Human FSH isoforms: carbohydrate complexity as determinant of in-vitro bioactivity

Creus, Silvina; Chaia, Zulema; Pellizzari, Eliana Herminia; Cigorraga, Selva Beatriz; Ulloa‐Aguirre, Alfredo; Campo, Stella

doi:10.1016/s0303-7207(00)00453-6

Cited by 72 publications

(48 citation statements)

References 45 publications

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“…In a previous study, we showed that not only the degree of sialylation but also the complexity of the FSH carbohydrate influences the biological response in the Sertoli cell in terms of oestradiol production (Creus et al 2001). Dimeric production in GCs was also affected by the oligosaccharide structure of rhFSH; however, it is worth noting that the differential effect induced by oligosaccharide complexity was not identical to that exerted by the degree of hormone sialylation.…”

Section: Discussionmentioning

confidence: 88%

“…Therefore, only a2,3-linked sialic acid residues are added to rhFSH carbohydrate chains and there is no possibility to add bisecting GlcNAc residues to generate oligosaccharide complex structures (Hård et al 1990, Xu et al 2011. Interestingly, the physiologically produced FSH in the human pituitary contains not only a2,3-linked but also a2,6-linked sialic acid residues (Green & Baenziger 1988), and glycoforms bearing complex oligosaccharides are predominant in human pituitary extracts (Creus et al 2001). It is worth noting that the differences in the characteristic of the carbohydrates present in the FSH molecule, currently used to stimulate follicular development and ovulation, may have a relevant impact on GC endocrine function.…”

Section: Discussionmentioning

confidence: 99%

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Effect of sialylation and complexity of FSH oligosaccharides on inhibin production by granulosa cells

Loreti¹,

Ambao²,

Andreone³

et al. 2013

Reproduction

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Granulosa cell (GC) inhibin A and B production is regulated by FSH and gonadal factors. This gonadotrophin is released as a mixture of glycoforms, which induce different biological responses in vivo and in vitro. Our aim was to determine the effect of recombinant human FSH (rhFSH) glycosylation variants on inhibin A and B production by rat GCs. Preparative isoelectro focusing was used to isolate more acidic/sialylated (pH !4.00) and less acidic/sialylated (pH O5.00) rhFSH charge analogues. Concanavalin A was used to isolate unbound and firmly bound rhFSH glycoforms on the basis of their oligosaccharide complexity. GCs, obtained from oestrogen-primed immature rats, were cultured with either native rhFSH or its glycosylation variants. Inhibin A and B were determined using specific ELISAs. Results were expressed as meanGS.E.M. Under basal conditions, inhibin A was the predominant dimer produced (inhibin A: 673G55; inhibin B: 80G4 pg/ml). More acidic/sialylated charge analogues stimulated inhibin B production when compared to inhibin A at all doses studied; by contrast, less acidic/sialylated charge analogues stimulated inhibin A production and elicited no effect on inhibin B. Glycoforms bearing complex oligosaccharides showed a potent stimulatory effect on inhibin B when compared to inhibin A production (i.e. dose 1 ng/ml: 4.9G0.5 vs 0.9G0.1-fold stimulation, P!0.001). Glycoforms bearing hybrid-type oligosaccharides favoured inhibin A production (i.e. dose 4 ng/ml 2.9G0.1 vs 1.6G0.1-fold stimulation, P!0.05). These results show that the sialylation degree as well as the complexity of oligosaccharides present in the rhFSH molecule may be considered additional factors that differentially regulate dimeric inhibin production by rat GCs.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Effect of sialylation and complexity of FSH oligosaccharides on inhibin production by granulosa cells

Loreti¹,

Ambao²,

Andreone³

et al. 2013

Reproduction

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“…Sialic acids in particular are the most common terminal carbohydrate residues in the glycan moiety of glycoproteins, contributing thereby significantly to the charge and activity of proteins. Along these lines, desialylation caused alterations in the structure and function of glycoproteins (35,36), affecting protein-protein interactions (37), integrin-mediated cell adhesion (38), and immune recognition (39). As expected, sialic acids may be involved in both physiological and pathological phenomena (40).…”

Section: -Dementioning

confidence: 88%

Marked Defects in the Expression and Glycosylation of α2-HS Glycoprotein/Fetuin-A in Plasma from Neonates with Intrauterine Growth Restriction

Karamessinis

Malamitsi‐Puchner

Boutsikou

et al. 2008

Molecular & Cellular Proteomics

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Intrauterine growth restriction (IUGR) has been associated with increased perinatal morbidity and mortality and increased morbidity and metabolic abnormalities later in life. IUGR is characterized as the failure of a fetus to achieve his or her genetic growth potential in utero. Altered protein expression profiles associated with IUGR may be informative on the pathologic mechanisms of this condition and might reveal potential markers for postnatal complications. The aim of this study was to compare protein profiles of umbilical cord plasma from IUGR and appropriate for gestational age full-term neonates. Blood samples from doubly clamped umbilical cord at delivery from 10 IUGR and 10 appropriate for gestational age fullterm neonates were analyzed by two-dimensional electrophoresis and MS. Prominent changes of the ␣ 2 -HS glycoprotein/fetuin-A were observed in IUGR cases. Specifically we showed that these changes occur primarily at the level of post-translational modifications of the protein. Using a combination of mass spectrometry and classical biochemical assays, single and heavy chain forms of fetuin-A were found to lack the normally present O-linked sialic acids in IUGR neonates. Fetuin A is a glycoprotein that has been associated with promotion of in vitro cell replication, fetal growth and osteogenesis, and protection from Gram-negative bacterial endotoxins. Prominent defects in glycosylation/sialylation of fetuin-A revealed by our study might be responsible for impaired function of fetuin-A, leading to deficient fetal growth, especially osteogenesis, and/or to the development of complications frequently seen later in the lives of IUGR neonates.

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“…Some of the sugar molecules have been found to be necessary for the GPHs' ability to bind and activate their respective receptors (Matzuk et al 1989, Bishop et al 1994, Grossmann et al 1995, 1997b, Creus et al 2001, Campo et al 2007). In the case of the GPH receptors, glycosylation has been found important for appropriate folding and function of the TSHR and the FSHR (Davies et al 1995, Rapoport et al 1998, Oda et al 1999.…”

Section: Discussionmentioning

confidence: 99%

FSH and TSH binding to their respective receptors: similarities, differences and implication for glycoprotein hormone specificity

Miguel¹,

Sanders²,

Chirgadze³

et al. 2008

Journal of Molecular Endocrinology

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The crystal structures of the leucine-rich repeat domain (LRD) of the FSH receptor (FSHR) in complex with FSH and the TSH receptor (TSHR) LRD in complex with the thyroid-stimulating autoantibody (M22) provide opportunities to assess the molecular basis of the specificity of glycoprotein hormone-receptor binding. A comparative model of the TSH-TSHR complex was built using the two solved crystal structures and verified using studies on receptor affinity and activation. Analysis of the FSH-FSHR and TSH-TSHR complexes allowed identification of receptor residues that may be important in hormone-binding specificity. These residues are in leucine-rich repeats at the two ends of the FSHR and the TSHR LRD structures but not in their central repeats. Interactions in the interfaces are consistent with a higher FSH-binding affinity for the FSHR compared with the binding affinity of TSH for the TSHR. The higher binding affinity of porcine (p)TSH and bovine (b)TSH for human (h)TSHR compared with hTSH appears not to be dependent on interactions with the TSHR LRD as none of the residues that differ among hTSH, pTSH or bTSH interact with the LRD. This suggests that TSHs are likely to interact with other parts of the receptors in addition to the LRD with these non-LRD interactions being responsible for affinity differences. Analysis of interactions in the FSH-FSHR and TSH-TSHR complexes suggests that the a-chains of both hormones tend to be involved in the receptor activation process while the b-chains are more involved in defining binding specificity.

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Human FSH isoforms: carbohydrate complexity as determinant of in-vitro bioactivity

Cited by 72 publications

References 45 publications

Effect of sialylation and complexity of FSH oligosaccharides on inhibin production by granulosa cells

Effect of sialylation and complexity of FSH oligosaccharides on inhibin production by granulosa cells

Marked Defects in the Expression and Glycosylation of α2-HS Glycoprotein/Fetuin-A in Plasma from Neonates with Intrauterine Growth Restriction

FSH and TSH binding to their respective receptors: similarities, differences and implication for glycoprotein hormone specificity

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