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IGF-I Receptor (igf-i + receptor)
Selected AbstractsIGF-I Receptor Is Required for the Anabolic Actions of Parathyroid Hormone on Bone,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2007Yongmei Wang Abstract We showed that the IGF-IR,null mutation in mature osteoblasts leads to less bone and decreased periosteal bone formation and impaired the stimulatory effects of PTH on osteoprogenitor cell proliferation and differentiation. Introduction: This study was carried out to examine the role of IGF-I signaling in mediating the actions of PTH on bone. Materials and Methods: Three-month-old mice with an osteoblast-specific IGF-I receptor null mutation (IGF-IR OBKO) and their normal littermates were treated with vehicle or PTH (80 ,g/kg body weight/d for 2 wk). Structural measurements of the proximal and midshaft of the tibia were made by ,CT. Trabecular and cortical bone formation was measured by bone histomorphometry. Bone marrow stromal cells (BMSCs) were obtained to assess the effects of PTH on osteoprogenitor number and differentiation. Results: The fat-free weight of bone normalized to body weight (FFW/BW), bone volume (BV/TV), and cortical thickness (C.Th) in both proximal tibia and shaft were all less in the IGF-IR OBKO mice compared with controls. PTH decreased FFW/BW of the proximal tibia more substantially in controls than in IGF-IR OBKO mice. The increase in C.Th after PTH in the proximal tibia was comparable in both control and IGF-IR OBKO mice. Although trabecular and periosteal bone formation was markedly lower in the IGF-IR OBKO mice than in the control mice, endosteal bone formation was comparable in control and IGF-IR OBKO mice. PTH stimulated endosteal bone formation only in the control animals. Compared with BMSCs from control mice, BMSCs from IGF-IR OBKO mice showed equal alkaline phosphatase (ALP)+ colonies on day 14, but fewer mineralized nodules on day 28. Administration of PTH increased the number of ALP+ colonies and mineralized nodules on days 14 and 28 in BMSCs from control mice, but not in BMSCs from IGF-IR OBKO mice. Conclusions: Our results indicate that the IGF-IR null mutation in mature osteoblasts leads to less bone and decreased bone formation, in part because of the requirement for the IGF-IR in mature osteoblasts to enable PTH to stimulate osteoprogenitor cell proliferation and differentiation. [source] Pubertal maturation modifies the regulation of insulin-like growth factor-I receptor signaling by estradiol in the rat prefrontal cortexDEVELOPMENTAL NEUROBIOLOGY, Issue 8 2008Amaya Sanz Abstract The transition from adolescence to adulthood is accompanied by substantial plastic modifications in the cerebral cortex, including changes in the growth and retraction of neuronal processes and in the rate of synaptic formation and neuronal loss. Some of these plastic changes are prevented in female rats by prepubertal ovariectomy. The ovarian hormone estradiol modulates neuronal differentiation and survival and these effects are in part mediated by the interaction with insulin-like growth factor-I (IGF-I). In this study, we have explored whether the activation by estradiol of some components of IGF-I receptor signaling is altered in the prefrontal cortex during puberty. Estradiol administration to rats ovariectomized after puberty resulted, 24 h after the hormonal administration, in a sustained phosphorylation of Akt and glycogen synthase kinase 3, in the prefrontal cortex. However, this hormonal effect was not observed in animals ovariectomized before puberty. These findings suggest that during pubertal maturation there is a programming by ovarian hormones of the future regulatory actions of estradiol on IGF-I receptor signaling in the prefrontal cortex. The modification in the regulation of IGF-I receptor signaling by estradiol during pubertal maturation may have implications for the developmental changes occurring in the prefrontal cortex in the transition from adolescence to adulthood. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2008. [source] Role of the IGF-II receptor in mediating acute, non-genomic effects of retinoids and IGF-II on keratinocyte cell deathEXPERIMENTAL DERMATOLOGY, Issue 4 2003F. Louafi Abstract:, In this study, we have examined the effects of retinoic acid (RA) on the human immortalized keratinocyte cell line (HaCaT). A significant twofold (P < 0.01) increase in apoptotic cell death compared with the control was found within 24 h of treatment with 10,5 M of RA. Apoptosis was confirmed by flow cytometry. Cycloheximide did not inhibit this acute RA-induced apoptosis. Interestingly, insulin-like growth factor-II (IGF-II, 50 ng/ml) was able to significantly (67.3%; P < 0.05) reduce RA effects, whereas IGF-I (50 ng/ml) and insulin (75 ng/ml) were without effect. Furthermore, analogues of IGF-II [leu27 IGF-II and Des(1-6) IGF-II], with altered affinities for the IGF-I receptor and IGF-binding proteins (IGFBPs), but retained affinities for the IGF-II receptor, also completely inhibited (100%; P < 0.01) RA-induced apoptosis, while an IGF-I receptor antagonist did not reduce the survival effects of IGF-II. Insulin pretreatment negates the survival effect of IGF-II. In contrast, mannose 6 phosphate (M6P) did not alter RA or IGF-II actions. These results indicate that rapid induction of cell death by RA is independent of production or secretion of new proteins. The inhibition of RA action by IGF-II was independent of its ability to signal through the IGF-I receptor or to interact with IGFBPs. [source] Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liverHEPATOLOGY RESEARCH, Issue 9 2008Lisa Longato Aim:, Insulin receptor substrate, type 1 (IRS-1) transmits growth and survival signals, and is overexpressed in more than 90% of hepatocellular carcinomas (HCCs). However, experimental overexpression of IRS-1 in the liver was found not to be sufficient to cause HCC. Since chronic alcohol abuse is a risk factor for HCC, we evaluated potential interactions between IRS-1 overexpression and chronic ethanol exposure by assessing premalignant alterations in gene expression. Methods:, Wild-type (wt) or IRS-1 transgenic (Tg) mice, constitutively overexpressing the human (h) transgene in the liver, were pair-fed isocaloric liquid diets containing 0% or 24% ethanol for 8 weeks. The livers were used for histopathologic study and gene expression analysis, focusing on insulin, insulin-like growth factor (IGF) and wingless (WNT),Frizzled (FZD) pathways, given their known roles in HCC. Results:, In wt mice, chronic ethanol exposure caused hepatocellular microsteatosis with focal chronic inflammation, reduced expression of proliferating cell nuclear antigen (PCNA) and increased expression of IGF-I and IGF-I receptor. In hIRS-1 Tg mice, chronic ethanol exposure caused hepatic micro- and macrosteatosis, focal chronic inflammation, apoptosis and disordered lobular architecture. These effects of ethanol in hIRS-1 Tg mice were associated with significantly increased expression of IGF-II, insulin, IRS-4, aspartyl,asparaginyl , hydroxylase (AAH), WNT-1 and FZD 7, as occurs in HCC. Conclusion:, In otherwise normal liver, chronic ethanol exposure mainly causes liver injury and inflammation with impaired DNA synthesis. In contrast, in the context of hIRS-1 overexpression, chronic ethanol exposure may serve as a cofactor in the pathogenesis of HCC by promoting expression of growth factors, receptors and signaling molecules known to be associated with hepatocellular transformation. [source] Increased expression of the mannose 6-phosphate/insulin-like growth factor-II receptor in breast cancer cells alters tumorigenic properties in vitro and in vivoINTERNATIONAL JOURNAL OF CANCER, Issue 4 2003Jason S. Lee Abstract The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR) is thought to act as a suppressor of tumor growth by binding the mitogenic peptide IGF-II and modulating its extracellular levels via degradation. This receptor has been found to be absent or nonfunctional in a high proportion of breast tumors as a result of LOH and mutation of the gene. In our study, we have examined the effect of increasing expression of M6P/IGF-IIR on breast cancer cell tumorigenicity. MDA-MB-231 breast cancer cells stably transfected with M6P/IGF-IIR cDNA exhibited not only a greatly reduced ability to form tumors but also a markedly reduced growth rate in nude mice. In vitro, increased M6P/IGF-IIR expression resulted in 2-fold reduced uptake of IGF-II and was associated with reduced cellular invasiness and motility. Cells with increased M6P/IGF-IIR expression exhibited reduced phosphorylation of IGF-I receptor and p44/42 MAPK compared to vector transfectants, or wild-type MDA-MB-231 cells. These results therefore suggest that M6P/IGF-IIR levels can modulate breast cancer cell tumorigenicity by a mechanism that may involve altered IGF-I receptor signaling. © 2003 Wiley-Liss, Inc. [source] Insulin-Like Growth Factor I Is Required for the Anabolic Actions of Parathyroid Hormone on Mouse Bone,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2002Daniel D. Bikle M.D., Ph.D. Abstract Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 ,g/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH. [source] Insulin-Like Growth Factor I Production Is Essential for Anabolic Effects of Thyroid Hormone in Osteoblasts,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2000Bill K. Huang Abstract Thyroid hormone (T3) and insulin-like growth factor I (IGF-I) are critical regulators of skeletal function. T3 increases IGF-I production in bone. To assess the potential role of IGF-I as a mediator of T3 actions, we characterized phenotypic markers of osteoblast activity in two osteoblast models, normal mouse osteoblasts and MC3T3-E1 cells, exposed to T3 alone or under conditions that interfere with IGF-I actions. T3 significantly increased osteoblast 3H-proline incorporation, alkaline phosphatase (ALP), and osteocalcin. Both ,IR3, a neutralizing monoclonal antibody to the IGF-I receptor, and JB1, an IGF-I analogue antagonist, attenuated the stimulatory effects of T3. T3 effects also were decreased in cells transfected with antisense oligonucleotide (AS-ODN) to the IGF-I receptor gene. Both IGF-I and T3 had mitogenic effects that were inhibited by the antagonists. IGF-I by itself did not stimulate 3H-proline incorporation, ALP, and osteocalcin in the models used, revealing that although IGF-I is essential for the anabolic effects of T3, it acts in concert with other factors to elicit these phenotypic responses. (J Bone Miner Res 2000;15:188,197) [source] TGF-, control of cell proliferationJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2005Shuan S. Huang Abstract This article focuses on recent findings that the type V TGF-, receptor (T,R-V), which co-expresses with other TGF-, receptors (T,R-I, T,R-II, and T,R-III) in all normal cell types studied, is involved in growth inhibition by IGFBP-3 and TGF-, and that TGF-, activity is regulated by two distinct endocytic pathways (clathrin- and caveolar/lipid-raft-mediated). TGF-, is a potent growth inhibitor for most cell types, including epithelial and endothelial cells. The signaling by which TGF-, controls cell proliferation is not well understood. Many lines of evidence indicate that other signaling pathways, in addition to the prominent T,R-I/T,R-II/Smad2/3/4 signaling cascade, are required for mediating TGF-,-induced growth inhibition. Recent studies revealed that T,R-V, which is identical to LRP-1, mediates IGF-independent growth inhibition by IGFBP-3 and mediates TGF-,-induced growth inhibition in concert with T,R-I and T,R-II. In addition, IRS proteins and a Ser/Thr-specific protein phosphatase(s) are involved in the T,R-V-mediated growth inhibitory signaling cascade. The T,R-V signaling cascade appears to cross-talk with the T,R-I/T,R-II, insulin receptor (IR), IGF-I receptor (IGF-IR), integrin and c-Met signaling cascades. Attenuation or loss of the T,R-V signaling cascade may enable carcinoma cells to escape from TGF-, growth control and may contribute to the aggressiveness and invasiveness of these cells via promoting epithelial-to-mesenchymal transdifferentiation (EMT). Finally, the ratio of TGF-, binding to T,R-II and T,R-I is a signal controlling TGF-, partitioning between two distinct endocytosis pathways and resultant TGF-, responsiveness. These recent studies have provided new insights into the molecular mechanisms underlying TGF-,-induced cellular growth inhibition, cross-talk between the T,R-V and other signaling cascades, the signal that controls TGF-, responsiveness and the role of T,R-V in tumorigenesis. © 2005 Wiley-Liss, Inc. [source] Cross-talk between the insulin-like growth factor (IGF) axis and membrane integrins to regulate cell physiologyJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2010James Beattie The biology of cross-talk between activated growth factor receptors and cell-surface integrins is an area which has attracted much interest in recent years (Schwartz and Ginsberg, 2002). This review discusses the relationship between the insulin-like growth factor (IGF) axis and cell-surface integrin receptors in the regulation of various aspects of cell physiology. Key to these interactions are signals transmitted between integrins and the IGF-I receptor (IGF-IR) when either or both are bound to their cognate ligands and we will review the current state of knowledge in this area. The IGF axis comprises many molecular components and we will also discuss the potential role of these species in cross-talk with the integrin receptor. With respect to integrin ligands, we will mainly focus on the well-characterized interactions of the two extracellular matrix (ECM) glycoproteins fibronectin (FN) and vitronectin (VN) with cell-surface ligands, and, how this affects activity through the IGF axis. However, we will also highlight the importance of other integrin activation mechanisms and their impact on IGF activity. J. Cell. Physiol. 224: 605,611, 2010. © 2010 Wiley-Liss, Inc. [source] Rapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent parathyroid hormone treatmentJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2009P.J. Niziolek The osteo-anabolic effects of intermittent parathyroid hormone (PTH) treatment require insulin-like growth factor (IGF) signaling through the IGF-I receptor. A major downstream target of the IGF-I receptor (via Akt) is the mammalian target of rapamycin (mTOR), a kinase involved in protein synthesis. We investigated whether the bone-building effects of intermittent PTH require functional mTOR signaling. Mice were treated with daily PTH 1,34 (0, 10, 30, or 90,µg/kg) for 6 weeks in the presence or absence of rapamycin, a selective inhibitor of mTOR. We found that all PTH doses were effective in enhancing bone mass, whether rapamycin was present or not. Rapamycin had little to no effect on the anabolic response at low (10,µg) PTH doses, small effects in a minority of anabolic measures at moderate doses (30,µg), but the anabolic effects of high-dose PTH (90,µg) were consistently and significantly suppressed by rapamycin (,4,36% reduction). Serum levels of Trap5b, a marker of resorption, were significantly enhanced by rapamycin, but these effects were observed whether PTH was absent or present. Our data suggest that intermittent PTH, particularly at lower doses, is effective in building bone mass in the presence of rapamycin. However, the full anabolic effects of higher doses of PTH are significantly suppressed by rapamycin, suggesting that PTH might normally activate additional pathways (including mTOR) for its enhanced high-dose anabolic effects. Clinical doses of intermittent PTH could be an effective treatment for maintaining or increasing bone mass among patients taking rapamycin analogs for unrelated health issues. J. Cell. Physiol. 221: 579,585, 2009. © 2009 Wiley-Liss, Inc. [source] Immunohistochemical detection of insulin-like growth factors, platelet-derived growth factor, and their receptors in ameloblastic tumorsJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 4 2007H. Kumamoto Background:, To evaluate the roles of growth factors in oncogenesis and cytodifferentiation of odontogenic tumors, expression of insulin-like growth factors (IGFs), platelet-derived growth factor (PDGF), and their receptors was analyzed in ameloblastic tumors as well as in tooth germs. Methods:, Tissue specimens of 10 tooth germs, 47 ameloblastomas, and five malignant ameloblastic tumors were examined immunohistochemically with the use of antibodies against IGF-I, IGF-II, IGF-I receptor (IGF-IR), PDGF A-chain, PDGF B-chain, PDGF , -receptor, and PDGF , -receptor. Results:, Immunohistochemical reactivity for IGFs, PDGF chains, and their receptors was detected predominantly in odontogenic epithelial cells near the basement membrane in tooth germs and in benign and malignant ameloblastic tumors. The expression levels of IGF-II and PDGF chains were significantly higher in ameloblastic tumors than in tooth germs. Malignant ameloblastic tumors showed higher reactivity for PDGF chains than benign ameloblastomas and higher reactivity for platelet-derived growth factor receptors than tooth germs. The expression levels of PDGF chains were significantly higher in follicular ameloblastomas than in plexiform ameloblastomas. Desmoplastic ameloblastomas showed higher expression of IGFs and IGF-IR when compared with other ameloblastoma subtypes. Conclusion:, Expression of IGFs, PDGF, and their receptors in tooth germs and ameloblastic tumors suggests that these growth factor signals contribute to cell proliferation or survival in both normal and neoplastic odontogenic tissues. Expression of these molecules in odontogenic tissues possibly affects interactions with the bone microenvironment during tooth development and intraosseous progression of ameloblastic tumors. Altered expression of the ligands and receptors in ameloblastic tumors may be involved in oncogenesis, malignant potential, and tumor cell differentiation. [source] Embryotropic effect of insulin-like growth factor (IGF)-I and its receptor on development of porcine preimplantation embryos produced by in vitro fertilization and somatic cell nuclear transferMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 1 2005Sue Kim Abstract Insulin-like growth factor (IGF)-I is a receptor-mediated autocrine/paracrine growth/survival factor for mammalian embryo development. The present study investigated the temporal expression and regulation of porcine IGF-I receptor (IGF-IR) mRNA and the role of IGF-I on development of porcine in vitro fertilized (IVF) and somatic cell nuclear transfer (SCNT) embryos. As assessed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), the level of IGF-IR mRNA expression was high in unfertilized oocytes, 2-cell and 4-cell embryos and gradually decreased in 8-cell embryos, morulae, and blastocysts in both IVF and SCNT series. The IVF or SCNT embryos were cultured with 0, 1, 10, 50, or 100 ng/ml IGF-I for 168 hr. Supplementing with 50 ng/ml IGF-I increased blastocyst formation and the number of cells in inner cell masses (ICMs) in both IVF and SCNT embryos. In a second experiment, more blastocysts were obtained when IVF or SCNT embryos were cultured for the first 48 hr or for the entire 168 hr with 50 ng/ml IGF-I compared to culturing without IGF-I for 48 hr or with IGF-I for the last 120 hr or without IGF-I for the entire 168 hr. Treating IVF or SCNT embryos with 50 ng/ml IGF-I significantly up-regulated IGF-IR mRNA compared to untreated control embryos. In conclusion, the present study demonstrated that IGF-IR mRNA is expressed in porcine IVF and SCNT embryos, and that IGF-I improved the developmental competence of IVF and SCNT embryos through its specific receptors. Mol. Reprod. Dev. © 2005 Wiley-Liss, Inc. [source] Age- and site-specific decline in insulin-like growth factor-I receptor expression is correlated with differential growth plate activity in the mouse hindlimbTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 4 2007Maria A. Serrat Abstract The proximal and distal growth plates of the principal long bones do not contribute equally to longitudinal growth. Most forelimb elongation occurs at the shoulder and wrist, while most hindlimb growth occurs at the knee. This study examined whether insulin-like growth factor-I (IGF-I), a potent growth regulator, could underlie this variation via differential receptor expression. The spatiotemporal distribution of the IGF-I receptor (IGF-IR) was mapped in hindlimb growth plates (overall and within regional zones) from immature mice using immunohistochemistry. Growth activity was assessed by size/morphology of the growth plate and proliferating cell nuclear antigen (PCNA) expression. Both IGF-IR and PCNA staining declined considerably with age in the proximal femur and distal tibia (hip and ankle), but expression remained high in the more active distal femur and proximal tibia (knee) throughout growth. Growth plate size decreased with age in all sites, but the absolute and relative decline in IGF-IR in the hips and ankles of older mice indicated a site-specific loss of IGF-I sensitivity in these less active regions. These results suggest that regulation of the IGF-IR may at least partially mediate differential long bone growth, thereby providing a local mechanism for altering skeletal proportions absent modification of systemic hormone levels. Anat Rec, 2007. © 2007 Wiley-Liss, Inc. [source] Insulin-like growth factor-I receptor signal transduction and the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathwayBIOFACTORS, Issue 1 2009Eddy Himpe Abstract The insulin-like growth factor IGF-I is an important fetal and postnatal growth factor, which is also involved in tissue homeostasis via regulation of proliferation, differentiation, and cell survival. To understand the role of IGF-I in the pathophysiology of a variety of disorders, including growth disorders, cancer, and neurodegenerative diseases, a detailed knowledge of IGF-I signal transduction is required. This knowledge may also contribute to the development of new therapies directed at the IGF-I receptor or other signaling molecules. In this review, we will address IGF-I receptor signaling through the JAK/STAT pathway in IGF-I signaling and the role of cytokine-induced inhibitors of signaling (CIS) and suppressors of cytokine signaling (SOCS). It appears that, in addition to the canonical IGF-I signaling pathways through extracellular-regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3K)-Akt, IGF-I also signals through the JAK/STAT pathway. Activation of this pathway may lead to induction of SOCS molecules, well-known feedback inhibitors of the JAK/STAT pathway, which also suppress of IGF-I-induced JAK/STAT signaling. Furthermore, other IGF-I-induced signaling pathways may also be modulated by SOCS. It is conceivable that the effect of these classical inhibitors of cytokine signaling directly affect IGF-I receptor signaling, because they are able to associate to the intracellular part of the IGF-I receptor. These observations indicate that CIS and SOCS molecules are key to cross-talk between IGF-I receptor signaling and signaling through receptors belonging to the hematopoietic/cytokine receptor superfamily. Theoretically, dysregulation of CIS or SOCS may affect IGF-I-mediated effects on body growth, cell differentiation, proliferation, and cell survival. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source] Involvement of ligand occupancy in Insulin-like growth factor-I (IGF-I) induced cell growth in osteoblast like MC3T3-E1 cellsBIOFACTORS, Issue 4 2007Seok-Kwun Kim Abstract Growth factors and matrix proteins regulate the proliferation and differentiation of osteoblasts. The insulin-like growth factor (IGF) system comprises IGF-I, IGF-II, and six high-affinity IGF-binding proteins (IGFBPs). IGFs stimulate cell growth in many types of tissue; IGF-binding proteins regulate cellular actions and can affect cell growth. IGF-I is involved in differentiation, proliferation, and matrix formation in osteoblasts; IGFBP-5 is associated with the extracellular matrix (ECM) and can potentiate the actions of IGF-I. We investigated the effect of ECM proteins on the responses of MC3T3-E1 osteoblast cells to IGF-I and IGFBP-5. In addition, because extracellular signal-regulated kinases 1 and 2 (Erk 1/2) affect cell growth, we evaluated the effects of IGFBP-5 on Erk 1/2 phosphorylation in MC3T3-E1 cells. IGF-I caused an increase in IGFBP-5 expression in cultured MC3T3-E1 cells, and IGF-I plus IGFBP-5 significantly increased cell growth. Likewise, the addition of IGF-I and IGFBP-5 to cultured MC3T3-E1 cells increased the synthesis of the ECM proteins osteopontin (OPN) and thrombospondin-1 (TSP-1), which can bind to ,V,3 integrin receptors on the cell surface. By contrast, the addition of an antibody against ECM proteins inhibited the effects of OPN and TSP-1 on IGFBP-5 expression. The stimulatory effect of IGFBP-5 was mediated via Erk 1/2 activation. These data suggest that IGFBP-5 regulates Erk 1/2 phosphorylation in cultured MC3T3-E1 cells via ECM proteins that may ultimately stimulate the growth of osteoblasts. We determined whether occupation of the ,V,3 integrin receptor affects IGF-I receptor (IGF-IR)-mediated signaling and function in MC3T3-E1 osteoblast cells. Occupation of the ,V,3 integrin receptor with ECM proteins induced IGF-I-stimulated IGF-IR phosphorylation. Conversely, in the presence of the ,V,3-specific disintegrin echistatin, IGF-I-stimulated IGF-IR activation was inhibited. IGF-I-stimulated IGF-IR phosphorylation was accompanied by IRS-1 phosphorylation and MAPK activation. However, these effects were attenuated by echistatin. Thus, occupancy of the ,V,3 disintegrin receptor modulates IGF-I-induced IGF-IR activation and IGF-IR-mediated function in MC 3T3-E1 osteoblasts. [source] Growth failure in a child showing characteristics of Seckel syndrome: possible effects of IGF-I and endogenous IGFBP-3CLINICAL ENDOCRINOLOGY, Issue 2 2002A. Schmidt Summary Seckel syndrome is an autosomal-recessive disorder with a frequency of less than 1/10 000 births in which there are multiple malformations including severe short stature. We report on a patient with Seckel syndrome with a current body height of ,7·5 SDS. Laboratory investigations at the age of 19 months revealed high levels of IGF-I, IGF-II and IGFBP-3. These data suggested the existence of IGF-I resistance possibly caused by impairment of the IGF-I receptor (IGF-IR) or altered IGFBPs. The purpose of this investigation was to examine whether the growth retardation in a Seckel syndrome patient is related to an alteration in the IGF system. Analysis of IGF-IR mRNA of patient's and control fibroblasts by solution hybridization/RNase protection assay did not show differences of IGF-IR transcript expression or size. Affinity crosslinking studies using [125I]-IGF-I showed normal-sized IGF-IR,ligand complexes. Mutation analysis of the complete coding regions of the IGF-I and IGF-IR genes showed no evidence of genetic alterations. Ligand blot analysis of IGFBPs secreted by the patient's fibroblasts showed stronger signals than control cells. Quantitative measurement of IGFBP-3 in cell-conditioned media was performed by radioimmunoassay (RIA) and revealed a sixfold increase when compared to control fibroblasts. We conclude that in this patient with Seckel syndrome and severe growth impairment IGF-I resistance is possibly related to altered production of IGFBP-3. [source] Differential effect of oestradiol and astroglia-conditioned media on the growth of hypothalamic neurons from male and female rat brainsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2000M. J. Cambiasso Abstract To determine whether soluble products from different CNS regions differ in their ability to support oestrogen-stimulated neurite growth, hypothalamic neurons from sexually segregated embryos were cultured with astroglia-conditioned medium (CM) derived from cortex, striatum and mesencephalon, with or without 17-,-oestradiol 100 n m added to the medium. After 48 h in vitro, neurite outgrowth was quantified by morphometric analysis. Astroglia-CM from mesencephalon (a target for the axons of hypothalamic neurons) induced the greatest axogenic response in males and in this case only a neuritogenic effect could be demonstrated for oestradiol. On the other hand, astroglia-CM from regions that do not receive projections from ventromedial hypothalamus inhibited axon growth. A sexual difference in the response of hypothalamic neurons to astroglia-CM and oestradiol was found; growth of neurons from female foetuses was increased by astroglia-CM from mesencephalon, but no neuritogenic effect could be demonstrated for oestradiol in these cultures. Blot immunobinding demonstrated the presence of receptors for neurotrophic factors in cultures of hypothalamic neurons; Western blot analysis of these cultures demonstrated that oestradiol increased the concentration of trkB and IGF-I R,, whereas trkA was not detected and the concentration of trkC was not modified. These results support the hypothesis that target regions produce some factor(s) that stimulate the growth of axons from projecting neurons and further indicate that in the case of males this effect is modulated by oestradiol, perhaps mediated through the upregulation of trkB and IGF-I receptors. [source] Insulin-like growth factor-I increases astrocyte intercellular gap junctional communication and connexin43 expression in vitroJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2003N. David Åberg Abstract Connexin43 (cx43) forms gap junctions in astrocytes, and these gap junctions mediate intercellular communication by providing transport of low-molecular-weight metabolites and ions. We have recently shown that systemic growth hormone increases cx43 in the brain. One possibility was that local brain insulin-like growth factor-I (IGF-I) could mediate the effect by acting directly on astrocytes. In the present study, we examined the effects of direct application of recombinant human IGF-I (rhIGF-I) on astrocytes in primary culture concerning cx43 protein expression and gap junctional communication (GJC). After 24 hr of stimulation with rhIGF-I under serum-free conditions, the GJC and cx43 protein were analyzed. Administration of 30 ng/ml rhIGF-I increased the GJC and the abundance of cx43 protein. Cell proliferation of the astrocytes was not significantly increased by rhIGF-I at this concentration. However, a higher concentration of rhIGF-I (150 ng/ml) had no effect on GJC/cx43 but increased cell proliferation. Because of the important modulatory role of IGF binding proteins (IGFBPs) on IGF-I action, we analyzed IGFBPs in conditioned media. In cultures with a low abundance of IGFBPs (especially IGFBP-2), the GJC response to 30 ng/ml rhIGF-I was 81%, compared with the average of 25%. Finally, as a control, insulin was given in equimolar concentrations. However, GJC was not affected, which suggests that rhIGF-I acted via IGF-I receptors. In summary, the data show that rhIGF-I may increase GJC/cx43, whereas a higher concentration of rhIGF-I,at which stimulation of proliferation occurred,did not affect GJC/cx43. Furthermore, IGFBP-2 appeared to modulate the action of rhIGF-I on GJC in astrocytes by a paracrine mechanism. © 2003 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||