Proteolytic degradation of IGF-binding protein (IGFBP)-2 in equine ovarian follicles: involvement of pregnancy-associated plasma protein-A (PAPP-A) and association with dominant but not subordinated follicles.
Abstract: In the ovary of mammalian species, terminal follicular growth is accompanied by a decrease in intrafollicular levels of IGF-binding protein-2 (IGFBP-2) and IGFBP-4. The decrease in IGFBP-4 levels is essentially due to an increase in proteolytic cleavage by intrafollicular pregnancy-associated plasma protein-A (PAPP-A) in growing healthy follicles. The decrease in IGFBP-2 levels is partly due to a decrease in mRNA expression by follicular cells. In addition, we have recently shown that IGFBP-2 is also proteolytically cleaved by PAPP-A in bovine and porcine growing follicles. In the present work, we showed that follicular fluid from late dominant equine follicles (35 mm diameter) contains a proteolytic activity against IGFBP-2. First follicular fluid from dominant follicles contained lower levels of native IGFBP-2 than the corresponding serum, as assessed by Western ligand blotting. In contrast, immunoblotting experiments showed much higher levels of a 12 kDa proteolytic fragment in dominant follicular fluid than in the serum. Moreover, equine dominant follicular fluid was able to induce proteolysis of exogenous recombinant bovine (rb)IGFBP-2, this degradation being dose-dependently enhanced by IGFs. The proteolytic activity against IGFBP-2 in equine follicles was partially immunoneutralized by a polyclonal antibody raised against human PAPP-A. Moreover, cleavage of rbIGFBP-2 by equine follicular fluid was dose-dependently inhibited by a peptide derived from the heparin-binding domain of IGFBP-5, as well as by peptides derived from other heparin-binding domain-containing proteins such as connective tissue growth factor, vitronectin and heparin-interacting protein, previously shown to inhibit PAPP-A. Finally, the proteolytic activity was very low in subordinate follicles, was high in both early (25 mm diameter) and late (35 mm diameter) dominant follicles, and was slightly lower in preovulatory follicles recovered 35 h after human chorionic gonadotropin (hCG) treatment.Overall, these data show that in the equine ovary, the selection of dominant follicles is associated with an increase of the proteolytic degradation of IGFBP-2 by PAPP-A, as for IGFBP-4, and potentially other protease(s), probably contributing to the increase in IGF bioavailability. In atretic subordinate follicles, the decrease in the proteolytic degradation of IGFBP-2, probably due in part to a direct inhibition by peptides containing heparin-binding domains, contributes to the increase in IGFBP-2 levels and the decrease in IGF bioavailability. The expression of PAPP-A and IGFBP-2 mRNA during folliculogenesis remain to be investigated in the mare.
Publication Date: 2004-09-08 PubMed ID: 15350187DOI: 10.1677/joe.0.1820457Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research explores the pattern of proteolytic degradation of IGFBP-2 in equine ovarian follicles, showing association with dominant follicles but not subordinate follicles. The degradation is linked with involvement of pregnancy-associated plasma protein-A (PAPP-A).
Introduction
- In the ovary of mammals, growth of terminal follicles (a stage of the maturation of eggs) is associated with lower levels of IGF-binding proteins (IGFBP-2 and IGFBP-4). This is due in part to increased cleavage by a substance called pregnancy-associated plasma protein-A (PAPP-A) in healthy follicles. The IGFBP-2 level reduction is also due to lesser mRNA expression in follicular cells.
- The researchers had previously demonstrated that IGFBP-2 is also cleaved by PAPP-A in growing follicles in bovines and porcines.
Methodology
- The current study aimed to demonstrate a therapy called proteolytic activity against IGFBP-2 present in late dominant equine follicles (35 mm diameter).
- The researchers found that dominant follicles had less native IGFBP-2 than their corresponding serum. On the other hand, they found higher levels of a 12kDa proteolytic fragment in dominant follicular fluid than in the serum.
- They also discovered the equine dominant follicular fluid induced proteolysis of exogenous recombinant bovine IGFBP-2, which was enhanced by IGFs in a dose-dependent manner.
Findings
- They observed that the proteolytic activity in equine follicles could be partially immunoneutralized by a polyclonal antibody raised against human PAPP-A.
- Cleavage of IGFBP-2 by equine follicular fluid was hindered in a dose-dependent manner by a peptide from the heparin-binding domain of IGFBP-5. This inhibitive effect was also seen by peptides derived from other proteins containing heparin-binding domains such as connective tissue growth factor, vitronectin, and heparin-interacting protein. These had been earlier established to inhibit PAPP-A.
- In subordinate follicles, proteolytic activity was very low, whereas in both early and late dominant follicles, it was high. It was slightly lower in preovulatory follicles retrieved 35 hours post treatment with human chorionic gonadotropin.
Conclusion
- This research concluded that the selection of dominant follicles in the equine ovary encourages the proteolytic degradation of IGFBP-2 via PAPP-A, as is the case for IGFBP-4, and possibly via other proteases too. This is thought to contribute to the rise of IGF bioavailability.
- In contrast, in atretic subordinate follicles, the decrease in proteolytic degradation of IGFBP-2, probably due to a direct inhibition by peptides containing heparin-binding domains, contributes to the rise in IGFBP-2 levels and the decrease in IGF bioavailability.
- The expression of PAPP-A and IGFBP-2 mRNA during follicle maturation is yet to be explored in mares.
Cite This Article
APA
Gérard N, Delpuech T, Oxvig C, Overgaard MT, Monget P.
(2004).
Proteolytic degradation of IGF-binding protein (IGFBP)-2 in equine ovarian follicles: involvement of pregnancy-associated plasma protein-A (PAPP-A) and association with dominant but not subordinated follicles.
J Endocrinol, 182(3), 457-466.
https://doi.org/10.1677/joe.0.1820457 Publication
Researcher Affiliations
- INRA, UMR Physiologie de la Reproduction et des Comportements 6073, (INRA/CNRS/Université) 37380 Nouzilly, France.
MeSH Terms
- Animals
- Blotting, Western / methods
- Female
- Follicular Fluid / chemistry
- Follicular Phase
- Horses
- Immunoblotting / methods
- Insulin-Like Growth Factor Binding Protein 2 / genetics
- Insulin-Like Growth Factor Binding Protein 2 / metabolism
- Insulin-Like Growth Factor Binding Protein 4 / genetics
- Insulin-Like Growth Factor Binding Protein 4 / metabolism
- Ovarian Follicle / metabolism
- Peptide Fragments / analysis
- Pregnancy-Associated Plasma Protein-A / metabolism
- RNA, Messenger / analysis
Citations
This article has been cited 12 times.- Zhong Q, Chu H, Wang G, Zhang C, Li R, Guo F, Meng X, Lei X, Zhou Y, Ren R, Tao L, Li N, Gao N, Wei Y, Qiao J, Hang J. Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2. Cell Discov 2022 Dec 22;8(1):137.
- Yao Z, Lin M, Lin T, Gong X, Qin P, Li H, Kang T, Ye J, Zhu Y, Hong Q, Liu Y, Li Y, Wang J, Fang F. The expression of IGFBP-5 in the reproductive axis and effect on the onset of puberty in female rats. Reprod Biol Endocrinol 2022 Jul 12;20(1):100.
- Rojas-Rodriguez R, Ziegler R, DeSouza T, Majid S, Madore AS, Amir N, Pace VA, Nachreiner D, Alfego D, Mathew J, Leung K, Moore Simas TA, Corvera S. PAPPA-mediated adipose tissue remodeling mitigates insulin resistance and protects against gestational diabetes in mice and humans. Sci Transl Med 2020 Nov 25;12(571).
- Mazerbourg S, Monget P. Insulin-Like Growth Factor Binding Proteins and IGFBP Proteases: A Dynamic System Regulating the Ovarian Folliculogenesis. Front Endocrinol (Lausanne) 2018;9:134.
- Yu KJ, Li JK, Lee YC, Yu G, Lin SC, Pan T, Satcher RL, Titus MA, Yu-Lee LY, Weng WH, Gallick GE, Lin SH. Cabozantinib-induced osteoblast secretome promotes survival and migration of metastatic prostate cancer cells in bone. Oncotarget 2017 Sep 26;8(43):74987-75006.
- Yau SW, Azar WJ, Sabin MA, Werther GA, Russo VC. IGFBP-2 - taking the lead in growth, metabolism and cancer. J Cell Commun Signal 2015 Jun;9(2):125-42.
- Jepsen MR, Kløverpris S, Mikkelsen JH, Pedersen JH, Füchtbauer EM, Laursen LS, Oxvig C. Stanniocalcin-2 inhibits mammalian growth by proteolytic inhibition of the insulin-like growth factor axis. J Biol Chem 2015 Feb 6;290(6):3430-9.
- Salazar-Ortiz J, Monget P, Guillaume D. The influence of nutrition on the insulin-like growth factor system and the concentrations of growth hormone, glucose, insulin, gonadotropins and progesterone in ovarian follicular fluid and plasma from adult female horses (Equus caballus). Reprod Biol Endocrinol 2014 Jul 31;12:72.
- Braga DP, Bonetti TC, da Silva ID, Setti AS, Iaconelli AJ, Borges EJ. The developmental competence of oocytes retrieved from the leading follicle in controlled ovarian stimulated cycles. Int J Fertil Steril 2013 Jan;6(4):272-7.
- Pan H, Hanada S, Zhao J, Mao L, Ma MZ. Protein secretion is required for pregnancy-associated plasma protein-A to promote lung cancer growth in vivo. PLoS One 2012;7(11):e48799.
- Skinner MK, Schmidt M, Savenkova MI, Sadler-Riggleman I, Nilsson EE. Regulation of granulosa and theca cell transcriptomes during ovarian antral follicle development. Mol Reprod Dev 2008 Sep;75(9):1457-72.
- Han B, Tian D, Li X, Liu S, Tian F, Liu D, Wang S, Zhao K. Multiomics Analyses Provide New Insight into Genetic Variation of Reproductive Adaptability in Tibetan Sheep. Mol Biol Evol 2024 Mar 1;41(3).
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