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Endometrial TIMP-4 mRNA is high at midcycle and in hyperplasia, but down-regulated in malignant tumours. Coordinated

R Pilka1, H Domanski, S Hansson

  • 1Department of Obstetrics & Gynaecology, University Hospital, S-221 85 Lund, Sweden.

Molecular Human Reproduction
|July 27, 2004
PubMed

Insights

Tissue inhibitor of metalloproteinase (TIMP)-4 mRNA expression in the endometrium follows a cyclic pattern, peaking in the early secretory phase. Its expression is linked to estrogen receptor alpha (ERalpha) and may play a role in human implantation.

Area of Science:

  • Reproductive biology
  • Molecular endocrinology
  • Gynecologic oncology

Background:

  • Endometrial matrix metalloproteinase (MMP)-26 mRNA expression peaks in the early secretory phase.
  • Tissue inhibitor of metalloproteinase (TIMP)-4 is a known potent inhibitor of MMP-26.

Purpose of the Study:

  • To investigate the cyclic expression pattern of TIMP-4 mRNA in normal endometrium.
  • To evaluate TIMP-4 mRNA expression in hyperplastic, atypical hyperplastic, and malignant endometrial tissues.
  • To explore the relationship between TIMP-4 mRNA and estrogen receptor alpha (ERalpha) expression.

Main Methods:

  • In situ hybridization for TIMP-4 mRNA localization in tissue sections.
  • Real-time PCR for quantitative analysis of TIMP-4 mRNA in tissue extracts.
  • Immunohistochemistry for ERalpha assay in endometrial samples.

Main Results:

  • TIMP-4 mRNA was localized in the stroma of normal and pathological endometrial tissues.
  • TIMP-4 mRNA expression increased during the proliferative phase, peaked in the early secretory phase, and decreased later in the cycle.
  • TIMP-4 mRNA levels were similar in normal, hyperplastic, and atypical hyperplastic tissues but lower in malignant tumors.
  • ERalpha expression was strong in proliferative phase, hyperplasia, and atypical hyperplasia, but weak in secretory phase and malignant tumors.
  • A putative estrogen response element (ERE) was identified in the TIMP-4 gene promoter region.

Conclusions:

  • TIMP-4 mRNA exhibits a cyclic pattern in the endometrium, suggesting estrogen dependence.
  • ERalpha likely contributes to the regulation of TIMP-4 gene expression.
  • The coordinated cyclic expression of TIMP-4 and MMP-26 suggests a functional relationship potentially involved in human implantation.

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