Insulin-like Growth Factor Bioavailability Research Articles

Implication of Pappalysins and Stanniocalcins in the Bioavailability of IGF-I in Children With Type 1 Diabetes Mellitus.

Anomalies in the growth hormone (GH)/insulin-like growth factor (IGF) axis, are common in children with type 1 diabetes mellitus (T1DM), even in those reaching a normal or near-normal final height. However, concentrations of the IGF bioavailability regulatory factors (pappalysins [PAPP-As] and stanniocalcins [STCs]) have not been reported in children with T1DM. To determine serum concentrations of PAPP-As and STCs in children at diagnosis of T1DM and after insulin treatment and the correlation of these factors with other members of the GH/IGF axis, beta-cell insulin reserve, auxology, and nutritional status. A single-center prospective observational study including 47 patients (59.5% male), with T1DM onset at median age of 9.2 years (interquartile range: 6.3, 11.9) was performed. Blood and anthropometric data were collected at diagnosis and after 6 and 12 months of treatment. At 6 and 12 months after T1DM diagnosis, there was improvement in the metabolic control (decrease in glycated hemoglobin [HbA1c] at 12 months -3.66 [95% CI: -4.81, -2.05], P = .001), as well as in body mass index SD and height SD (not statistically significant). STC2 increased (P < .001) and PAPP-A2 decreased (P < .001) at 6 and 12 months of treatment onset (P < .001), which was concurrent with increased total IGF-I and IGF-binding protein concentrations, with no significant modification in free IGF-I concentrations. HbA1c correlated with PAPP-A2 (r = +0.41; P < .05) and STC2 (r = -0.32; P < .05). Implementation of insulin treatment after T1DM onset modifies various components of the circulating IGF system, including PAPP-A2 and STC2. How these modifications modulate linear growth remains unknown.

Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments

BackgroundChildren with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations resulting in low levels of bioactive insulin-like growth factor-1 (IGF1) and progressive postnatal growth retardation have improved growth velocity and height following recombinant human (rh)IGF1 treatment. The present study aimed to evaluate whether Pappa2 deficiency and pharmacological manipulation of GH/IGF1 system are associated with sex-specific differences in growth-related signaling pathways.MethodsPlasma, hypothalamus, pituitary gland and liver of Pappa2ko/ko mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed.ResultsReduced body and femur length of Pappa2ko/ko mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5/Igfbp5, Igfbp3, Igfals) in plasma, hypothalamus and/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3β, ERK1/2 and AMPKα) in hypothalamus, pituitary gland and/or liver, with Pappa2ko/ko females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in Pappa2ko/ko females; and (2) increased Igf1 and Igf1r levels and decreased Ghr, Igfbp3 and Igfals levels in the liver of Pappa2ko/ko females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of Pappa2ko/ko females.ConclusionsSex-specific differences in IGF1 system and signaling pathways are associated with Pappa2 deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.

Increased IGFBP proteolysis, IGF-I bioavailability and pappalysin levels in children with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. We determined serum levels of PAPP-As and STCs in association with IGF axis components in pre- and pubertal patients with PWS, also analyzing the effect of GH treatment. Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at six months of treatment in 11 children. Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and higher concentrations of free IGF-I, IGFBP-5 and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients.

Runx1 regulates critical factors that control uterine angiogenesis and trophoblast differentiation during placental development.

During early pregnancy in humans and rodents, uterine stromal cells undergo a remarkable differentiation to form the decidua, a transient maternal tissue that supports the growing fetus. It is important to understand the key decidual pathways that orchestrate the proper development of the placenta, a key structure at the maternal-fetal interface. We discovered that ablation of expression of the transcription factor Runx1 in decidual stromal cells in a conditional Runx1-null mouse model (Runx1d/d) causes fetal lethality during placentation. Further phenotypic analysis revealed that uteri of pregnant Runx1d/d mice exhibited severely compromised decidual angiogenesis and a lack of trophoblast differentiation and migration, resulting in impaired spiral artery remodeling. Gene expression profiling using uteri from Runx1d/d and control mice revealed that Runx1 directly controls the decidual expression of the gap junction protein connexin 43 (also known as GJA1), which was previously shown to be essential for decidual angiogenesis. Our study also revealed that Runx1 controls the expression of insulin-like growth factor (IGF) 2 and IGF-binding protein 4 (IGFBP4) during early pregnancy. While Runx1 deficiency drastically reduced the production of IGF2 by the decidual cells, we observed concurrent elevated expression of the IGFBP4, which regulates the bioavailability of IGFs, thereby controlling trophoblast differentiation. We posit that dysregulated expression of GJA1, IGF2, and IGFBP4 in Runx1d/d decidua contributes to the observed defects in uterine angiogenesis, trophoblast differentiation, and vascular remodeling. This study therefore provides unique insights into key maternal pathways that control the early phases of maternal-fetal interactions within a critical window during placental development.

Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function: Clinical Significance in the Ageing Brain and in Age-Related Neurological Conditions.

Insulin-like growth factor-1 (IGF-1) function declines with age and is associated with brain ageing and the progression of age-related neurological conditions. The reversible binding of IGF-1 to IGF binding protein (IGFBP)-3 regulates the amount of bioavailable, functional IGF-1 in circulation. Cyclic glycine-proline (cGP), a metabolite from the binding site of IGF-1, retains its affinity for IGFBP-3 and competes against IGF-1 for IGFBP-3 binding. Thus, cGP and IGFBP-3 collectively regulate the bioavailability of IGF-1. The molar ratio of cGP/IGF-1 represents the amount of bioavailable and functional IGF-1 in circulation. The cGP/IGF-1 molar ratio is low in patients with age-related conditions, including hypertension, stroke, and neurological disorders with cognitive impairment. Stroke patients with a higher cGP/IGF-1 molar ratio have more favourable clinical outcomes. The elderly with more cGP have better memory retention. An increase in the cGP/IGF-1 molar ratio with age is associated with normal cognition, whereas a decrease in this ratio with age is associated with dementia in Parkinson disease. In addition, cGP administration reduces systolic blood pressure, improves memory, and aids in stroke recovery. These clinical and experimental observations demonstrate the role of cGP in regulating IGF-1 function and its potential clinical applications in age-related brain diseases as a plasma biomarker for-and an intervention to improve-IGF-1 function.

Molecular phenotypes of bovine blastocyst derived from in vitro-matured oocyte supplemented with PAPP-A.

Insulin-like growth factor-1 (IGF-1) regulates cellular lipid content, whereas pregnancy-associated plasma protein-A (PAPP-A) increases IGF-1 bioavailability. Using in vitro-matured cumulus-oocyte complexes, we aimed to evaluate the impact of PAPP-A on the blastocyst lipid content, embryo cryotolerance and embryonic transcriptional profile. We determined that PAPP-A did not affect the lipid content of oocytes, blastocysts, or blastocyst yield (P > 0.05). However, PAPP-A modulated the embryo transcriptional profiles by downregulating PPARGC1A and AKR1B1, which are related to lipid metabolism; CASP9, a pro-apoptotic gene; and IFN-τ, a marker of embryo quality (P < 0.05). Furthermore, the use of PAPP-A improved blastocyst re-expansion in the first 3h of culture after vitrification (P < 0.05). Although PAPP-A did not affect the blastocyst lipid content or embryo production, we suggest that embryonic transcriptional modulation could contribute to maintain the balance in embryo lipid metabolism. Furthermore, PAPP-A's approach seems to control key intracellular pathways that improve post-cryopreservation development of blastocysts.

Cyclo-glycylproline attenuates hydrogen peroxide-induced cellular damage mediated by the MDM2-p53 pathway in human neural stem cells.

Cyclo-glycylproline (cGP), a cyclic dipeptide containing a condensation bond between glycine and proline, is produced by the cyclization of the N-terminal tripeptide of insulin-like growth factor-1. Previous studies have shown that cGP administration exerts a neuroprotective effect and enhances the regenerative ability in rats with ischemic brain injury. The efficacy of cGP is medicated by regulating the bioavailability of insulin-like growth factor-1 (IGF-1), however, the molecular mechanisms underlying the neuroprotective effects of cGP on brain damage remains to be elucidated. In the current study, we investigated the cGP-mediated molecular mechanism in human fetal neural stem cells (hfNSCs) exposed to oxidative stress, which is a key factor affecting the development of several brain diseases, including traumatic brain injury and Parkinson's disease. We found that cGP treatment attenuated oxidative stress-induced cell death in cultured hfNSCs in a dose-dependent manner. Transcriptome analysis revealed that under oxidative stress conditions, p53-mediated signaling was activated, accompanied by upregulation of mouse double minute 2 homolog (MDM2), a p53-specific E3 ubiquitin ligase, in cGP-treated hfNSCs. By using a comprehensive protein phosphorylation array, we found that cGP induced the activation of Akt signaling pathway, which enhanced the expression of MDM2, in hfNSCs exposed to oxidative stress. Moreover, the MDM2 inhibitor nutlin-3 inhibited the protective effect of cGP on oxidative stress-induced cell death and apoptosis. Therefore, cGP attenuates oxidative stress-induced cell death mediated by the interplay between IGF-1 signaling and the MDM2-p53 pathway in human NSCs. We revealed the molecular mechanism underlying cGP-induced neuroprotective properties in a model of brain damage.

Association between gestational diabetes mellitus and bioavailability of insulin-like growth factors and role of their binding proteins

ObjectiveInsulin-like growth factors (IGFs) are involved in regulating growth and metabolism and increase insulin sensitivity, improve glucose metabolism, and are potentially related to gestational diabetes mellitus (GDM) and its complications for mothers and fetuses. DesignThis study aimed to assess serum levels and cord blood levels of IGF system components in pregnant women with (39 participants) and without GDM (22 participants). Blood samples were obtained at 28–32 and 36–38 weeks of gestation and 6–12 months after delivery. Cord blood samples were obtained during delivery. Results between both groups as well as between single visits were statistically compared. ResultsBoth IGF1 and IGF2 maternal serum levels did not differ between the GDM and non-GDM groups. However, levels of IGF-binding proteins (IGFBPs) were different. IGFBP4 levels were decreased during pregnancy and after delivery in women with GDM, while IGFBP7 levels were increased during pregnancy in women with GDM. Cord blood IGFBP3 and IGFBP7 levels were increased (p < 0.001 for IGFBP3, p = 0.003 for IGFBP7), while IGFBP4 levels were decreased (p < 0.001) in the GDM group compared with the non-GDM group. ConclusionsAlthough IGF levels did not differ, changes in their function level could still persist possibly because of the effects of the binding proteins, especially their promoting or inhibitory effects on IGFs. These results should be considered in interpretation of IGF levels.

Structure of the PAPP-ABP5 complex reveals mechanism of substrate recognition

Insulin-like growth factor (IGF) signaling is highly conserved and tightly regulated by proteases including Pregnancy-Associated Plasma Protein A (PAPP-A). PAPP-A and its paralog PAPP-A2 are metalloproteases that mediate IGF bioavailability through cleavage of IGF binding proteins (IGFBPs). Here, we present single-particle cryo-EM structures of the catalytically inactive mutant PAPP-A (E483A) in complex with a peptide from its substrate IGFBP5 (PAPP-ABP5) and also in its substrate-free form, by leveraging the power of AlphaFold to generate a high quality predicted model as a starting template. We show that PAPP-A is a flexible trans-dimer that binds IGFBP5 via a 25-amino acid anchor peptide which extends into the metalloprotease active site. This unique IGFBP5 anchor peptide that mediates the specific PAPP-A-IGFBP5 interaction is not found in other PAPP-A substrates. Additionally, we illustrate the critical role of the PAPP-A central domain as it mediates both IGFBP5 recognition and trans-dimerization. We further demonstrate that PAPP-A trans-dimer formation and distal inter-domain interactions are both required for efficient proteolysis of IGFBP4, but dispensable for IGFBP5 cleavage. Together the structural and biochemical studies reveal the mechanism of PAPP-A substrate binding and selectivity.

Structural basis for assembly and disassembly of the IGF/IGFBP/ALS ternary complex

Insulin-like growth factors (IGFs) have pleiotropic roles in embryonic and postnatal growth and differentiation. Most serum IGFs are bound in a ternary complex with IGF-binding protein 3 (IGFBP3) and acid-labile subunit (ALS), extending the serum half-life of IGFs and regulating their availability. Here, we report cryo-EM structure of the human IGF1/IGFBP3/ALS ternary complex, revealing the detailed architecture of a parachute-like ternary complex and crucial determinants for their sequential and specific assembly. In vitro biochemical studies show that proteolysis at the central linker domain of IGFBP3 induces release of its C-terminal domain rather than IGF1 release from the ternary complex, yielding an intermediate complex that enhances IGF1 bioavailability. Our results provide mechanistic insight into IGF/IGFBP3/ALS ternary complex assembly and its disassembly upon proteolysis for IGF bioavailability, suggesting a structural basis for human diseases associated with IGF1 and IGFALS gene mutations such as complete ALS deficiency (ACLSD) and IGF1 deficiency.

Increased Colocalization and Interaction Between Decidual Protein Kinase A and Insulin-like Growth Factor-Binding Protein-1 in Intrauterine Growth Restriction.

Increased phosphorylation of decidual insulin-like growth factor-binding protein-1 (IGFBP-1) can contribute to intrauterine growth restriction (IUGR) by decreasing the bioavailability of insulin-like growth factor-1 (IGF-1). However, the molecular mechanisms regulating IGFBP-1 phosphorylation at the maternal-fetal interface are poorly understood. Protein kinase A (PKA) is required for normal decidualization. Consensus sequences for PKA are present in IGFBP-1. We hypothesized that the expression/interaction of PKA with decidual IGFBP-1 is increased in IUGR. Parallel reaction monitoring-mass spectrometry (PRM-MS) identified multiple PKA peptides (n=>30) co-immunoprecipitating with IGFBP-1 in decidualized primary human endometrial stromal cells (HESC). PRM-MS also detected active PKApThr197 and greater site-specific IGFBP-1 phosphorylation(pSer119), (pSer98+pSer101) (pSer169+pSer174) in response to hypoxia. Hypoxia promoted colocalization [dual immunofluorescence (IF)] of PKA with IGFBP-1 in decidualized HESC. Colocalization (IF) and interaction (proximity ligation assay) of PKA and IGFBP-1 were increased in decidua collected from placenta of human IUGR pregnancies (n=8) compared with decidua from pregnancies with normal fetal growth. Similar changes were detected in decidual PKA/IGFBP-1 using placenta from baboons subjected to maternal nutrient reduction (MNR) vs controls (n=3 each). In baboons, these effects were evident in MNR at gestational day 120 prior to IUGR onset. Increased PKA-mediated phosphorylation of decidual IGFBP-1 may contribute to decreased IGF-1 bioavailability in the maternal-fetal interface in IUGR.

IGF-dependent dynamic modulation of a protease cleavage site in the intrinsically disordered linker domain of human IGFBP2.

Functional regulation via conformational dynamics is well known in structured proteins but less well characterized in intrinsically disordered proteins and their complexes. Using NMR spectroscopy, we have identified a dynamic regulatory mechanism in the human insulin-like growth factor (IGF) system involving the central, intrinsically disordered linker domain of human IGF-binding protein-2 (hIGFBP2). The bioavailability of IGFs is regulated by the proteolysis of IGF-binding proteins. In the case of hIGFBP2, the linker domain (L-hIGFBP2) retains its intrinsic disorder upon binding IGF-1, but its dynamics are significantly altered, both in the IGF binding region and distantly located protease cleavage sites. The increase in flexibility of the linker domain upon IGF-1 binding may explain the IGF-dependent modulation of proteolysis of IGFBP2 in this domain. As IGF homeostasis is important for cell growth and function, and its dysregulation is a key contributor to several cancers, our findings open up new avenues for the design of IGFBP analogs inhibiting IGF-dependent tumors.

Insulin-like growth factor role in determining the anti-cancer effect of metformin: RCT in prostate cancer patients.

ObjectiveAndrogen deprivation therapy (ADT), a principal therapy in patients with prostate cancer, is associated with the development of obesity, insulin resistance, and hyperinsulinemia. Recent evidence indicates that metformin may slow cancer progression and improves survival in prostate cancer patients, but the mechanism is not well understood. Circulating insulin-like growth factors (IGFs) are bound to high-affinity binding proteins, which not only modulate the bioavailability and signalling of IGFs but also have independent actions on cell growth and survival. The aim of this study was to investigate whether metformin modulates IGFs, IGF-binding proteins (IGFBPs), and the pregnancy-associated plasma protein A (PAPP-A) – stanniocalcin 2 (STC2) axis.Design and methodsIn a blinded, randomised, cross-over design, 15 patients with prostate cancer on stable ADT received metformin and placebo treatment for 6 weeks each. Glucose metabolism along with circulating IGFs and IGFBPs was assessed.ResultsMetformin significantly reduced the homeostasis model assessment as an index of insulin resistance (HOMA IR) and hepatic insulin resistance. Metformin also reduced circulating IGF-2 (P < 0.05) and IGFBP-3 (P < 0.01) but increased IGF bioactivity (P < 0.05). At baseline, IGF-2 correlated significantly with the hepatic insulin resistance (r2= 0.28, P < 0.05). PAPP-A remained unchanged but STC2 declined significantly (P < 0.05) following metformin administration. During metformin treatment, change in HOMA IR correlated with the change in STC2 (r2= 0.35, P < 0.05).ConclusionMetformin administration alters many components of the circulating IGF system, either directly or indirectly via improved insulin sensitivity. Reduction in IGF-2 and STC2 may provide a novel mechanism for a potential metformin-induced antineoplastic effect.

A Mixture of Valine and Isoleucine Restores the Growth of Protein-Restricted Pigs Likely through Improved Gut Development, Hepatic IGF-1 Pathway, and Plasma Metabolomic Profile.

Valine (Val) alone or in combination with isoleucine (Ile) improves the growth under severe protein restriction; however, the underlying mechanisms remain unknown. In this study, we assessed whether Val/Ile-induced growth in protein-restricted pigs is associated with changes in gut development, hepatic insulin-like growth factor 1 (IGF-1) production, and blood metabolomics. Forty piglets were assigned to five dietary groups: positive control (PC) with standard protein content; low protein (LP) with very low protein content; and LP supplemented with Val (LPV), Ile (LPI), and Val and Ile (LPVI). LPVI reversed the negative effects of VLP diets on growth and gut morphology. Both LPV and LPVI restored the reduced transcript of IGF-1 while decreasing the transcript of insulin-like growth factor binding protein 1 (IGFBP1) in the liver. LPV and LPVI recovered the reduced plasma Val, glycine, and leucine concentrations, which were positively correlated with improved gut morphology and the hepatic IGF-1 gene expression and negatively correlated with hepatic IGFBP1 mRNA abundance. In conclusion, supplementation with a combination of Val and Ile into the VLP diets restored the decreased growth performance of pigs fed with these diets likely through improved gut development, hepatic IGF-1 expression and bioavailability, and plasma metabolomics profile.

Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia

ABSTRACT Cerebral ischemia is a pathology involving a cascade of cellular mechanisms, leading to the deregulation of proteostasis, including macroautophagy/autophagy, and finally to neuronal death. If it is now accepted that cerebral ischemia induces autophagy, the effect of thrombolysis/energy recovery on proteostasis remains unknown. Here, we investigated the effect of thrombolysis by PLAT/tPA (plasminogen activator, tissue) on autophagy and neuronal death. In two in vitro models of hypoxia reperfusion and an in vivo model of thromboembolic stroke with thrombolysis by PLAT/tPA, we found that ischemia enhances neuronal deleterious autophagy. Interestingly, PLAT/tPA decreases autophagy to mediate neuroprotection by modulating the PI3K-AKT-MTOR pathways both in vitro and in vivo. We identified IGF1R (insulin-like growth factor I receptor; a tyrosine kinase receptor) as the effective receptor and showed in vitro, in vivo and in human stroke patients and that PLAT/tPA is able to degrade IGFBP3 (insulin-like growth factor binding protein 3) to increase IGF1 (insulin-like growth factor 1) bioavailability and thus IGF1R activation. Abbreviations: AKT/protein kinase B: thymoma viral proto-oncogene 1; EGFR: epidermal growth factor receptor; Hx: hypoxia; IGF1: insulin-like growth factor 1; IGF1R: insulin-like growth factor I receptor; IGFBP3: insulin-like growth factor binding protein 3; Ka: Kainate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OGD: oxygen and glucose deprivation; OGDreox: oxygen and glucose deprivation + reoxygentation; PepA: pepstatin A1; PI3K: phosphoinositide 3-kinase; PLAT/tPA: plasminogen activator, tissue; PPP: picropodophyllin; SCH77: SCH772984; ULK1: unc-51 like kinase 1; Wort: wortmannin

Insulin-Like Growth Factor-1 (IGF-1) and Its Monitoring in Medical Diagnostic and in Sports

Insulin-like growth factor-1 (IGF-1) is the principal mediator of growth hormone (GH), plays a crucial role in promoting cell growth and differentiation in childhood and continues to have an anabolic effect in adults. IGF-1 is part of a wide network of growth factors, receptors and binding proteins involved in mediating cellular proliferation, differentiation and apoptosis. Bioavailability of IGF-1 is affected by insulin-like growth factor binding proteins (IGFBPs) which bind IGF-1 in circulation with an affinity equal to or greater than that of the IGF-1 receptor (IGF-1R). The six IGFBPs serve as carrier proteins and bind approximately 98% of all circulating IGF-1. Other proteins known to bind IGF-1 include ten IGFBP-related proteins (IGFBP-rPs), albeit with lower affinities than the IGFBPs. IGF-1 expression levels vary in a number of clinical conditions suggesting it has the potential to provide crucial information as to the state of an individual’s health. IGF-1 is also a popular doping agent in sport and has featured in many high-profile doping cases in recent years. However, the existence of IGFBPs significantly reduces the levels of immunoreactive IGF-1 in samples, requiring multiple pre-treatment steps that reduce reproducibility and complicates interpretation of IGF-1 assay results. Here we provide an overview of the IGF network of growth factors, their receptors and the entirety of the extended family of IGFBPs, IGFBP-rPs, E peptides as well as recombinant IGF-1 and their derivatives. We also discuss issues related to the detection and quantification of bioavailable IGF-1.

Genome-wide association study across pediatric central nervous system tumors implicates shared predisposition and points to 1q25.2 (PAPPA2) and 11p12 (LRRC4C) as novel candidate susceptibility loci.

Central nervous system (CNS) tumors constitute the most common form of solid neoplasms in children, but knowledge on genetic predisposition is sparse. In particular, whether susceptibility attributable to common variants is shared across CNS tumor types in children has not been investigated. The purpose of this study was to explore potential common genetic risk variants exhibiting pleiotropic effects across pediatric CNS tumors. We also investigated whether such susceptibility differs between early and late onset of disease. A Danish nationwide genome-wide association study (GWAS) of 1,097 consecutive patients (< 15years of age) with CNS tumors and a cohort of 4,745 population-based controls. For both the overall cohort and patients diagnosed after the age of four, the strongest association was rs12064625 which maps to PAPPA2 at 1q25.2 (p = 3.400 × 10-7 and 9.668 × 10-8, respectively). PAPPA2 regulates local bioavailability of insulin-like growth factor I (IGF-I). IGF-I is fundamental to CNS development and is involved in tumorigenesis across a wide range of different cancers. For the younger children, the strongest association was provided by rs11036373 mapping to LRRC4C at 11p12 (p = 7.620 × 10-7), which encoded protein acts as an axon guidance molecule during CNS development and has not formerly been associated with brain tumors. This GWAS indicates shared susceptibility attributable to common variants across pediatric CNS tumor types. Variations in genetic loci with roles in CNS development appear to be involved, possibly via altered IGF-I related pathways.

The Multi-Faced Role of PAPP-A in Post-Partum Breast Cancer: IGF-Signaling is Only the Beginning.

Insulin-like growth factor (IGF) signaling and control of local bioavailability of free IGF by the IGF binding proteins (IGFBP) are important regulators of both mammary development and breast cancer. A recent genome-wide association study (GWAS) identified small nucleotide polymorphisms that reduce the expression of IGFBP-5 as a risk factor of developing breast cancer. This observation suggests that genetic alterations leading to a decreased level of IGFBP-5 may also contribute to breast cancer. In the current review, we focus on Pregnancy-Associated Plasma Protein A (PAPP-A), a protease involved in the degradation of IGFBP-5. PAPP-A is overexpressed in the majority of breast cancers but its role in cancer has only begun to be explored. More specifically, this review aims at highlighting the role of post-partum involution in the oncogenic function of PAPP-A. Notably, we summarize recent studies indicating that PAPP-A plays a role not only in the degradation of IGFBP-5 but also in the deposition of collagen and activation of the collagen receptor discoidin 2 (DDR2) during post-partum involution. Finally, considering the immunosuppressive microenvironment of post-partum involution, we also discuss the unexpected finding made in Ewing Sarcoma that PAPP-A plays a role in immune evasion. While the immunosuppressive role of PAPP-A in breast cancer remains to be determined, collectively these studies highlight the multifaced role of PAPP-A in cancer that extends well beyond its effect on IGF-signaling.

Glucose-Regulated Protein 94 (GRP94): A Novel Regulator of Insulin-Like Growth Factor Production.

Mammals have two insulin-like growth factors (IGF) that are key mediators of somatic growth, tissue differentiation, and cellular responses to stress. Thus, the mechanisms that regulate the bioavailability of IGFs are important in both normal and aberrant development. IGF-I levels are primarily controlled via the growth hormone-IGF axis, in response to nutritional status, and also reflect metabolic diseases and cancer. One mechanism that controls IGF bioavailablity is the binding of circulating IGF to a number of binding proteins that keep IGF in a stable, but receptor non-binding state. However, even before IGF is released from the cells that produce it, it undergoes an obligatory association with a ubiquitous chaperone protein, GRP94. This binding is required for secretion of a properly folded, mature IGF. This chapter reviews the known aspects of the interaction and highlights the specificity issues yet to be determined. The IGF–GRP94 interaction provides a potential novel mechanism of idiopathic short stature, involving the obligatory chaperone and not just IGF gene expression. It also provides a novel target for cancer treatment, as GRP94 activity can be either inhibited or enhanced.

Effects of suppressing bioavailability of insulin-like growth factor on age-associated intervertebral disc degeneration.

Suppression of the insulin‐like growth factor‐1 (IGF‐1) signaling pathway reduces age‐related disorders and increases lifespan across species, making the IGF‐1 pathway a key regulator of aging. Previous in vitro intervertebral disc cell studies have reported the pro‐anabolic effect of exogenously adding IGF‐1 on matrix production. However, the overall effects of suppressing IGF‐1 signaling on age‐related intervertebral disc degeneration (IDD) is not known. Here, the effects of suppressing IGF‐1 signaling on age‐related IDD in vivo were examined using PAPPA −/− mice. These are animals with targeted deletion of pregnancy‐associated plasma protein A (PAPPA), the major protease that cleaves inhibitory IGF binding proteins that control bioavailability of IGF‐1 for cell signaling. Compared to age‐matched wild‐type (Wt) littermates, reduced levels of matrix proteoglycan (PG) and aggrecan were seen in discs of 23‐month old PAPPA −/− mice. Decreased aggrecanolysis and expression of two key catabolic markers, matrix metalloproteinase‐3 and a disintegrin and metalloproteinase with thrombospondin motifs‐4, were also observed in discs of old PAPPA −/− mice compared to Wt littermates. Suppressing IGF‐1 signaling has been implicated to shift cellular metabolism toward maintenance rather than growth and decreasing cellular senescence. Along this line, discs of old PAPPA −/− mice also exhibited lower cellular senescence, assessed by p53 and lamin B1 markers. Collectively, the data reveal complex regulation of disc matrix homeostasis by PAPPA/IGF‐1 signaling during chronologic aging, that is, reduced IGF‐1 bioavailability confers the benefit of decreasing disc cellular senescence and matrix catabolism but also the disadvantage of decreasing disc PG matrix anabolism. This pathway requires further mechanistic elucidation before IGF‐1 could be considered as a therapeutic growth factor for treating IDD.