Stromelysin-1 Regulates Adipogenesis during Mammary Gland Involution

Abstract

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.

Matrix Metalloproteinases Are Differentially Expressed in Adipose Tissue during Obesity and Modulate Adipocyte Differentiation

“…Interestingly, treatment of 3T3-F442A preadipocytes with synthetic MMP inhibitors and by neutralizing antibodies decreased differentiation, suggesting that MMP activities were required for adipocyte conversion (12). In contrast, another study showed that addition of TIMP-1 or MMP inhibitor GM6001 accelerated 3T3-L1 adipocyte differentiation (14). In addition, this study also demonstrated that stromelysin-1 (MMP-3) determined the rate of adipose reconstitution during mammary gland involution in mice (14).…”

“…In contrast, another study showed that addition of TIMP-1 or MMP inhibitor GM6001 accelerated 3T3-L1 adipocyte differentiation (14). In addition, this study also demonstrated that stromelysin-1 (MMP-3) determined the rate of adipose reconstitution during mammary gland involution in mice (14). Moreover, on a high fat diet, stromelysin-3 (MMP-11)-deficient mice developed adipocyte hypertrophy compared with wild-type mice (15).…”

Differential Expression of Matrix Metalloproteinase 3 (MMP3) in Preadipocytes/Stromal Vascular Cells From Nonobese Nondiabetic Versus Obese Nondiabetic Pima Indians

“…For example, Maquoi et al (18) demonstrated that MMP3 Ϫ/Ϫ mice had increased adipocyte hypertrophy when fed a high-fat diet, and Alexander et al (17) showed that MMP3 Ϫ/Ϫ (Str1 Ϫ/Ϫ ) mice had accelerated adipocyte differentiation during mammary gland involution. In the same study, Alexander et al noted that MMP3 Ϫ/Ϫ mice backcrossed onto another background (FVB/N) became obese with age (17). In contrast to our study, both Maquoi et al (5), in an earlier study, and Chavey et al (4) found that MMP3 expression levels were upregulated in adipose tissue isolated from obese mice.…”

Matrix metalloproteinases and the regulation of tissue remodelling

“…• Adipocyte maturation requires the replacement of the surrounding interstitial matrix with a basement membrane 148,149 *Reviewed in REFS [121][122][123][124] .…”