Distinct expression of gelatinase A [matrix metalloproteinase (MMP)-2], collagenase-3 (MMP-13), membrane type MMP 1 (MMP-14), and tissue inhibitor of MMPs type 1 mediated by physiological signals during formation and regression of the rat corpus luteum

Abstract

The corpus luteum (CL) is a transient endocrine organ that secretes progesterone to support pregnancy. The CL is formed from an ovulated follicle in a process that involves extensive angiogenesis and tissue remodeling. If fertilization does not occur or implantation is unsuccessful, the CL will undergo regression, which involves extensive tissue degradation. Extracellular proteases, such as serine proteases and matrix metalloproteinases (MMPs), are thought to play important roles in both the formation and regression of the CL. In this study, we have examined the physiological regulation pattern and cellular distribution of messenger RNAs coding for gelatinase A (MMP-2), collagenase-3 (MMP-13), membrane type MMP 1 (MT1-MMP, MMP-14), and the major MMP inhibitor, tissue inhibitor of MMPs type 1 (TIMP-1) in the CL of adult pseudopregnant (psp) rat. Northern blot and in situ hybridization analyses revealed that gelatinase A messenger RNA was mainly expressed during luteal development, indicating that gelatinase A may be associated with the neovascularization and tissue remodeling that takes place during CL formation. Collagenase-3 had a separate expression pattern and was only expressed in the regressing CL, suggesting that this MMP may be related with luteal regression. MT1-MMP that in vitro can activate progelatinase A and procollagenase-3 was constitutively expressed during the formation, function, and regression of the CL and may therefore be involved in the activation of these MMPs. TIMP-1 was induced during both the formation and regression of the CL, suggesting that this inhibitor modulates MMP activity during these processes. To test whether the induction of collagenase-3 and TIMP-1 is coupled with luteal regression, we prolonged the luteal phase by performing hysterectomies, and induced premature luteal regression by treating the pseudopregnant rats with a PGF(2α) analog, cloprostenol. In both treatments, collagenase-3 and TIMP-1 were induced only after the serum level of progesterone had decreased, suggesting that collagenase-3 and TIMP-1 are induced by physiological signals, which initiate functional luteolysis to play a role in tissue degradation during structural luteolysis. In conclusion, our data suggest that gelatinase A, collagenase-3, and MT1-MMP may have separate functions during the CL life span: gelatinase A mainly takes part in CL formation, whereas collagenase-3 mainly takes part in luteal regression; MT1-MMP is constitutively expressed during the CL life span and may therefore serve as an in vivo activator of both gelatinase A and collagenase-3. TIMP-1 is up-regulated both during the formation and regression of the CL and may therefore regulate MMP activity during both processes.