:98168]

Shapiro SD; Goldstein NM; Houghton AM; Kobayashi DK; Kelley D; Belaaouaj A. 2003. Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. Am J Pathol 163(6):2329-35. [PubMed: 14633606]  [MGI Ref ID J:86599]

Warner RL; Lewis CS; Beltran L; Younkin EM; Varani J; Johnson KJ. 2001. The role of metalloelastase in immune complex-induced acute lung injury. Am J Pathol 158(6):2139-44. [PubMed: 11395391]  [MGI Ref ID J:114408]

Warner RL; Lukacs NW; Shapiro SD; Bhagarvathula N; Nerusu KC; Varani J; Johnson KJ. 2004. Role of metalloelastase in a model of allergic lung responses induced by cockroach allergen. Am J Pathol 165(6):1921-30. [PubMed: 15579436]  [MGI Ref ID J:109719]

Weaver A; Goncalves da Silva A; Nuttall RK; Edwards DR; Shapiro SD; Rivest S; Yong VW. 2005. An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization. FASEB J 19(12):1668-70. [PubMed: 16081501]  [MGI Ref ID J:102657]

Wells JE; Biernaskie J; Szymanska A; Larsen PH; Yong VW; Corbett D. 2005. Matrix metalloproteinase (MMP)-12 expression has a negative impact on sensorimotor function following intracerebral haemorrhage in mice. Eur J Neurosci 21(1):187-96. [PubMed: 15654856]  [MGI Ref ID J:100812]

Wells JE; Rice TK; Nuttall RK; Edwards DR; Zekki H; Rivest S; Yong VW. 2003. An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice. J Neurosci 23(31):10107-15. [PubMed: 14602826]  [MGI Ref ID J:86556]

Zhang L; Ikegami M; Korfhagen TR; McCormack FX; Yoshida M; Senior RM; Shipley JM; Shapiro SD; Whitsett JA. 2006. Neither SP-A nor NH2-terminal domains of SP-A can substitute for SP-D in regulation of alveolar homeostasis. Am J Physiol Lung Cell Mol Physiol 291(2):L181-90. [PubMed: 16500946]  [MGI Ref ID J:121212]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

Breeding & Husbandry	The resulting chimeric animals were crossed to C57BL/6J mice, and then backcrossed to the same for 10 generations. The strain is maintained as a homozygote. Homozygous females have reduced litter sizes (60% of wildtype).
Mating System	Homozygote x Homozygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Ordering and Purchasing Information

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Contact Information
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Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
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Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries

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phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

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In no event shall The Jackson Laboratory, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, products or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

MICE and biological materials are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

Acceptance of delivery of MICE, products or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on The Jackson Laboratory, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, products services by The Jackson Laboratory.