Components Of Insulin-like Growth Factor System Research Articles

Relative Expression and Localization of the Insulin-Like Growth Factor System Components in the Fetal, Child and Adult Intestine

The insulin-like growth factors (IGFs) are important in the development and maintenance of the gastrointestinal tract. To compare the expression of IGFs and their receptors in the stomach and duodenum of the fetus, the child and the adult. To identify the cells mainly responsible for the production of the members of the IGF system. Tissue was obtained from fetus after abortion and from children and adults during diagnostic endoscopy and biopsy. The expression of the IGFs and their receptors was estimated by an RNAse protection assay and sections were stained with antisera to the components of IGF system. The tissues from the stomach and the duodenum expressed the two IGFs and their receptors at all stages of life. The fetal IGF receptors I and II, were approximately ten times higher than in the child and IGF-II was five times higher. Immunohistochemical staining showed the components of the IGF system to be localized to the gastric glands and to the basotlateral border of the gastric epithelial cells. In the duodenum, they were concentrated at the apical portion of the epithelial tissue. They could also be identified in ganglion cells and nerves. The IGFs and their receptors in the stomach and duodenum are expressed in all age groups and mostly are highest in the fetus. The IGF system proteins were located in the gastric glands and epithelium and in the apical portion of the villous epithelium of the duodenum.

Gene Expression of Insulin-Like Growth Factor Binding Proteins (IGFBP-2 and IGFBP-3) in Childhood Acute Myeloblastic Leukemia. Intr. by Herbert Sayer.

Insulin-like growth factor (IGF) system plays an important role in regulating cellular proliferation. Alterations to the Insulin-like growth factor system have been reported for different tumors. They are of particular interest in the search for new prognostic and therapeutic approaches to cancer treatment. This study aimed to investigate the expression of IGFBP-2, IGFBP-3, IGF-I and IGF-II genes in leukemic cells from children with previously untreated acute myeloblastic leukemia (AML).The expression of IGF-I and IGF-II genes as well as IGFBP-2 and IGFBP-3 genes were measured using TaqMan real-time PCR in 50 children (mean age 10.8±4.8 years). All four genes were expressed with a great variability. RNA samples were extracted from leukemic cells enriched by Ficoll-Hypaque density gradient separation of bone marrow or peripheral blood mononuclear cells (MNC). MNC samples from peripheral blood and bone marrow of healthy children were used as controls. The median expression of IGFBP-2 was 25 times higher in AML cells than in peripheral MNC (p<0.001) and 10 times higher in bone marrow of healthy children (p<0.01). Increased IGFBP-2 gene expression at time of diagnosis was associated with a poor prognosis and a shortened survival time. Leukemic cells of patients who remained in continuous complete remission during the follow up showed a significant decreased IGFBP-2 gene expression at time of diagnosis compared to patients who suffered from relapse (p=0.05).On the other hand, AML cells showed a significantly lower IGFBP-3 gene expression than controls. The median expression of IGFBP-3 was 30 times lower in AML cells than in peripheral MNC (p<0.001) and 20 times lower than in bone marrow of healthy children (p<0.001). No significant difference could be found in IGF-I and IGF-II expression between leukemic and normal cells. Leukemic cells from children with previously untreated AML express components of IGF system. Especially IGFBP-2 seems to play an important role. By this mechanism, IGFBP-2 promotes their own growth in an autocrine, paracrine or endocrine manner. Whether these components will be useful as prognostic factors in stratification of AML treatment in children needs to be evaluated.

The Emerging Role of the Insulin-like Growth Factors in Oral Biology

The insulin-like growth factors (IGF) are a family of growth factors, receptors and binding proteins that are involved in numerous growth and differentiation processes, as well as in various pathological conditions. The aim of this review is to summarize data that has been accumulating in recent years linking the IGF system to a number of physiological and pathological oral processes. The IGF system fulfills an important role in growth and development of teeth, mandible, maxillae, and tongue. It has been postulated that IGF-I may be of great value in the treatment of periodontal defects and in tissue healing. Furthermore, IGF-II has been shown to be overexpressed in salivary gland adenomas, suggesting that aberrant IGF signaling may be a key factor in the etiology of oral malignancies. Understanding the role and regulation of IGF system components in salivary glands and other oral structures will be of significant basic and clinical relevance.

Selective Activation of Insulin Receptor Substrate-1 and -2 in Pleural Mesothelioma Cells

Molecular mechanisms active in transforming human pleural cells remain incompletely understood. Our previous microarray analysis of malignant pleural mesothelioma revealed alterations in components of the insulin-like growth factor (IGF) system, implicating this signaling axis in tumorigenesis. Therefore, in this current study, we characterized the molecular phenotype and investigated the key signaling pathways of the IGF system in malignant pleural mesothelioma specimens. For the major IGF components, we assessed mRNA abundance and total protein levels. We measured IGF-I ligand-dependent activation of signaling pathways downstream of the type I IGF receptor in a subset of malignant pleural mesothelioma cell lines and determined the corresponding biological consequences. At the transcriptional level, we observed consistent changes in IGF components that may contribute to a malignant phenotype. IGF-I stimulation of cells resulted in enhanced activation of type I IGF receptor and IRS adaptor proteins. Differential activation of IRS-1 signaling was associated with cell growth, whereas IRS-2 signaling was associated with cell motility. Thus, these data suggest that multiple mechanisms likely contribute to malignant pleural mesothelioma tumorigenesis. Therefore, IGF system components represent novel malignant pleural mesothelioma therapeutic targets for investigation.

C6 Rat Glioma Cell에서 리튬에 의한 성장 억제와 Insulin-like Growth Factor System Components의 발현과의 관계

Insulin-like growth factors(IGF)s-I과 -II ligands와 이들의 receptors 및 6종류의 IGF-binding proteins(IGFBPs)로 구성된 IGF systim은 여러 종류의 세포의 생존, 증식 및 분화에 있어서 매우 중요한 역할을 한다. 리튬은 in vitro에서 여러 종류의 세포의 생존과 증식의 조절제로 알려져 있다. 본 연구는 IGF-I, IGF-I receptor 및 IGF carrier로서 주로 IGFBP-3를 발현하는 rat C6 glioma cell에서 LiCl로 유도된 세포 생존 및 증식의 변화와 IGF system components의 발현간의 관계를 구명하고자 수행되었다. 10%혈청을 함유하는 배양액에서 0, 2mM, 혹은 5mM LiCl을 첨가하여 C6 cell을 24시간 배양했을 시 세포의 생존률과 세포 수는 리튬 첨가에 의해 영향을 받지 않았다. 그러나 72시간 배양 했을 때 C6 cell은 명백히 리튬의 첨가수준에 따라 반응하였다. 0, 2m, 5mM LiCl 첨가수준에서 72시간 배양한 C6 cell은 각각 전형적인 세포분열, 세포분열 중지 및 세포사멸 양상을 보였다. 더욱이 사멸돼가는 세포는 reverse transcription-polymerase chain reaction으로 조사한 IGF-I, IGF receptor 및 IGFBP-3의 발현수준이 저하되었다. 흥미롭게도 혈청을 첨가하지 않은 배양조건 하에서 IGFBP-3에 대한 antisense oligodeoxyribonucleotide를 10<TEX>${\mu}M$</TEX> 수준의로 첨가하여 배양했을 때도 표적 mRNA는 물론 세포 수도 줄었다. 종합하자면, C6 cell에서 리튬의 독성 효과의 일부는 이 제제에 의한 IGF system components의 발현 억제 효과에 의해 매개될 소지가 크다. 이러한 관점에서 IGRBP-3는 적어도 이 세포의 정상적인 증식을 위해 꼭 필요한(‘prrmissive') 역할을 할 수 있다는 점을 시사한다. The insulin-like growth factor(IGF) system, consisting of IGFs-I and -II ligands and their receptors and six IGF-binding proteins(IGFBPs), plays an important role in survival, proliferation and differentiation of a variety of cell types. Lithium is a known modulator of survival and proliferation of many cell types in vitro. The present study was undertaken to investigate the relationship between LiCI-induced changes in cell survival and growth and the expression of the IGF system components in C6 rat glioma cell line which, besides IGF-I and its receptor, is known to express IGFBP-3 as its major IGF carrier. When C6 cells were cultured for 24h in the absence or presence of 2mM or 5mM LiCl in a 10% serwn-containing medium, the viability and the number of cells were not affected by added lithium. In 72-h culture, however, C6 cells clearly exhibited a dose-dependent response to added LiCl. The cells cultured for 72h in the presence of 0, 2mM and 5mM LiCl exhibited a typical mitotic, a growth-arrested and an apoptotic appearances, respectively. Moreover, the apoptotic cells were accompanied by reduced expression of IGF-I, IGF-I receptor and IGFBP-3 as examined by semi-quantitative reverse transcription-polymerase chain reaction. Interestingly, blockade of IGFBP-3 mRNA translation by addition of 101<TEX>${\mu}M$</TEX> IGFBP-3 anti-sense oligodeoxyribonucleotide in serum-free, 24-h culture resulted in a decrease in the number of cells as well as relative abundance of the target mRNA. In summary, results suggest that the cytotoxic effect of lithium in C6 cell is likely to be mediated, in part, by suppression by this agent of the expression of the IGF system components. In this regard, IGFBP-3 may play at least a 'permissive' role in normal proliferation of this cell.

The anabolic effects of GH/IGF system on bone.

Osteoporosis is the result of imbalance in bone remodeling caused by increased bone resorption and decreased bone formation. In terms of the mechanisms for the age-related impairment in bone formation, a deficiency in growth hormone (GH)/insulin-like growth factor (IGF) system that occurs with age has been proposed to play a major role. The potential causes for age-related decline in GH secretion are under active investigation and may involve multiple mechanisms including GH secretagogues, sex hormones, nutritional status and physical activity. Although a number of animal and clinical studies have provided experimental evidence for potential use of GH/IGF system components to increase bone mass, the clinical utility of GH/IGF system components for treatment of osteoporosis has not come to fruition because of our incomplete understanding of the regulation of production and actions of GH/IGF system components. Regarding the actions of GH in target tissues, there is evidence that IGF system plays a major role in mediating the GH effects. In addition, GH may also exert effects on certain target tissues independent of IGFs. It is also known that GH effects on target tissue involve multiple components of the IGF system including the ligands, receptors, IGF binding proteins (IGFBP), IGFBP proteases and activators and inhibitors of IGFBP proteases. Future studies on the mechanisms that contribute to age-related impairment in GH/IGF axis and the molecular pathways that contribute to the bone forming effects of GH/IGF axis may provide a foundation for the development of safe and effective therapies involving one or more IGF system components to correct bone formation deficit in the elderly subjects.

Insulin-like growth factor-I regulates glucose-induced mitochondrial depolarization and apoptosis in human neuroblastoma.

Neuroblastoma, a pediatric peripheral nervous system tumor, frequently contains alterations in apoptotic pathways, producing chemoresistant disease. Insulin-like growth factor (IGF) system components are highly expressed in neuroblastoma, further protecting these cells from apoptosis. This study investigates IGF-I regulation of apoptosis at the mitochondrial level. Elevated extracellular glucose causes rapid mitochondrial enlargement coupled with an increase in the mitochondrial membrane potential (Delta Psi(M)) followed by mitochondrial membrane depolarization (MMD), uncoupling protein 3 (UCP3) downregulation, caspase-3 activation and decreased Bcl-2. MMD inhibition by Bongkrekic acid prevents high-glucose-induced loss of UCP3 and apoptosis. Glucose exposure induces caspase-9 cleavage within 30 min, and caspase-9 inhibition prevents glucose-mediated apoptosis. IGF-I prevents caspase activation and mitochondrial events leading to apoptosis. These results suggest that elevated glucose produces early initiator caspase activation, followed by Delta Psi(M) changes, in neuroblastoma cells; in turn, IGF-I prevents apoptosis by preventing downstream caspase activation, maintaining Delta Psi(M) and regulating Bcl proteins.

Alterations of circulating insulin-like growth factor system components and androgen insensitivity in patients with Kennedy’s disease

Our study aimed to provide information on the interactions of the endocrine system and neurodegeneration in Kennedy’s disease (KD). This disease known also as X-linked spinal and bulbar muscular atrophy is caused by an expansion of CAG repeats of a polyglutamine (polyQ) tract in the first exon of the androgen receptor gene. Clinical symptoms consist of a weakness of the limbs and bulbar symptoms. Postpubertal gynecomastia is the first sign of partial androgen resistance in most of the patients. A type 2 diabetes mellitus can occur during the clinical course. Histopathology reveals a depletion of motor neurons in brainstem and spinal cord.

The correlation between serum and normal breast tissue Insulin-like Growth Factor (IGF-I) system components

Receptors do not know any stereochemistry and yet they display exquisite discrimination toward the stereostructure of those molecules they recognize. Pedro Lehmann lists what constitutes a full description of a drug's stereostructure, discusses chiral drugs as the most important and interesting representatives of stereoisomeric ligands. Quantitative Stereo-Structure Activity Relations (QSSAR) are not yet a part of QSAR but eudismic analyses, including those of ‘promiscuous’ ligands, show promise for a better understanding of the receptor-pharmacophore interaction. He draws attention to the importance of the correct and complete stereochemical identification of a drug as well as to the need for a stereoselectivity database in rational drug design.

Co-expression of messenger ribonucleic acids encoding IGF-I, IGF-II, type I and II IGF receptors and IGF-binding proteins (IGFBP-1 to -6) during follicular development in the ovary of seasonally anoestrous ewes

In recent years, it has become apparent that components of the insulin-like growth factor (IGF) system are involved in the regulation of ovarian follicular development in sheep. The majority of previous studies have concentrated on investigating only a select few components and not the whole system. The aim of the present study was to use five seasonally anoestrous ewes to investigate the expression of mRNA encoding all 10 components of the sheep IGF system among various-sized follicles within the ovary, using sheep-specific ribonucleotide probes and in situ hybridisation. IGF-I mRNA expression was low and did not vary with follicle size. IGF-II mRNA expression was significantly higher ( P<0.05) in small follicles compared to large follicles. Both IGF receptors had significantly higher ( P<0.05) levels of mRNA expression in small follicles, with the type I receptor being expressed to a slightly greater extent than the type II receptor. IGFBP-2, -3, -4 and -5 gene expression followed a similar pattern to IGF-II and the IGF receptors, whereby expression decreased with increasing follicle size. Similar to IGF-I, IGFBP-6 mRNA expression showed little variation with follicle size. IGFBP-1 mRNA expression was observed at low and constant levels, albeit in small and medium-sized follicles only. These data demonstrate that all of the components of the IGF system are produced in the ovine follicle, and for some of the components, their gene expression varied with stage of follicle development. This study further emphasises the importance of IGF-II as the major IGF in the autocrine and paracrine regulation of follicle development in sheep.

Effects of Reduced Dialysate Calcium on Calcium-Phosphorus Product and Bone Metabolism in Hemodialysis Patients

Background: The safety of using reduced calcium dialysate (RDC) in hemodialysis (HD) patients is controversial due to related changes in bone metabolism. In the present study we investigated whether an 18-month treatment period with RDC may induce significant changes in calcium-phosphorus product (CaxP), bone metabolism, and components of the insulin-like growth factor (IGF) system in HD patients. Study Design: In this prospective study, 13 HD patients with biochemical signs of diminished or low-normal bone turnover and high CaxP due to high serum calcium level were treated by lowering dialysate calcium from 3.5 to 2.5 mEq/l for 18 months. By specific immunometric assays, serum levels of intact parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), pyridinoline (PYR), desoxypyridinoline (D-PYR), 25-OH-vitamin D₃ (25-vit D₃), 1,25-(OH)₂-vitamin D₃ (1,25-vit D₃), free IGF-I, IGF-II, and IGF-binding protein (IGFBP)-1 to -6 were measured. Results: CaxP decreased significantly from 5.62 (baseline) to 3.95 mmol²/l² (at 18 months), whereas PTH increased from 81 ± 57 pg/ml at baseline to 236 ± 188 at 12 months (p < 0.01), remaining in this range thereafter. Parameters of bone resorption (PYR) as well as formation (B-ALP) significantly increased during RDC, with peak levels after 12 months. Despite increasing doses of oral alfacalcidol, levels of 25-vit D₃ and 1,25-vit D₃ subsequently declined during RDC. In parallel with the changes in bone markers, free IGF-I levels decreased (baseline: 1.9 ± 0.9 ng/ml, after 18 months: 1.1 ± 0.7; p < 0.01). The decline of free IGF-I correlated with decreasing levels of IGFBP-3 and increasing levels of IGFBP-1/-4. Conclusion: The treatment with RDC effectively lowered CaxP and stimulated bone formation and resorption. The different changes in bone markers and IGF system components mirror the complex effects on bone metabolism.

MRNA expression of components of the IGF system and of GH and insulin receptors in ovaries of broiler breeder hens fed ad libitum or restricted from 4 to 16 weeks of age

An evaluation of the insulin-like growth factors (IGF) system in the ovaries of heavy breeder hens during the growing phase was performed to measure the effect of feed restriction. The transcripts of IGF-I, IGF-II, IGF receptor (IGF-R), two IGF binding proteins (IGFBP-2 and IGFBP-5), GH receptor (GH-R) and insulin receptor (I-R) were measured by RT-PCR at 4, 8, 12 and 16 weeks of age in the ovaries of ad libitum fed and feed restricted hens. The transcripts of all genes screened were detected in all feed regime groups and at all ages sampled. However, no significant overall effects of feed restriction on these transcripts were found despite the marked difference in body growth (200% at 16 weeks of age). Similarly there were no significant age effects except for the expression of GH-R—that showed a decrease after 8 weeks of age ( P<0.01). Although feed restriction seems to have a relatively limited effect on the expression of these components of the ovarian IGF system in juveniles, a more detailed determination is necessary to determine possible changes nearer to sexual maturity (16 weeks of age onwards). It is concluded that components of the IGF system, GH or insulin may not be involved in the mechanisms that, through restricted feeding, alter ovarian development and function during growth to enable better reproductive performance during lay.

Could exemestane affect insulin-like growth factors, interleukin 6 and bone metabolism in postmenopausal advanced breast cancer patients after failure on aminoglutethimide, anastrozole or letrozole?

Postmenopausal hormone-sensitive breast cancer is currently treated with either antioestrogens or aromatase inhibitors (AIs), due to the clinical efficacy and safety of these drugs. Today's challenge is the sequential use of AIs with different structure and no cross-resistance to improve the therapeutic outcome. The present study describes the biological action of the steroidal structure (SS)-AI exemestane (EXE), in patients progressing on aminoglutethimide (AG) or other non-steroidal structure (NSS)-AIs (letrozole or anastrozole). Thirteen patients were evaluated for serum insulin-like growth factor (IGF) components [total IGF-1, IGF-2 and IGF binding protein (IGFBP)-3], interleukin (IL)-6 system [IL-6 and soluble IL-6 receptor (sIL-6-R)] and bone metabolism markers [bone gla protein/osteocalcin (BGP), bone-specific isoform of alkaline phosphatase (BAP) and carboxy-telopeptide of type I procollagen (ICTP)]. IGF system components show a trend to increase both in patients progressing on AG and in patients progressing on other NSS-AIs. Such an increase depends on the wash-out length from the previous treatment and is strictly linked to the circulating oestrogen levels. Serum IL-6 and sIL-6-R are mainly related to the patients' clinical outcome. Bone formation (BGP and BAP) and bone resorption (ICTP) markers seem to be at equilibrium with oestrogen levels when starting EXE and do not appear to be uncoupled over treatment. The observed variations seem to be mainly linked to the circulating oestrogen levels rather than directly to the way of action of the AI employed.

Serum levels of insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-1 to -6 and their relationship to bone metabolism in osteoporosis patients

Background: Insulin-like growth factor (IGF) system components are important regulators of bone formation. Alterations of individual IGF system components have been described in osteoporosis (OP) patients; however, no study has addressed changes in free IGF-I and in all six IGF binding proteins (IGFBPs). Methods: A cross-sectional study was performed in 45 OP patients and 100 healthy matched controls. Serum levels of free and total insulin-like growth factor I (IGF-I), IGFBP-1 through -6, intact parathyroid hormone (PTH), 25-OH-vitamin D 3 (25OHD 3), 1,25-(OH) 2-vitamin D 3 (1,25-(OH) 2D 3), osteocalcin (OSC), bone alkaline phosphatase (B-ALP), and carboxyterminal propeptide of type-I procollagen (PICP) were measured with specific assays. Bone mineral density (BMD) of the lumbar spine was determined by dual-energy X-ray absorptiometry (DEXA). Results: Compared with age- and sex-matched control subjects, OP patients showed a 73% decrease in free IGF-I, a 29% decrease in total IGF-I, a 10% decrease in IGFBP-3, and a 52% decrease in IGFBP-5 levels; they had higher levels of IGFBP-1 (4.1-fold), IGFBP-2 (1.8-fold), IGFBP-4 (1.3-fold), and IGFBP-6 (2.1-fold). Alterations in IGF system components were most evident in 13 OP patients with vertebral fractures in the past 4 years compared to patients without fractures. In OP patients with fractures, the ratio between IGFBP-4 and IGFBP-5 was increased whereas levels of OSC were decreased. Conclusions: Our data provide strong indirect evidence for a functional connection between circulating IGF system components and bone metabolism and the susceptibility to fractures in OP patients.

Effects of BST on Oviductal and Uterine Genes Encoding Components of the IGF System in Lactating Dairy Cows

Lactating Holstein cows, averaging 80 d in milk, were used to examine effects of exogenous bovine somatotropin (bST) on oviductal and uterine genes encoding components of the insulin-like growth factor (IGF) system. About 12h before expected ovulation in an Ovsynch protocol, cows were assigned randomly to receive bST (500mg; n = 11) or serve as untreated controls (n = 10). Cows that ovulated (n = 9 bST, 8 control) were divided within treatment to be sacrificed on d 3 or 7 postovulation. Samples of oviductal and intercaruncular endometrial tissue from oviducts and uterine horns ipsilateral to the corpus luteum (CL) were collected and immediately frozen at−80°C for subsequent mRNA analyses. Northern blots revealed mRNAs for IGF-II, IGF-binding protein-2 (IGFBP-2), and IGFBP-3 in all oviductal and endometrial tissues. Significant amounts of IGF-I and growth hormone receptor-1A (GHR-1A) mRNAs were detected in uteri but not in oviducts. The bST treatment had no effect on amount of IGF-I mRNA transcript in uterine endometrium. The mRNA encoding IGF-II was induced by bST in oviducts collected on both d 3 and 7 but was down-regulated in endometrium on d 7. Transcript of IGFBP-2 mRNA was greater in endometrial than oviductal tissues and did not differ between treatments. Both oviductal and endometrial IGFBP-3 mRNA concentrations increased between d 3 and 7 postovulation, with a tendency for greater endometrial IGFBP-3 mRNA in bST-treated cows on d 7. On d 7, concentrations of endometrial GHR-1A mRNA were 30% lower in bST-treated cows. Results indicate complex and tissue-specific regulation of the uterine IGF system components by exogenous bST. Some of those biological responses to bST may be important in early development of bovine embryos.

Differential expression of the two GH genes during embryonic development of rainbow trout Oncorhynchus mykiss in relation with the IGFs system.

The Growth hormone (GH)/insulin-like growth factor (IGF) system promotes embryonic growth in higher vertebrates. Such a system exists in salmonids, but exhibits an additional level of complexity resulting from a recent whole genome tetraploidisation. Thus, two nonallelic GH genes are present in the trout genome. Although the two GH genes are similar, the possibility remains that the two genes have evolved separately, acquiring a distinct expression pattern. In this study, using whole mounted in situ hybridisation, we observed a one stage delay between the appearance of GH-2 (Stage 22) and GH-1 (Stage 23) soon after pituitary formation (Stage 21). In addition, by double in situ hybridisation, we clearly evidenced two types of somatotroph, one expressing only GH-2 and the other type both GH-1 and GH-2 at Stage 24. Consequently, at this stage more cells expressed GH-2 than GH-1 as confirmed by quantitative RT-PCR. However at hatching, as in adult, the difference between the expression of the two GH genes was no longer observed. In addition, our immunohistochemical studies did not show any delay between the expression of the mRNA and its translation as a protein at Stage 24. A comparison of the expression pattern of the IGF system components (IGF-1, IGF-2, and the receptor type I) determined by real time RT-PCR, have shown an IGF-1 mRNA increase concomitantly to the appearance of GH expression. On the whole, our results demonstrate a differential regulation of GH-1 and GH-2 genes in rainbow trout embryo. The relationship observed between the expression of different component of the GH/IGF system seems to indicate that this system could be functional early on during embryonic development.

Insulin-Like Growth Factor System Components in Relation to Erythropoietin Therapy and Bone Metabolism in Dialyzed Patients and Kidney Transplant Recipients

Insulin-like growth factor (IGF) system components appear to be the most important regulators of bone cell function. On the other hand, IGF-1 is shown to be an important regulator for erythropoiesis. The aim of the study was to examine the relationships between IGF system, requirements of erythropoietin, endogeneous erythropoietin levels, bone metabolism assesed by biochemical markers, markers of nutrition such as cholesterol and albumin in recombinant human erythropoietin (rHuEPO)-treated patients maintained on chronic hemodialyses or peritoneal dialyses as well as in kidney transplant recipients. The studies were performed on 79 chronically hemodialyzed patients; 28 of them did not receive rHuEPO, 51 subjects received rHuEPO, 34 patients on continuous ambulatory peritoneal dialysis (CAPD), 16 of them did not receive rHuEPO, 18 were given rHuEPO and 46 kidney allograft recipients. Endogeneous erythropoietin concentration, bone-specific alkaline phosphatase and serum CrossLaps were assayed by ELISA. Intact PTH, osteocalcin, 1,25-(OH)₂ D₃, 25-OH D₃, IGF-1, procollagen type I carboxy-terminal extension peptide (PICP) and procollagen type I cross-linked carboxy-terminal telopeptide (ICTP) were studied by RIA, whereas IGFBP-1 and IGFBP-3 concentrations were assayed by IRMA. We found a significantly higher IGF-1 and IGFBP-3 in rHuEPO-treated HD patients when compared to CAPD subjects given rHuEPO as well as to hemodialysis (HD) patients not treated with rHuEPO. IGF-1 was significantly higher in kidney transplant recipients when compared to dialyzed patients without rHuEPO therapy. IGFBP-1 was similar in all groups of patients (including kidney transplant recipients) studied. In CAPD patients not given rHuEPO concentrations of ICTP and PICP were significantly lower when compared to rHuEPO-treated CAPD subjects and HD patients not receiving rHuEPO therapy. Serum CrossLaps in CAPD patients treated with rHuEPO were significantly higher when compared to CAPD subjects without rHuEPO treatment and to kidney transplant recipients. In rHuEPO-treated CAPD subjects IGF-1 and IGFBP-1 correlated positively with serum CrossLaps (r = 0.61, p < 0.05 and r = 0.64, p < 0.05, respectively), whereas in hemodialyzed patients without rHuEPO a significant negative correlation between IGFBP-3 and serum CrossLaps was found (r = –0.69, p < 0.001) as well as between IGFBP-3 and aluminium (r = 0.51, p < 0.05), IGF-1 and ICTP (r = –0.43, p < 0.05). In conclusion, our data indicate a probable functional relationship between IGF system components, erythropoietin treatment in dialyzed patients and bone metabolism in renal replacement therapy in a form of hemodialyses, peritoneal dialyses and kidney transplantation. Dialyzed patients exhibit more pronounced renal osteodystrophy than kidney allograft recipients. IGF system components are influenced by erythropoietin therapy, but are not related to serum erythropoietin levels and rHuEPO requirements.

Response of the insulin-like growth factor system to vitamin A depletion and repletion in rats.

Vitamin A (VA) and insulin-like growth factors (IGF) are important regulators of a wide range of physiological processes. To investigate the IGF system's involvement in the physiological actions of VA, we examined the effects of VA status on components of the IGF system in rats. Male rats (3-wk-old) fed a VA-deficient diet for 11 wk developed VA deficiency, as confirmed by the depletion of serum retinol and hepatic retinyl palmitate. Rats fed the VA-deficient diet had significantly lower body weight (p < 0.05) and lower serum IGF-I concentrations than the rats fed the control diet. The decreases in serum IGF-I levels were accompanied by approximately 40% lower levels of the IGF-I mRNA in the liver and lungs. With respect to the gene expression of other IGF system components, VA deficiency caused a twofold induction of IGF-I receptor (IGF-IR) mRNA in the heart and a twofold reduction in IGFBP-6 mRNA in the lungs, but did not alter the expression of IGF-II, IGFBP-1, IGFBP-3, IGFBP-4 or IGFBP-5 in all tissues examined. When VA-deficient rats received a single injection of retinoic acid (2 mg/rat), tissue IGF-I and IGF-IR gene expression did not change after 4 or 8 h, while the expression of IGF-II, IGFBP-4, and IGFBP-6 mRNAs in some tissues increased rapidly. These results suggest a possible involvement of the IGF system in mediating the physiological actions of VA, including VA-supported growth, in the rat.

Gene Expression of Insulin-Like Growth Factors and Receptors in Neoplastic Prostate Tissues: Correlation with Clinico-pathological Parameters

The insulin-like growth factor (IGF) system has been shown to regulate prostate cell growth in vitro and, possibly, in vivo. In this study we examined RNA expression of IGF ligands and their receptors in 23 paired benign and neoplastic prostate tissues. In addition to comparing gene expression of IGF ligands and receptors between benign and neoplastic tissue samples, we correlated IGF-I, IGF-II, IGFR-1, and IGFR-2 RNA levels in tumor samples with prognostic clinico-pathological parameters such as stage, grade, Gleason score, perineural or extraprostatic invasion. We found higher IGF-I RNA levels in benign vs. malignant tissues (p = 0.014), whereas IGF-II RNA expression was higher in tumors with high Gleason score (GS) (p = 0.045). Using the Spearman rank correlation test we also found a positive correlation between IGFR-2 RNA levels and GS (p = 0.01). No correlation was found between expression of IGF ligands and receptors and tumor grade, stage perineural invasion, or extrapros-tatic involvement. We conclude that differential expression of certain IGF system components may be important in the biology and clinical behavior of prostate cancer.

Immunohistochemical Localization of Components of the Insulin-Like Growth Factor-System in Human Deciduous Teeth

To investigate the occurrence of components of the insulin-like growth factor (IGF) system during the resorption process of shedding human deciduous teeth, we investigated sections of 13 decalcified and paraffin-embedded deciduous teeth immunohistochemically with antibodies against IGF-I and -II, six IGF binding proteins (IGFBPs 1-6) and the IGF receptors IGFIR and IGF2R. The teeth were in different stages of resorption and all showed reparative cementum formation. It was found that acellular extrinsic fiber cementum, reversal lines and reparative cellular intrinsic fiber cementum were immunoreactive for both IGFs and various IGFBPs. Therefore, in human deciduous teeth, all subgroups of cementum, but not dentine, may represent sources of components of the IGF system. Odontoclasts did not carry IGFs or the IGF1R, but IGFBPs and the IGF2R. Therefore, these cells, in contrast to osteoclasts, may not respond to IGFs, but may be involved in the release and sequestration of IGFs from cementum during the resorption process. In contrast to odontoclasts, cementoblasts and periodontal ligament (PDL) fibroblasts carried IGF1R. The influence of the IGF system on the function of these cells with respect to periodontal matrix turnover and cementogenesis is discussed. On the behalf of the IGFBP immunoreactivities found, the PDL extracellular matrix can be considered to be a reservoir for IGF system components, where binding proteins may regulate IGF distribution and activity.