Original Article

Stromelysin-1 Regulates Adipogenesis during Mammary Gland Involution

Correspondence to: Caroline M. Alexander, McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, 1400 University Avenue, Madison, WI 53706-1599. Tel:(608) 265 5182 Fax:(608) 262 2824 E-mail:alexander{at}oncology.wisc.edu.

The matrix metalloproteinase MMP-3/stromelysin-1 (Str1) is highly expressed during mammary gland involution induced by weaning. During involution, programmed cell death of the secretory epithelium takes place concomitant with the repopulation of the mammary fat pad with adipocytes. In this study, we have used a genetic approach to determine the role of Str1 during mammary involution. Although Str1 has been shown to induce unscheduled apoptosis when expressed ectopically during late pregnancy (Alexander, C.M., E.W. Howard, M.J. Bissell, and Z. Werb. 1996. J. Cell Biol. 135:1669–1677), we found that during post-lactational involution, mammary glands from transgenic mice that overexpress the tissue inhibitor of metalloproteinases, TIMP-1 (TO), or mice carrying a targeted mutation in Str1 showed accelerated differentiation and hypertrophy of adipocytes, while epithelial apoptosis was unaffected. These data suggest that matrix metalloproteinases (MMPs) do not induce unscheduled epithelial cell death after weaning, but instead alter the stromal microenvironment. We used adipogenic 3T3-L1 cells as a cell culture model to test the function of MMPs during adipocyte differentiation. Fibroblastic 3T3-L1 progenitor cells expressed very low levels of MMPs or TIMPs. The transcription of a number of MMP and TIMP mRNAs [Str1, MT1-MMP, (MMP-14) collagenase-3 (MMP-13), gelatinase A (MMP-2), and TIMP-1, -2 and -3] was induced in committed preadipocytes, but only differentiated adipocytes expressed an activated MMP, gelatinase A. The addition of MMP inhibitors (GM 6001 and TIMP-1) dramatically accelerated the accumulation of lipid during differentiation. We conclude that MMPs, especially Str1, determine the rate of adipocyte differentiation during involutive mammary gland remodeling.

Key Words: transgenic mouse, mammary involution, MMP-3, TIMP-1, 3T3-L1 adipocytes

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Weise, S., Kralisch, S., Sommer, G., Lossner, U., Bluher, M., Stumvoll, M., Fasshauer, M. (2008). Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1{beta} in 3T3-L1 adipocytes. J Endocrinol 198: 169-174 [Abstract] [Full Text]  
• Lijnen, H. R. (2008). Angiogenesis and obesity. Cardiovasc Res 78: 286-293 [Abstract] [Full Text]  
• Monks, J., Smith-Steinhart, C., Kruk, E. R., Fadok, V. A., Henson, P. M. (2008). Epithelial Cells Remove Apoptotic Epithelial Cells During Post-Lactation Involution of the Mouse Mammary Gland. Biol. Reprod. 78: 586-594 [Abstract] [Full Text]  
• Maury, E., Ehala-Aleksejev, K., Guiot, Y., Detry, R., Vandenhooft, A., Brichard, S. M. (2007). Adipokines oversecreted by omental adipose tissue in human obesity. Am. J. Physiol. Endocrinol. Metab. 293: E656-E665 [Abstract] [Full Text]  
• Russell, D. L., Robker, R. L. (2007). Molecular mechanisms of ovulation: co-ordination through the cumulus complex. Hum Reprod Update 13: 289-312 [Abstract] [Full Text]  
• Zaragoza, R., Gimeno, A., Miralles, V. J., Garcia-Trevijano, E. R., Carmena, R., Garcia, C., Mata, M., Puertes, I. R., Torres, L., Vina, J. R. (2007). Retinoids induce MMP-9 expression through RAR{alpha} during mammary gland remodeling. Am. J. Physiol. Endocrinol. Metab. 292: E1140-E1148 [Abstract] [Full Text]  
• Kralisch, S., Bluher, M., Tonjes, A., Lossner, U., Paschke, R., Stumvoll, M., Fasshauer, M. (2007). Tissue inhibitor of metalloproteinase-1 predicts adiposity in humans. Eur J Endocrinol 156: 257-261 [Abstract] [Full Text]  
• Kwak, H.-I., Gustafson, T., Metz, R. P., Laffin, B., Schedin, P., Porter, W. W. (2007). Inhibition of breast cancer growth and invasion by single-minded 2s. Carcinogenesis 28: 259-266 [Abstract] [Full Text]  
• Traurig, M. T., Permana, P. A., Nair, S., Kobes, S., Bogardus, C., Baier, L. J. (2006). Differential Expression of Matrix Metalloproteinase 3 (MMP3) in Preadipocytes/Stromal Vascular Cells From Nonobese Nondiabetic Versus Obese Nondiabetic Pima Indians. Diabetes 55: 3160-3165 [Abstract] [Full Text]  
• Kralisch, S, Lossner, U, Bluher, M, Paschke, R, Stumvoll, M, Fasshauer, M (2006). Tissue inhibitor of metalloproteinase 1 expression and secretion are induced by {beta}-adrenergic stimulation in 3T3-L1 adipocytes.. J Endocrinol 189: 665-670 [Abstract] [Full Text]  
• Mannello, F., Tonti, G. A.M., Bagnara, G. P., Papa, S. (2006). Role and Function of Matrix Metalloproteinases in the Differentiation and Biological Characterization of Mesenchymal Stem Cells. Stem Cells 24: 475-481 [Abstract] [Full Text]  
• McDaniel, S. M., Rumer, K. K., Biroc, S. L., Metz, R. P., Singh, M., Porter, W., Schedin, P. (2006). Remodeling of the Mammary Microenvironment after Lactation Promotes Breast Tumor Cell Metastasis. Am. J. Pathol. 168: 608-620 [Abstract] [Full Text]  
• Andarawewa, K. L., Motrescu, E. R., Chenard, M.-P., Gansmuller, A., Stoll, I., Tomasetto, C., Rio, M.-C. (2005). Stromelysin-3 Is a Potent Negative Regulator of Adipogenesis Participating to Cancer Cell-Adipocyte Interaction/Crosstalk at the Tumor Invasive Front. Cancer Res. 65: 10862-10871 [Abstract] [Full Text]  
• Hanayama, R., Nagata, S. (2005). Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8. Proc. Natl. Acad. Sci. USA 102: 16886-16891 [Abstract] [Full Text]  
• Granneman, J. G., Li, P., Zhu, Z., Lu, Y. (2005). Metabolic and cellular plasticity in white adipose tissue I: effects of {beta}3-adrenergic receptor activation. Am. J. Physiol. Endocrinol. Metab. 289: E608-E616 [Abstract] [Full Text]  
• McCawley, L. J., Crawford, H. C., King, L. E. Jr., Mudgett, J., Matrisian, L. M. (2004). A Protective Role for Matrix Metalloproteinase-3 in Squamous Cell Carcinoma. Cancer Res. 64: 6965-6972 [Abstract] [Full Text]  
• Matsumoto, K.-i., Sato, T., Oka, S., Orba, Y., Sawa, H., Kabayama, K., Inokuchi, J.-i., Ariga, H. (2004). Triglyceride accumulation and altered composition of triglyceride-associated fatty acids in the skin of tenascin-X-deficient mice. GENES CELLS 9: 737-748 [Abstract] [Full Text]  
• Pendas, A. M., Folgueras, A. R., Llano, E., Caterina, J., Frerard, F., Rodriguez, F., Astudillo, A., Noel, A., Birkedal-Hansen, H., Lopez-Otin, C. (2004). Diet-Induced Obesity and Reduced Skin Cancer Susceptibility in Matrix Metalloproteinase 19-Deficient Mice. Mol. Cell. Biol. 24: 5304-5313 [Abstract] [Full Text]  
• Kawaguchi, N., Sundberg, C., Kveiborg, M., Moghadaszadeh, B., Asmar, M., Dietrich, N., Thodeti, C. K., Nielsen, F. C., Moller, P., Mercurio, A. M., Albrechtsen, R., Wewer, U. M. (2003). ADAM12 induces actin cytoskeleton and extracellular matrix reorganization during early adipocyte differentiation by regulating {beta}1 integrin function. J. Cell Sci. 116: 3893-3904 [Abstract] [Full Text]  
• Wiseman, B. S., Sternlicht, M. D., Lund, L. R., Alexander, C. M., Mott, J., Bissell, M. J., Soloway, P., Itohara, S., Werb, Z. (2003). Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis. J. Cell Biol. 162: 1123-1133 [Abstract] [Full Text]  
• Bradshaw, A. D., Graves, D. C., Motamed, K., Sage, E. H. (2003). SPARC-null mice exhibit increased adiposity without significant differences in overall body weight. Proc. Natl. Acad. Sci. USA 100: 6045-6050 [Abstract] [Full Text]  
• Chavey, C., Mari, B., Monthouel, M.-N., Bonnafous, S., Anglard, P., Van Obberghen, E., Tartare-Deckert, S. (2003). Matrix Metalloproteinases Are Differentially Expressed in Adipose Tissue during Obesity and Modulate Adipocyte Differentiation. J. Biol. Chem. 278: 11888-11896 [Abstract] [Full Text]  
• Webber, C. A., Hocking, J. C., Yong, V. W., Stange, C. L., McFarlane, S. (2002). Metalloproteases and Guidance of Retinal Axons in the Developing Visual System. J. Neurosci. 22: 8091-8100 [Abstract] [Full Text]  
• Humphreys, R. C., Bierie, B., Zhao, L., Raz, R., Levy, D., Hennighausen, L. (2002). Deletion of Stat3 Blocks Mammary Gland Involution and Extends Functional Competence of the Secretory Epithelium in the Absence of Lactogenic Stimuli. Endocrinology 143: 3641-3650 [Abstract] [Full Text]  
• Wiseman, B. S., Werb, Z. (2002). Stromal Effects on Mammary Gland Development and Breast Cancer. Science 296: 1046-1049 [Abstract] [Full Text]  
• Lilla, J., Stickens, D., Werb, Z. (2002). Metalloproteases and Adipogenesis: A Weighty Subject. Am. J. Pathol. 160: 1551-1554 [Full Text]  
• Kawaguchi, N., Xu, X., Tajima, R., Kronqvist, P., Sundberg, C., Loechel, F., Albrechtsen, R., Wewer, U. M. (2002). ADAM 12 Protease Induces Adipogenesis in Transgenic Mice. Am. J. Pathol. 160: 1895-1903 [Abstract] [Full Text]  
• Maquoi, E., Munaut, C., Colige, A., Collen, D., Lijnen, H. R. (2002). Modulation of Adipose Tissue Expression of Murine Matrix Metalloproteinases and Their Tissue Inhibitors With Obesity. Diabetes 51: 1093-1101 [Abstract] [Full Text]  
• Lijnen, H.R., Maquoi, E., Hansen, L.B., Van Hoef, B., Frederix, L., Collen, D. (2002). Matrix Metalloproteinase Inhibition Impairs Adipose Tissue Development in Mice. Arterioscler. Thromb. Vasc. Bio. 22: 374-379 [Abstract] [Full Text]  
• Kheradmand, F., Rishi, K., Werb, Z. (2002). Signaling through the EGF receptor controls lung morphogenesis in part by regulating MT1-MMP-mediated activation of gelatinase A/MMP2. J. Cell Sci. 115: 839-848 [Abstract] [Full Text]  
• Landry, R., Rioux, V., Bensadoun, A. (2001). Characterization of Syndecan-4 Expression in 3T3-F442A Mouse Adipocytes: Link between Syndecan-4 Induction and Cell Proliferation. Cell Growth Differ. 12: 497-504 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents