Complex mediation of uterine endometrial epithelial cell growth by insulin-like growth factor-II (IGF-II) and IGF-binding protein-2

Abstract

The coexpression of IGF (-I and -II) peptides, corresponding receptors, and IGF binding proteins (IGFBPs) in uterine endometrium suggests that a significant component of IGF action in this tissue is via autocrine or paracrine pathways, or both. The present study examined whether IGF-II and a major uterine-expressed IGF-II binding protein, IGFBP-2, modulate endometrial epithelial cell mitogenesis. Serum-deprived porcine endometrial glandular epithelial (GE) cells of early pregnancy were treated with various concentrations of IGFs, recombinant porcine (rp) IGFBP-2, or both, and examined for changes in cellular mitogenesis by incorporation of [ ]-IGF-II or rhIGF-II stimulated thymidine incorporation to a greater extent than did rhIGF-I alone. Ligand blot analysis of GE cell conditioned medium revealed the presence of four IGFBPs with molecular masses of 48, 31, 23, and 15 kDa. Physiological concentrations of rpIGFBP-2 (nM range) increased both basal and IGF-induced DNA synthesis in GE cells. At equimolar concentrations, Des(1-6)IGF-II (an IGF-II analog with much reduced affinity for IGFBPs) and rpIGFBP-2 had additive effects on GE cell mitogenesis, suggesting that the IGFBP-2 modulation of uterine cell growth may involve both IGF-dependent and IGF-independent pathways. Our results demonstrate the complex interplay of IGF system components in uterine endometrial epithelial growth regulation in vitro, identify IGF-II and IGFBP-2 as locally coexpressed uterine epithelial cell mitogens, and suggest the presence of a functional signaling pathway by which IGF-II stimulates epithelial cell proliferation via the type II receptor.

Insulin-like Growth Factor–Binding Protein Contributes to the Proliferation of Less Proliferative Cells in Forming Skin Equivalents

“…Further, it was proposed that the mitogenic effect of IGFBP-2 may be IGF independent. 18,19 More recently, IGF-independent actions of IGFBP-2 have been recognized. For example, IGFBP-2 stimulated the proliferation of human epithelial ovarian cancer cells and activated the extracellular signal regulated kinase (ERK1=2) signaling pathway.…”

Insulin-Like Growth Factor-I Stimulated DNA Replication in Mouse Endometrial Stromal Cells

“…In addition to the IGFBP transport functions, IGFBPs are involved in cell cycle, apoptosis, cell adhesion and motility in various tissues [32,33]. IGFBP expression in the uterus is highly associated with IGF-I activity [34][35][36]. In the human endometrium, the expression of mRNAs for the six IGFBPs are detected during the menstrual cycle.…”

Up date on IGFBP-4: regulation of IGFBP-4 levels and functions, in vitro and in vivo

“…Indeed, in several cell culture models, addition of IGFBPs to cell culture medium is able to inhibit IGF-I and IGF-II action, but not or only partially the action of analogs of IGF-I (LongR3-IGF-I, Des1-3-IGF-I, [QAYL]-IGF-I) that bind weakly to IGFBPs [2][3][4][5][6]. However, it has been shown that IGFBP-2, -3 and -5 can also potentiate IGF actions possibly by their ability to bind to the extracellular matrix, which induces a reduction of their affinity for IGFs [7,8]. Potentiating effects on IGF action can also be the consequence of the proteolytic degradation of IGFBPs that results in a strong reduction in their affinity for their ligands [9][10][11].…”