Differential expression of matrix metalloproteinases and their tissue inhibitors in leiomyomata: a mechanism for gonadotrophin releasing hormone agonist-induced tumour regression.

Abstract

Tissue remodelling involving extracellular matrix (ECM) turnover plays a major role in leiomyoma growth and regression, regulated by the combined action of matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs). We postulated that leiomyomata express MMP and TIMP mRNA and protein, and their expression is inversely regulated during tumour growth and gonadotrophin releasing hormone agonist (GnRHa)-induced regression. We therefore examined the expression of mRNA and protein for MMPs (interstitial collagenase, MMP-1; gelatinases, MMP-2 and MMP-9; and stromelysin, MMP-3) and TIMPs (TIMP-1 and TIMP-2) in leiomyoma and matched unaffected myometrium from GnRHa (lupron)-treated and untreated patients. Reverse transcription-polymerase chain reaction (RT-PCR) and restriction enzyme analysis revealed that leiomyomata and myometrium expressed MMP-1, -2, -3 and -9, as well as TIMP-1 and -2 mRNA. Quantitative RT-PCR indicated that leiomyomata and myometrium during the secretory phase of the menstrual cycle expressed higher levels of MMP and TIMP mRNA compared to the proliferative phase (P < 0.05), with low to undetectable levels of MMP-1, -2 and -3 mRNA in the tumours. GnRHa therapy induced an overall reduction in MMP and TIMP mRNA expression in both leiomyomata and myometrium, but a significant decrease in TIMP-1, and an increase in MMP mRNA expression compared with untreated tumours (P < 0.05). Immunohistochemically, MMP-1, -2, -3 and -9 and TIMP-1 and -2 proteins were localized in leiomyomata and myometrial smooth muscle cells, arteriole wall and connective tissue fibroblasts, with an overall increase in MMP and a decrease in TIMP staining intensity in GnRHa-treated groups. The results suggest that MMP and TIMP expression in leiomyoma and myometrium are hormonally regulated, and that GnRHa-induced tumour regression is accompanied by an increase in MMP expression with a concomitant decrease in TIMP-1 expression, which may potentially provide an environment favouring ECM degradation.