Interrelationships between follicle stimulating hormone and the growth hormone - insulin-like growth factor - IGF-binding proteins axes in human granulosa cells in culture

Abstract

As it has been hypothesized that IGF-binding proteins (IGFBPs) may have a role as autocrine/paracrine factors in regulating the local actions of the insulin-like growth factors (IGFs) in the ovary, we studied the production of the IGFBPs by human granulosa cells (GC) in culture and the role of IGFBP-3 in the modulation of ovarian cell responsiveness to IGF-I and FSH. To this purpose, human luteinizing GC were cultured in serum-free conditions for 24 h and subsequently submitted to increasing concentrations (2-8 nmol/l) of recombinant non-glycosylated or partially glycosylated IGF-BP-3 for 48 h, in the presence or absence of IGF-I, des(1-3)IGF-I- a truncated analog of human IGF-I with markedly reduced binding ability to IGFBPs - and FSH (5-20 mIU/ml). The results demonstrate that human GC release IGFBP-1-2 and -3 into the medium, and that FSH is able to inhibit this release, while GH is clearly inhibitory on IGFBP-1 and stimulatory on IGFBP-3. Both IGF-I and des(1-3)IGF-I significantly (p < 0.001) stimulate E2 production by human GC in culture in a manner comparable to that of FSH in the dose range used. Preincubation for 2 h at 22 C with IGFBP-3, to allow the formation of the IGF-IGFBP complex, drastically reduced the stimulatory effect of IGF-I but not that of des(1-3)IGF-I. IGFBP-3 was also able to inhibit the stimulatory effect of FSH. These data show that: i) the IGF peptide is less active when bound to IGFBP-3; ii) as IGFBP-3 does not affect the potency of des(1-3)IGF-I, its inhibitory action is exerted upstream of the membrane receptor binding; iii) as the action of IGFBP-3 is exerted by binding the IGF peptide, its inhibitory effect on FSH points out the role of the locally produced IGF-II in potentiating the FSH action on human GC.

Insulin-Like Growth Factor Binding Proteins: New Proteins, New Functions

“…In this cancer cell line, membrane-bound IGFBP-3 inhibited growth induced by IGF-I and not by des-(1-3)-IGF-I [101]. Similar sequestration effects have been demonstrated in human osteoarthritic chondrocytes [102]and human granulosa cells [103]. A comparison of serum levels of IGF-I and IGF-II versus IGFBP-2 through -5 in bovine first-wave dominant follicles showed that the IGF-I/IGFBP ratio decreased with atresia of the follicles [104].…”

The role of insulin‐like growth factor‐I and its binding proteins in glucose homeostasis and type 2 diabetes

“…IGFBP-3, for example, can directly bind to cellular targets involved in the cell-cycle, including the ribonucleic acid polymerase II binding subunit 3 (Rpb3), suggesting a possible role of IGFBP-3 in directly regulating gene transcription [43]. The effects of IGFBP-3 on cell-cycle are largely opposite to those of IGF-I since IGFBP-3 is pro-apoptotic [44–53] and anti-proliferative [52,54–58]. Although the IGFBP family was recently expanded to include nine IGFBP-rPs that can bind IGF-I and IGF-II [3,59], some investigators have challenged their inclusion due to absence of clear phylogenetic relationships between the IGFBP-rPs and the IGFBPs [60], and the limited understanding of IGFBP-rP function.…”

Cellular Actions of Insulin-Like Growth Factor Binding Proteins

“…IGFBPs clearly modulate the interactions between IGFs and Type I IGF receptors on the cell surface ( [102] and human granulosa cells [103]. A comparison of serum levels of IGF-I and IGF-II versus IGFBP-2 through -5 in bovine first-wave dominant follicles showed that the IGF-I/IGFBP ratio decreased with atresia of the follicles [104].…”