Expression of Apolipoprotein J in the Uterus is Associated with Tissue Remodeling1

Abstract

The endometrium is a dynamic tissue that, in response to hormonal cues, undergoes cycles of growth and involution. Extracellular factors required for this remodeling are poorly understood. The potential role in endometrial turnover of apolipoprotein J (apoJ), a secretory glycoprotein that can bind lipids and membrane-active proteins, is proposed on the basis of its spatial and temporal patterns of expression during normal cycling, after ovariectomy, and in response to hormone manipulation. In the mouse, apoJ mRNA was expressed in uterine luminal and glandular epithelial cells coincident with the presence of apoJ protein. The apoJ gene was differentially expressed in the glandular and uterine luminal epithelial cells during the estrous cycle and following hormone depletion. Expression of apoJ was not induced in ovariectomized mice by estrogen, progesterone, or dexamethasone treatment alone. Progesterone administration after an initial estrogen pretreatment, however, resulted in dramatic induction of apoJ as the progesterone level declined. In contrast, apoJ was not induced when a long-lived progesterone analog, medroxyprogesterone, was substituted for progesterone. In the human menstrual cycle, apoJ was present in glandular lumens only during the late secretory phase. Declining progesterone levels, causing substantial tissue reorganization, are characteristic of the times of marked apoJ induction in uterine epithelial cells. These expression patterns are consistent with apoJ functioning as an extracellular cytoprotectant by mediating clearance of and/or neutralizing cytolytic tissue debris.

Changes in lipid metabolism during last month of pregnancy and first two months of lactation in primiparous cows – analysis of apolipoprotein expression pattern and changes in concentration of total cholesterol, HDL, LDL, triglycerides

“…Brown et al (1995) observed an increase in apo J expression in the uterine cells from mice and humans in response to lowering concentration of progesterone. The authors observed an increase in the apo J expression during uterus involution before menstruation in women, and during and just after oestrus in mice.…”

“…Tissue regeneration and changes in hormonal balance might affect apolipoprotein J (clusterin) expression (Brown et al 1995(Brown et al , 1996. Brown et al (1995) observed an increase in apo J expression in the uterine cells from mice and humans in response to lowering concentration of progesterone.…”

Regulation of Clusterin Gene Expression by Transforming Growth Factor β

“…Several TGF␤-inhibitory elements have also been identified in the first intron of the rat clusterin gene and in the upstream regulatory region of the avian clusterin gene (38,40,41). These cis-elements have been implicated in the regulation of clusterin gene expression by various stimuli (37)(38)(39)(40)(41). For example, the T64 gene of quail embryo fibroblasts, corresponding to clusterin in mammals, contains an AP-1-binding site located at position Ϫ25 to Ϫ19 of the single transcriptional start site.…”

“…Clusterin is present in almost all mammalian body fluids and can also be induced or constitutively expressed in almost all cell types (30,31). The protein has been implicated in a variety of biological processes including lipid transport, inhibition of complement attack, sperm maturation, epithelial cell differentiation, and membrane remodeling during apoptosis and implantation (31)(32)(33)(34)(35)(36)(37). Analysis of the 5Ј-regulatory region of the clusterin gene has revealed TGF␤ inhibitory elements as well as AP-1, Sp1, and AP-2 regulatory elements in the quail, rat, and human clusterin genes (38 -41).…”

Estrogenic regulation of clusterin mRNA in normal and malignant endometrial tissue

“…In MCF-7 breast cancer cells it has been shown that estrogen withdrawal in vivo (Kyprianou et al, 1991 andtreatment with vitamin D3 analogs (Simboli-Campbell et al, 1996) induce apoptosis and increase clusterin expression. In the uterus, hormone ablation induces apoptosis of the epithelial tissue compartment and the expression of clusterin in the luminal and glandular epithelial cells (Brown et al, 1995). The expression of clusterin in the mouse uterus, while it requires estrogens, appears to be induced primarily in response to the fall in progesterone levels, which is usually associated with the tissue remodeling that occurs after regression (Brown et al, 1995).…”