Stromelysin-1 regulates adipogenesis during mammary gland involution

The matrix metalloproteinase MMP3/stromelysin-1 (Str1) is highly expressed during mammary gland involution induced by weaning. During involution, prog rammed 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 i nvolution. Although Str1 has been shown to induce unscheduled apoptosis whe n 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 th at during post-lactational involution, mammary glands from transgenic mice that overexpress the tissue inhibitor of metalloproteinases, TIMP-1 (TO), o r mice carrying a targeted mutation in Str1 showed accelerated differentiat ion and hypertrophy of adipocytes, while epithelial apoptosis was unaffecte d. These data suggest that matrix metalloproteinases (MMPs) do not induce u nscheduled epithelial cell death after weaning, but instead alter the strom al microenvironment. We used adipogenic 3T3-L1 cells as a cell culture mode l to test the function of MMPs during adipocyte differentiation. Fibroblast ic 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) co llagenase-3 (MMP-13), gelatinase A (MMP-2), and TIMP-1, -2 and -3] was indu ced in committed preadipocytes, but only differentiated adipocytes expresse d an activated MMP, gelatinase A. The addition of MMP inhibitors (GM 6001 a nd TIMP-1) dramatically accelerated the accumulation of lipid during differ entiation. We conclude that MMPs, especially Str1, determine the rate of ad ipocyte differentiation during involutive mammary gland remodeling.