Regulation of ovarian extracellular matrix remodelling by metalloproteinases and their tissue inhibitors: effects on follicular development, ovulation and luteal function.

In most organs, remodelling of tissues after morphogenesis is minimal; however, normal ovarian function depends upon cyclical remodelling of the extracellular matrix (ECM). The ECM has a profound effect on cellular functions and probably plays an important role in the processes of follicular development and atresia, ovulation, and development, maintenance and regression of corpora lutea. Matrix metalloproteinases (MMPs; collagenases, gelatinases, stromelysins and membrane-type MMPs) cleave specific components of the ECM and are inhibited by tissue inhibitors of metalloproteinases (TIMPs). MMPs have been detected at all stages of follicular development and probably modulate follicular expansion or atresia within the ovarian stroma. In addition, increased MMP activity appears to be required for ovulation since follicular rupture occurred in the absence of plasminogen activator activity and inhibitors of MMPs blocked follicular rupture. Development and luteolysis of the corpus luteum are accompanied by extensive remodelling of the ECM. Differentiation and regression of luteal cells are associated with construction and degradation of ECM, respectively. There is increasing evidence that ECM components enhance luteinization; whereas loss of ECM results in luteal cell death. Ovine large luteal cells may be the primary type of cell responsible for controlling the extent of remodelling of luteal ECM since they produce TIMP-1, TIMP-2 and plasminogen activator inhibitor 1. The ratio of active MMPs to TIMPs may be important in maintaining an ECM microenvironment conducive to the differentiation of follicular-derived cells into luteal cells, and maintenance of the phenotype of luteal cells.