MMPS and TIMPS in ovarian physiology and pathophysiology

Abstract

The matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been postulated to play a critical role in the extracellular matrix (ECM) remodeling associated with follicular development. The gelatinases were localized to the theca of developing follicles and in the stroma of the rodent ovary. Gelatinolytic activity corresponded with the localization of MMP-2 and MMP-9 around the developing follicles and at the apex of preovulatory follicles. The TIMPs-1, -2, and -3 were localized to the stroma and theca of developing follicles and correlation between MMPs and the quality of the developing follicles was found. During the process of ovulation, MMP-1 protein was found in the theca interna and externa, interstitial glands, and germinal epithelium. Synthetic inhibitor of mammalian tissue collagenases was documented to be inhibitory to ovulation in perfused rat ovaries. MMP-19 and TIMP-1 messenger RNA were localized to the granulosa and thecal-interstitial cells of large preovulatory and ovulating follicles. Both were induced and upregulated 5-10 fold by human chorionic gonadotropin (hCG). MMP-2 mRNA found in theca-interstitial cells and membrane-type (MT) 1-MMP mRNA found in granulosa and theca-interstitial cells were both induced after stimulation with pregnant mare's serum gonadotropin (PMSG). Gelatinolytic activity was observed throughout the formation of the corpus luteum. At 12 h after hCG, luteinizing granulosa cells expressed TIMP-1 and TIMP-3 mRNA. In the newly forming corpus luteum at 24 h after hCG administration, the luteal cells expressed TIMP-1, -2, and -3 mRNA with unique pattern of cellular expression for each of the TIMPs. Regression of the corpus luteum is associated with a significant increase in the activity of the metalloproteinases. In luteinized granulosa cells from women with polycystic ovarian syndrome (PCOS) the MMP-TIMP balance is shifted towards greater MMP activity. Cultured luteinized granulosa cells obtained from PCOS patients secrete higher levels of MMP-9 and MMP-2 compared to granulosa cells from normal ovulatory patients whereas the secreted basal level of TIMP-1 was similar in both types of granulosa cells. These results indicate a higher net gelatinolytic activity within the luteinizing granulosa cells of patients with PCOS. It has been shown that in sheep, diversion of normal follicles to atresia by hypophysectomy is followed by a significant increase of intrafollicular levels of MMP-2 and MMP-9 and the disappearance of connexin-43. It is therefore reasonable to speculate that MMP-9 and MMP-2 may be associated with inappropriate atresia in PCOS.

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

“…In fact, it has been shown that their expression is significantly increased in inflammation (Shamamian et al, 2001) and in tumour invasiveness and metastatisation (Turck et al, 1996) processes. Metalloproteinases are in turn regulated by inhibitory molecules (Goldman and Shalev, 2004); the balance between the two molecular families being critical for control of proteolysis (Lu et al, 2004).…”

Localization and temporal regulation of tissue inhibitor of metalloproteinases-4 in mouse ovary

“…Many studies have indicated that MMPs and their inhibitors are important regulators in the tissue remodeling of the above-mentioned process (Hagglund et al 1999, Nothnick 2000, Simpson et al 2003, Goldman & Shalev 2004. Unlike its counterparts TIMP-1, -2, -3, the localization and temporal regulation of TIMP-4 in rodent ovary have so far not been investigated in detail (Curry & Wheeler 2002).…”

Protein pathways working in human follicular fluid: the future for tailored IVF?

“…Accordingly, MMPs failure or reduced activity has been called into question for ECM derangements in subfertility and infertility, for aberrant follicle growth and deficiencies in ovulation ( Refs 29,31,32,33,34,35,36). Controlling ECM organisation, MMPs are actually involved in the bioavailability control of hormones, growth factors, and osmotically active molecules by regulating local accumulation and activation of these factors, as well as cell response to extracellular stimuli and cell to cell communications ( Refs 13,37,38,39,40,41).…”

“…In this respect, a down-regulation of TIMP-1 may have a detrimental effect in the ovulation and an altered MMPs/TIMPs ratio may lead to a precocious regression of the corpus luteum with consequent depletion in progesterone and estradiol synthesis, thus to reduce the negative feedback to LH pituitary secretion (Ref. 36).…”