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

The corpus luteum (CL) is a transient endocrine organ that secretes progest erone to support pregnancy. The CL is formed from an ovulated follicle in a process that involves extensive angiogenesis and tissue remodeling. If fer tilization does not occur or implantation is unsuccessful, the CL will unde rgo regression, which involves extensive tissue degradation. Extracellular proteases, such as serine proteases and matrix metalloproteinases (MMPs), a re thought to play important roles in both the formation and regression of the CL. In this study, we have examined the physiological regulation patter n 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 ana lyses 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 format ion. 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 procolla genase-3 was constitutively expressed during the formation, function, and r egression of the CL and may therefore be involved in the activation of thes e MMPs. TIMP-1 was induced during both the formation and regression of the CL, suggesting that this inhibitor modulates MMP activity during these proc esses. To test whether the induction of collagenase-3 and TIMP-1 is coupled with luteal regression, we prolonged the luteal phase by performing hyster ectomies, and induced premature luteal regression by treating the pseudopre gnant rats with a PGF(2 alpha) analog, cloprostenol. In both treatments, co llagenase-3 and TIMP-1 were induced only after the serum level of progester one 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 fu nctions during the CL life span: gelatinase A mainly takes part in CL forma tion, whereas collagenase-3 mainly takes part in luteal regression; MT1-MMP is constitutively expressed during the CL life span and may therefore serv e 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 th erefore regulate MMP activity during both processes.