Pharmacokinetics of IGF-1 in PAPP-A2-Deficient Patients, Growth Response, and Effects on Glucose and Bone Density

Cabrera-Salcedo, Catalina; Mizuno, Tomoyuki; Tyzinski, Leah; Andrew, Melissa; Vinks, Alexander A.; Frystyk, Jan; Wasserman, Halley; Gordon, Catherine M.; Hwa, Vivian; Backeljauw, Philippe; Dauber, Andrew

doi:10.1210/jc.2017-01411

Cited by 28 publications

(27 citation statements)

References 32 publications

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“…The differential response to rhIGF-1 treatment, including a lower growth velocity than that of our patients [2], could be explained by the differences in the affectation of the IGF-1 system due to the different genetic mutations. Indeed, our patients have a total lack of PAPP-A2 compared to a mutated form of this protease in the patient reported by Cabrera-Salcedo et al [11]. Although the descriptions of this patient and his brother and sister were published together with the two Spanish subjects, our patients have been under treatment for a longer period due to their earlier diagnosis [1, 12], and it will be of interest to see how the other patient responds to longer treatment.…”

Section: Discussionsupporting

confidence: 52%

“…Longer studies in large series of children with healthy and chronic diseases are necessary to analyze the relationship between TBS and anthropometric clinical variables. Unfortunately, results of TBS cannot be compared with the study by Cabrera-Salcedo et al [11] as this analysis was not performed.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study, Cabrera-Salcedo et al [11] reported a moderate increase in total BMD in a patient with a missense mutation in PAPP-A2 after 1 year of treatment. The differential response to rhIGF-1 treatment, including a lower growth velocity than that of our patients [2], could be explained by the differences in the affectation of the IGF-1 system due to the different genetic mutations.…”

Section: Discussionmentioning

confidence: 99%

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rhIGF-1 Treatment Increases Bone Mineral Density and Trabecular Bone Structure in Children with PAPP-A2 Deficiency

et al. 2018

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Aim: Our objective was to determine changes in bone mineral density (BMD), trabecular bone score (TBS), and body composition after 2 years of therapy with recombinant human insulin-like growth factor-1 (rhIGF-1) in 2 prepubertal children with a complete lack of circulating PAPP-A2 due to a homozygous mutation in PAPP-A2 (p.D643fs25*) resulting in a premature stop codon. Methods: Body composition, BMD, and bone structure were determined by dual-energy X-ray absorptiometry at baseline and after 1 and 2 years of rhIGF-1 treatment. Results: Height increased from 132 to 145.5 cm (patient 1) and from 111.5 to 124.5 cm (patient 2). Bone mineral content increased from 933.40 to 1,057.97 and 1,152.77 g in patient 1, and from 696.12 to 773.26 and 911.51 g in patient 2, after 1 and 2 years, respectively. Whole-body BMD also increased after 2 years of rhIGF-1 from baseline 0.788 to 0.869 g/cm² in patient 1 and from 0.763 to 0.829 g/cm² in patient 2. After 2 years of treatment, both children had an improvement in TBS. During therapy, a slight increase in body fat mass was seen, with a concomitant increase in lean mass. No adverse effects were reported. Conclusion: Two years of rhIGF-1 improved growth, with a tendency to improve bone mass and bone microstructure and to modulate body composition.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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rhIGF-1 Treatment Increases Bone Mineral Density and Trabecular Bone Structure in Children with PAPP-A2 Deficiency

et al. 2018

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“…Pregnancy-associated pregnancy protein-A2 (PAPP-A2) is a protease of insulin-like growth factor binding proteins (IGFBPs) [1] and therefore contributes to the regulation of insulin-like growth factor (IGF) availability [2]. Recently, loss-of-function mutations in the human PAPPA2 gene were found to cause short stature and slightly reduced bone density [3,4], and these conditions were improved by treatment with IGF-I [5][6][7]. IGF-I is known to play important roles in bone physiology [8][9][10] while IGFBP-5 is one of the most abundant IGFBPs in bone [11] and is a target of PAPP-A2 [1].…”

Section: Introductionmentioning

confidence: 99%

Pappa2 deletion has sex- and age-specific effects on bone in mice

Christians

Amiri

Schipilow

et al. 2019

Growth Hormone & IGF Research

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Objective In humans, loss-of-function mutations in the gene encoding pregnancy-associated pregnancy protein-A2 cause short stature and slightly reduced bone density. The goal of this study was to determine the effects of Pappa2 deletion on bone in mice. Design Pappa2 deletion mice and littermate controls were culled at 10, 19 or 30 weeks of age and femurs were analysed by micro-computed tomography. Serum markers of bone turnover and insulin-like growth factor binding protein 5 (IGFBP-5), a proteolytic target of PAPP-A2, were measured by ELISA. Results At 10 and 19 weeks of age, Pappa2 deletion mice had slightly reduced trabecular parameters, but by 19 weeks of age, female deletion mice had increased cortical tissue mineral density, and this trait was increased by a small amount in deletion mice of both sexes at 30 weeks. Cortical area fraction was increased in Pappa2 deletion mice at all ages. Deletion of Pappa2 increased circulating IGFBP-5 levels and reduced markers of bone turnover (PINP and TRACP 5b). Conclusions PAPP-A2 contributes to the regulation of bone structure and mass in mice, likely through control of IGFBP-5 levels. The net effect of changes in bone formation and resorption depend on sex and age, and differ between trabecular and cortical bone.

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“…The younger brother’s height velocity also increased from 5.8 cm/year (-1.6 SD) pre-treatment to 7 cm/year (+1.1 SD) on rhIGF-1 treatment ( 15 ). For the Palestinian family, the two younger patients carrying the PAPPA2 p.A1033V mutation were treated with 120 mg/kg of rhIGF-1 ( 16 ). The youngest sibling’s height increased by 0.4 SD over a period of one year with a doubling of his height velocity from 3 cm/year pre-treatment to 6.2 cm/year on treatment.…”

Section: Introductionmentioning

confidence: 99%

Novel Modulators of the Growth Hormone - Insulin-Like Growth Factor Axis: Pregnancy-Associated Plasma Protein-A2 and Stanniocalcin-2

Fujimoto

Hwa

Dauber

2018

Jcrpe

Self Cite

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Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), play a critical role in human growth. In circulation, IGF-1 is found in a ternary complex with IGF binding proteins (IGFBPs) and acid labile subunit (ALS) but little attention has been paid to the regulation of IGF-1 bioavailability. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) and stanniocalcin-2 (STC2) were identified as novel modulators of IGF-I bioavailability. PAPP-A2 is a protease which cleaves IGFBP-3 and -5, while STC2 inhibits PAPP-A and PAPP-A2 activity. In collaboration with a group in Madrid, we reported the first human cases carrying mutations in the PAPPA2 gene who presented with short stature, elevated total IGF-1, IGFBP-3, IGFBP-5 and ALS, but low free IGF-1. Additionally, the patients demonstrated insulin resistance and below average bone mineral density (BMD). The PAPP-A2 deficient patients were treated with recombinant human IGF-1, resulting in improvements in growth velocity, insulin resistance, and BMD. These findings suggested that the bioactive, free IGF-1 liberated from IGFBPs by PAPP-A2 is important for human growth. Mouse models of PAPP-A2 and STC2 provide further insights into their roles in growth physiology. This review will summarize new insights into PAPP-A2 and STC2 and their role in the GH-IGF axis, thereby highlighting the importance of the regulation of IGF-1 bioavailability in human health and disease.

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Pharmacokinetics of IGF-1 in PAPP-A2-Deficient Patients, Growth Response, and Effects on Glucose and Bone Density

Cited by 28 publications

References 32 publications

rhIGF-1 Treatment Increases Bone Mineral Density and Trabecular Bone Structure in Children with PAPP-A2 Deficiency

rhIGF-1 Treatment Increases Bone Mineral Density and Trabecular Bone Structure in Children with PAPP-A2 Deficiency

Pappa2 deletion has sex- and age-specific effects on bone in mice

Novel Modulators of the Growth Hormone - Insulin-Like Growth Factor Axis: Pregnancy-Associated Plasma Protein-A2 and Stanniocalcin-2

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