Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF-1.
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ABSTRACT:
SUBMITTER: Dobie R
PROVIDER: S-EPMC4949688 | biostudies-literature | 2015 Nov
REPOSITORIES: biostudies-literature
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Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF-1.
Dobie Ross R Ahmed Syed F SF Staines Katherine A KA Pass Chloe C Jasim Seema S MacRae Vicky E VE Farquharson Colin C
Journal of cellular physiology 20151101 11
Growth hormone (GH) signaling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver derived insulin like-growth factor-1 (IGF-1) for endochondral growth has recently been challenged. Here, we investigate linear growth in Suppressor of Cytokine Signaling-2 (SOCS2) knockout mice, which have enhanced growth despite normal systemic GH/IGF-1 levels. Wild-type embryonic ex vivo metat ...[more]
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Project description:The suppressor of cytokine signalling (Socs2(-/-))-knockout mouse is characterised by an overgrowth phenotype due to enhanced GH signalling. The objective of this study was to define the Socs2(-/-) bone phenotype and determine whether GH promotes bone mass via IGF1-dependent mechanisms. Despite no elevation in systemic IGF1 levels, increased body weight in 4-week-old Socs2(-/-) mice following GH treatment was associated with increased cortical bone area (Ct.Ar) (P<0.01). Furthermore, detailed bone analysis of male and female juvenile and adult Socs2(-/-) mice revealed an altered cortical and trabecular phenotype consistent with the known anabolic effects of GH. Indeed, male Socs2(-/-) mice had increased Ct.Ar (P<0.05) and thickness associated with increased strength. Despite this, there was no elevation in hepatic Igf1 expression, suggesting that the anabolic bone phenotype was the result of increased local GH action. Mechanistic studies showed that in osteoblasts and bone of Socs2(-/-) mice, STAT5 phosphorylation was significantly increased in response to GH. Conversely, overexpression of SOCS2 decreased GH-induced STAT5 signalling. Although an increase in Igf1 expression was observed in Socs2(-/-) osteoblasts following GH, it was not evident in vivo. Igf1 expression levels were not elevated in response to GH in 4-week-old mice and no alterations in expression was observed in bone samples of 6-week-old Socs2(-/-) mice. These studies emphasise the critical role of SOCS2 in controlling the local GH anabolic bone effects. We provide compelling evidence implicating SOCS2 in the regulation of GH osteoblast signalling and ultimately bone accrual, which maybe via mechanisms that are independent of IGF1 production in vivo.
| S-EPMC4166176 | biostudies-literature
Project description:ContextNon-alcoholic fatty liver disease (NAFLD) is a leading causes of liver-related morbidity and mortality. While data on acromegaly, a state of chronic growth hormone (GH)/insulin-like growth factor I (IGF-I) excess, suggest an inverse relationship with intrahepatic lipid (IHL) content, less is known about the impact of the GH/IGF-I axis on IHL, lipid composition, and phosphor metabolites in individuals without disorders of GH secretion.ObjectiveThe aim was to investigate the relation between activity of the GH/IGF-I axis and IHL content and phosphor metabolism.MethodsWe performed a cross-sectional study in 59 otherwise metabolically healthy individuals (30 females), of which 16 met the criteria of NAFLD with IHL of ≥5.6%. The GH/IGF-I axis was evaluated in a fasting state and during an oral glucose tolerance test (OGTT). Insulin sensitivity was estimated by validated indices. IHL, lipid composition (unsaturation index), and phosphate metabolites were analyzed by using 1H/31P magnetic resonance spectroscopy.ResultsIn the overall cohort (40.6 ± 15 years; body mass index: 24.5 ± 3 kg/m2; IGF-I: 68.0 ± 17% upper limit of normal), fasting GH (R = -0.31; P = .02), GH during oral glucose tolerance test (R = -0.51; P < .01), and IGF-I (R = -0.28; P = .03) inversely correlated with IHL. GH levels during OGTT were significantly lower in NAFLD than in controls (47.7 [22; 143] ng/mL/min vs 16.8 [7; 32] ng/mL/min; P = .003). GH/IGF-I axis activity correlated with lipid composition and with phosphor metabolites. In multiple regression analysis, the GH/IGF-I axis activity was a strong predictor for IHL and lipid composition independent from insulin sensitivity.ConclusionGH/IGF-I axis activity impacts hepatic lipid and phosphate metabolism in individuals without disorders in GH secretion. Lower GH axis activity is associated with higher IHL and an unfavorable lipid composition, probably mediated by changes in hepatic energy metabolism.
| S-EPMC10505545 | biostudies-literature
Project description:BackgroundSex steroids influence GH secretion in complex ways.HypothesisAnalyses in a low sex-steroid milieu will help unveil the effects of age and other nonsteroidal regulators on GH secretion.ContextThe study was conducted in a tertiary medical center.SubjectsThe study group included 13 healthy young men and 12 healthy older men.MethodsWe used GnRH agonist-induced down-regulation of testosterone and estradiol secretion, followed by consecutive infusion of l-arginine and GHRH or GHRP-2, to test secretagogue efficacies.OutcomesWe measured basal and pulsatile GH secretion.ResultsDuring experimental testosterone/estradiol deprivation, older (57 +/- 1.7 yr) men maintained: 1) 6.8-fold less pulsatile GH secretion (P < 0.001); and 2) 2-fold lower maximal GH responses to GHRH (P = 0.0065) and GHRP-2 (P = 0.022) than young (23 +/- 1.1 yr old) individuals. Stepwise forward-selection regression analyses identified: 1) abdominal visceral fat as a dominant negative predictor of both GHRH (R(2) = 0.49; P = 0.001) and GHRP-2 (R(2) = 0.38; P = 0.005) efficacies; and 2) fasting IGF-I concentration as a major positive correlate of GHRH (R(2) = 0.52; P < 0.001) and GHRP-2 (R(2) = 0.31; P = 0.018) efficacies. Unstimulated pulsatile GH secretion was jointly correlated with IGF-I and IGFBP-3 (P = 0.039).ConclusionMeasures of body composition (abdominal visceral fat) and pulsatile GH action (IGF-I) explain up to one half of interindividual variability in the efficacies of GHRH and GHRP-2 in sex steroid-depleted men. Accordingly, normative ranges for maximal single peptide-stimulated GH secretion in short-term hypogonadal states should incorporate the influence of these determinants as well as age.
| S-EPMC2690428 | biostudies-literature
Project description:The relative contributions of circulating and locally produced IGF-I in growth remain controversial. The majority of circulating IGF-I is produced by the liver, and numerous mouse models have been developed to study the endocrine actions of IGF-I. A common drawback to these models is that the elimination of circulating IGF-I disrupts a negative feedback pathway, resulting in unregulated GH secretion. We generated a mouse with near total abrogation of circulating IGF-I by disrupting the GH signaling mediator, Janus kinase (JAK)2, in hepatocytes. We then crossed these mice, termed JAK2L, to GH-deficient little mice (Lit). Compound mutant (Lit-JAK2L) and control (Lit-Con) mice were treated with equal amounts of GH such that the only difference between the two groups was hepatic GH signaling. Both groups gained weight in response to GH but there was a reduction in the final weight of GH-treated Lit-JAK2L vs. Lit-Con mice. Similarly, lean mass increased in both groups, but there was a reduction in the final lean mass of Lit-JAK2L vs. Lit-Con mice. There was an equivalent increase in skeletal length in response to GH in Lit-Con and Lit-JAK2L mice. There was an increase in bone mineral density (BMD) in both groups, but Lit-JAK2L had lower BMD than Lit-Con mice. In addition, GH-mediated increases in spleen and kidney mass were absent in Lit-JAK2L mice. Taken together, hepatic GH-dependent production of IGF-I had a significant and nonredundant role in GH-mediated acquisition of lean mass, BMD, spleen mass, and kidney mass; however, skeletal length was dependent upon or compensated for by locally produced IGF-I.
| S-EPMC3125097 | biostudies-literature
Project description:BackgroundSuppressor of cytokine signaling (SOCS) proteins comprise a protein family, which has initially been described as STAT induced inhibitors of the Jak/Stat pathway. Recent in vivo and in vitro studies suggest that SOCS proteins are also implicated in cancer. The STAT5 induced IGF-I acts as an endocrine and para/autocrine growth and differentiation factor in mammary gland development. Whereas high levels of circulating IGF-I have been associated with increased cancer risk, the role of autocrine acting IGF-I is less clear. The present study is aimed to elucidate the clinicopathological features associated with SOCS1, SOCS2, SOCS3, CIS and IGF-I expression in breast cancer.MethodsWe determined the mRNA expression levels of SOCS1, SOCS2, SOCS3, CIS and IGF-I in 89 primary breast cancers by reverse transcriptase PCR. SOCS2 protein expression was further evaluated by immuno-blot and immunohistochemistry.ResultsSOCS2 expression inversely correlated with histopathological grade and ER positive tumors exhibited higher SOCS2 levels. Patients with high SOCS2 expression lived significantly longer (108.7 vs. 77.7 months; P = 0.015) and high SOCS2 expression proved to be an independent predictor for good prognosis (HR = 0.45, 95% CI 0.23 - 0.91, P = 0.026). In analogy to SOCS2, high IGF-I expression was an independent predictor for good prognosis in the entire patient cohort. In the subgroup of patients with lymph-node negative disease, high IGF-I was a strong predictor for favorable outcome in terms of overall survival and relapse free survival (HR = 0.075, 95% CI 0.014 - 0.388, P = 0.002).ConclusionThis is the first report on the favorable prognostic value of high SOCS2 expression in primary mammary carcinomas. Furthermore a strong association of high IGF-I expression levels with good prognosis was observed especially in lymph-node negative patients. Our results suggest that high expression of the STAT5 target genes SOCS2 and IGF-I is a feature of differentiated and less malignant tumors.
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Project description:ObjectiveTo investigate the concordance/discordance of IGF-1 and peak stimulated GH in identifying subjects with reduced GH secretion and to determine the physiological significance of any discordance in obese subjects.Design, patients and methods95 obese and 43 normal weight men and women underwent measurement of IGF-1 and GH stimulation testing with GH releasing hormone (GHRH)-arginine. Reduced IGF-1 and GH secretion were defined using pre-determined cut-points. Cardiovascular disease risk was determined by measuring carotid intima-media thickness (cIMT). In a second study, IGF-1 was measured in 52 obese men and women who underwent GH stimulation testing and overnight frequent blood sampling. The association of IGF-1 and peak stimulated GH with parameters of endogenous GH secretion was assessed.Results60% of obese subjects had normal IGF-1 and peak stimulated GH while 8.4% of obese subjects had reduced IGF-1 and GH secretion. Discordance rate for IGF-1 and peak GH was 31.6%. Subjects with both low IGF-1 and low peak GH had the highest cIMT, while subjects with both normal IGF-1 and peak GH had the lowest cIMT. Subjects with reduction in either IGF-1 or peak GH, had intermediate cIMT (P=0.02). IGF-1 and peak stimulated GH were associated with maximum and mean overnight serum GH and GH AUC as well as maximum peak mass and median pulse mass. Peak stimulated GH, but not IGF-1, was also associated with nadir overnight serum GH concentration and basal GH secretion.ConclusionPeak stimulated GH and IGF-1 demonstrate significant discordance in identification of subjects with reduced GH secretion in obesity. Subjects with reduction of either IGF-1 or peak GH had higher cIMT compared to subjects with both normal IGF-1 and peak GH. Subjects with reductions in both IGF-1 and peak GH had the highest cIMT. Peak GH, compared to IGF-1, has broader associations with various parameters of endogenous GH secretion which support its utility in identifying those with reduced GH secretion.
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Project description:Dysfunction and destruction of pancreatic islet ?-cells is a hallmark of diabetes. Better understanding of cell signals regulating ?-cell growth and antiapoptosis will allow development of therapeutic strategies for diabetes by preservation and expansion of ?-cell mass. GH and IGF-I share a complicated physiological relationship and have both been implicated in ?-cell function. GH and IGF-I exert their biological effects through binding to respective receptors (GHR and IGF-IR) and subsequently engaging downstream signaling pathways. However, their collaborative roles in modulation of ?-cell mass and the underlying molecular mechanisms remain poorly understood. In this study, we demonstrate that cultured ?-cells are appealing systems for investigating potential GH-IGF-I signaling cross talk. We uncover that GH specifically promotes formation of a protein complex containing GHR, Janus kinase 2 (a nonreceptor kinase coupled to GH/GHR signaling), and IGF-IR. More importantly, GH and IGF-I synergistically activate both signal transducer and activator of transcription 5 and Akt pathways. Concomitantly, ?-cells proliferate more robustly and are better protected from serum deprivation-induced apoptosis when exposed to GH and IGF-I in combination vs. GH or IGF-I alone. The augmented proliferative effects by GH and IGF-I are confirmed in isolated islets. Taken together, our findings strongly suggest that there exists a novel signaling relationship between GH/GHR and IGF-I/IGF-IR systems in ?-cells, i.e. IGF-IR may serve as a proximal component of GH/GHR signaling, contributing to enhancement of ?-cell mass and function. In support of this, IGF-IR knockdown in ?-cells resulted in the desensitization of acute GH-induced signal transducer and activator of transcription 5 activation.
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Project description:Insulin-like growth factor-I (IGF-I) levels, which are reduced by age, and cortical bone dimensions are major determinants of fracture risk in elderly subjects. Inactivation of liver-derived circulating IGF-I results in reduced periosteal bone expansion in young and older mice. In mice with lifelong depletion of IGF-I in osteoblast lineage cells, the long bones display reduced cortical bone width. However, it has not previously been investigated whether inducible inactivation of IGF-I locally in bone in adult/old mice affects the bone phenotype. Adult tamoxifen-inducible inactivation of IGF-I using a CAGG-CreER mouse model (inducible IGF-IKO mice) substantially reduced IGF-I expression in bone (-55%) but not in liver. Serum IGF-I and body weight were unchanged. We used this inducible mouse model to assess the effect of local IGF-I on the skeleton in adult male mice, avoiding confounding developmental effects. After tamoxifen-induced inactivation of the IGF-I gene at 9 months of age, the skeletal phenotype was determined at 14 months of age. Computed tomography analyses of tibia revealed that the mid-diaphyseal cortical periosteal and endosteal circumferences and calculated bone strength parameters were decreased in inducible IGF-IKO mice compared with controls. Furthermore, 3-point bending showed reduced tibia cortical bone stiffness in inducible IGF-IKO mice. In contrast, the tibia and vertebral trabecular bone volume fraction was unchanged. In conclusion, inactivation of IGF-I in cortical bone with unchanged liver-derived IGF-I in older male mice resulted in reduced radial growth of cortical bone. This suggests that not only circulating IGF-I but also locally derived IGF-I regulates the cortical bone phenotype in older mice.
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Project description:Human genetic defects in the growth hormone (GH)-IGF-I axis affecting the IGF system present with growth failure as their principal clinical feature. This is usually associated with GH insensitivity (GHI) presenting in childhood as severe or mild short stature. Dysmorphic features and metabolic abnormalities may also be present. The field of GHI due to mutations affecting GH action has evolved rapidly since the first description of the extreme phenotype related to homozygous GH receptor (GHR) mutations in 1966. A continuum of genetic, phenotypic, and biochemical abnormalities can be defined associated with clinically relevant defects in linear growth. The mechanisms of the GH-IGF-I axis in the regulation of normal human growth is discussed followed by descriptions of mutations in GHR, STAT5B, IGF-I, IGFALS, IGF1R, and GH1 defects causing bio-inactive GH or anti-GH antibodies. These GH-IGF-I axis defects are associated with a range of clinical, and hormonal characteristics. An up-dated approach to the clinical assessment of the patient with GHI focusing on investigation of the GH-IGF-I axis and relevant molecular studies contributing to the identification of causative genetic defects is also discussed.
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Project description:Noonan syndrome (NS) is a disorder characterized by a typical facial gestalt, congenital heart defects, variable cognitive deficits, skeletal defects, and short stature. NS is caused by germline pathogenic variants in genes coding proteins with a role in the RAS/mitogen-activated protein kinase signaling pathway, and it is typically associated with substantial genetic and clinical complexity and variability. Short stature is a cardinal feature in NS, with evidence indicating that growth hormone (GH) deficiency, partial GH insensitivity, and altered response to insulin-like growth factor I (IGF-1) are contributing events for growth failure in these patients. Decreased IGF-I, together with low/normal responses to GH pharmacological provocation tests, indicating a variable presence of GH deficiency/resistance, in particular in subjects with pathogenic PTPN11 variants, are frequently reported. Nonetheless, short- and long-term studies have demonstrated a consistent and significant increase in height velocity (HV) in NS children and adolescents treated with recombinant human GH (rhGH). While the overall experience with rhGH treatment in NS patients with short stature is reassuring, it is difficult to systematically compare published data due to heterogeneous protocols, potential enrolment bias, the small size of cohorts in many studies, different cohort selection criteria and varying durations of therapy. Furthermore, in most studies, the genetic information is lacking. NS is associated with a higher risk of benign and malignant proliferative disorders and hypertrophic cardiomyopathy, and rhGH treatment may further increase risk in these patients, especially as dosages vary widely. Herein we provide an updated review of aspects related to growth, altered function of the GH/IGF axis and cell response to GH/IGF stimulation, rhGH treatment and its possible adverse events. Given the clinical variability and genetic heterogeneity of NS, treatment with rhGH should be personalized and a conservative approach with judicious surveillance is recommended. Depending on the genotype, an individualized follow-up and close monitoring during rhGH treatments, also focusing on screening for neoplasms, should be considered.
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