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PubMed1998

Outpatient assessment of residual growth hormone secretion in treated acromegaly with overnight urinary growth hormone excretion, random serum growth hormone and insulin like growth factor-1.

OBJECTIVE: To assess the outpatient investigations, overnight urinary growth hormone (uGH) excretion, random serum GH and insulin like growth factor 1 (IGF-1), and GH indices from the oral glucose tolerance test (OGTT) (fasting, nadir and mean GH), as measures of mean GH secretion in treated acromegaly, in comparison with a GH day series, which served as a gold standard. DESIGN: Prospective cross-sectional study, with patients admitted to a metabolic ward for the following investigations: random GH, IGF-1, 6 point GH day series (day 1), 9 h timed overnight uGH excretion, OGTT with GH response (day 2). Agreements between the mean GH during the day series and the other outcome measures, and the diagnostic performance of the latter, for the presence or absence of active acromegaly (mean GH during day series > or = 5 or < 5 mU/l, respectively) were determined. PATIENTS: 26 patients with treated acromegaly (11 with inactive acromegaly off drug therapy). MEASUREMENTS: Serum GH and uGH were measured by immunoradiometric assays and IGF-1 by radioimmunoassay. RESULTS: Agreements with the mean GH during the day series were perfect for the nadir GH during the OGTT with a 2 mU/l cutoff (Cohen's kappa (kappa) = 1, P < 0.00001), almost perfect for the fasting and mean GH throughout the OGTT (both kappa = 0.92, P < 0.0001) and random GH (kappa = 0.85, P < 0.0001), and substantial for the nadir GH with a 5 mU/l cutoff (kappa = 0.77, P < 0.0001), IGF-1 (kappa = 0.62, P < 0.001) and overnight uGH excretion (kappa = 0.61, P = 0.002). Nadir GH with a 2 mU/l cutoff was completely accurate for diagnosing the presence or absence of active acromegaly (positive and negative predictive values (% +/- standard error percentage) 100 +/- 8% and 100 +/- 10%). None of the outpatient tests used alone was an adequate diagnostic test (positive and negative predictive values: overnight uGH excretion -86 +/- 10% and 75 +/- 13%; random GH -100 +/- 11% and 85 +/- 11%; IGF-1 -92 +/- 10% and 71 +/- 13%) and so combinations of tests were assessed. The best was overnight uGH excretion plus random GH (positive and negative predictive values 88 +/- 9% and 100 +/- 12%). Using all three outpatient investigations, the positive predictive value of three raised results was 100 +/- 13%. CONCLUSIONS: In treated acromegaly, residual GH secretion can be reliably assessed with the OGTT, using standard diagnostic criteria. It can also be assessed on an outpatient basis with overnight uGH excretion and random GH, as direct measures, and IGF-1. If these are all normal, active acromegaly is excluded. Three raised results denote active acromegaly, and one or two raised results would need further investigation with a GH day series.

Acromegaly↗
PubMed1991

Growth hormone secretion and the therapeutic effects of human growth hormone: first Japanese results of the Kabi Pharmacia International Growth Study/International Cooperative Growth Study.

Data for a total of 942 new cases of hypopituitarism, out of 3493 patients treated with recombinant human growth hormone (GH) for more than 1 year, have been analysed. The mean peak GH correlated well with clinical variables related to growth and was considered to be a good index of GH secretory capacity. Mean peak GH was correlated inversely with obesity (r = -0.253, p less than 0.01). The lower the height velocity before treatment, the mean peak GH and the height SDS, the greater was the therapeutic effect achieved. The patients with mean peak GH less than or equal to 5 ng/ml were defined as having complete GH deficiency (GHD), and those with a mean peak GH of 5-10 ng/ml as having partial GHD. The clinical entity of GH neurosecretory dysfunction could not be identified from either the clinical variables examined or the therapeutic effect. The appearance of GH antibody was considered to be of no clinical significance because its incidence and titre were both low.

Body Height↗
PubMed1988

Heparin-binding growth factor/prostatropin attenuates inhibition of rat prostate tumor epithelial cell growth by transforming growth factor type beta.

Normal rat prostate epithelial cell growth requires both epidermal growth factor and heparin-binding growth factor/prostatropin. In contrast, epithelial cells derived from the transplantable Dunning R3327H rat tumor require either epidermal growth factor or heparin-binding growth factor/prostatropin. Transforming growth factor type beta inhibited normal epithelial cell growth. Transforming growth factor beta inhibited epidermal growth factor-dependent growth of tumor epithelial cells, independent of epidermal growth factor concentrations. Transforming growth factor beta increased the effective dose of heparin-binding growth factor type 1 required to support tumor epithelial cell growth by 10-fold but saturating levels of heparin-binding growth factor type 1 (290 pM) completely attenuated the inhibitory effect of transforming growth factor beta. These results suggest that prostate tumor epithelial cells may escape the inhibitory effect of transforming growth factor beta as a consequence of alteration of the concurrent requirement for both epidermal growth factor (or homologues) and heparin-binding growth factors.

Animals↗
PubMed1999

The role of transforming growth factor-beta, insulin-like growth factor I, and basic fibroblast growth factor in distraction osteogenesis of the mandible.

Distraction osteogenesis is a viable method for regenerating large amounts of bone. In contrast to fracture healing, the mode of bone formation in distraction osteogenesis is primarily intramembranous ossification. The basic biology of the process is still not well understood. The growth factor cascade is likely to play an important role in distraction. This study examines the growth factor cascade in a lengthened ovine mandible model. Twenty-four animals were divided into four groups with varying rates of distraction (1, 2, 3, and 4 mm/day). A unilateral distractor at the angle of the mandible was used. The mandibles were lengthened to 24 mm and fixed for a period of 5 weeks, after which the animals were killed. The sections were probed for transforming growth factor-beta, basic fibroblast growth factor, and insulin-like growth factor I. The growth factors studied were present in all four groups. Transforming growth factor-beta, basic fibroblast growth factor, and insulin-like growth factor I were present in both the bony matrix of the sections and the cytoplasm of the cells, osteoblasts, and a small number of mesenchymal cells. The sections obtained from groups distracted at faster rates showed stronger presence of the growth factors examined by more intense staining. In fracture healing, the localization of transforming growth factor-beta in stage I of healing corresponded with the precise region of intramembranous ossification in stage II. Diffuse presence of transforming growth factor-beta throughout the lengthened region corresponded with the process of intramembranous ossification observed in distraction. In fracture healing, insulin-like growth factor I and basic fibroblast growth factor have been shown to promote proliferation and differentiation of osteoblasts from precursor cells. The intense presence of insulin-like growth factor I and basic fibroblast growth factor in the distracted region may account for osteoblast proliferation and formation from precursor mesenchymal cells. Mechanical strain has been shown to increase the expression of transforming growth factor-beta and insulin-like growth factor I. Distraction may serve as a source of mechanical strain, which may explain, in part, the expression of these growth factors, particularly in the faster groups.

Animals↗
PubMed1995

Inhibition of proliferation of human cerebral meningioma cells by suramin: effects on cell growth, cell cycle phases, extracellular growth factors, and PDGF-BB autocrine growth loop.

The growth of human cerebral meningiomas depends on various growth factors, including epidermal growth factor (EGF), transforming growth factor (TGF)-alpha and TGF-beta, platelet-derived growth factor (PDGF)-BB, insulin-like growth factor (IGF)-I and IGF-II, and acidic and basic fibroblast growth factors. The latter three have been shown to form autocrine loops that are thought to be a major component of uncontrolled growth in meningioma tissue. Suramin is known to prevent binding of a variety of growth factors to their receptors in mammalian tissue, thus abolishing para- and/or autocrine-mediated cell growth. The authors therefore tested the effect of suramin on the proliferation of cultured human meningioma cells. Suramin (10(-5) to 10(-4) M) significantly inhibited the growth of meningioma cells in culture. The maximum effect observed was with the higher dose (10(-4) M), which resulted in a 40% to 70% reduction in cellular proliferation. This effect was observed in all 15 tumor samples studied and was confirmed by [3H]thymidine uptake. In studies using DNA flow cytometry, suramin inhibited meningioma cell proliferation in five tumor samples by arresting cells in the S and G2/M phases of the cell cycle. Growth factor (EGF, IGF-I, and PDGF-BB)-induced cell proliferation was completely abolished in five tumor samples when 10(-4) M suramin was applied to meningioma cells. Western blot analysis of three tumor samples showed that the intracellular PDGF-BB content of meningioma cells was significantly reduced after treating the cells with 10(-4) M suramin. Binding of iodinated growth factors (that is, [125I]EGF, [125I]IGF-I, and [125I]PDGF-BB) to their receptor sites was prevented by suramin in a dose-dependent manner in 10 meningioma membrane fractions. Lowering of the intracellular PDGF content and prevention of extracellular growth factor receptor binding demonstrates that suramin disrupts autocrine loops and paracrine growth stimulation in meningioma tissue. These data provide evidence that growth of cerebral meningiomas in culture is strongly inhibited by suramin at a concentration of 10(-4) M. Suramin acts as a scavenger neutralizing exogenous growth factors; thus it can interrupt autocrine loops and paracrine stimulation of human meningioma cell growth. The evidence favors suramin as a therapeutic option for controlling meningioma proliferation in patients with inoperable and recurrent high-grade meningiomas.

Blotting, Western↗
PubMed2000

G1 kinases and transforming growth factor-beta signaling are associated with a growth pattern switch in diabetes-induced renal growth.

BACKGROUND: Diabetes mellitus-induced nephromegaly is thought to involve both hyperplastic and hypertrophic proximal tubule cell growth. The temporal relationship between these growth patterns and the mechanisms that mediate them are unknown. METHODS: Renal growth was assayed in isolated renal proximal tubules harvested from diabetic rats. Diabetes mellitus was induced by streptozotocin. RESULTS: Following the induction of a diabetic state, there was a progressive increase in the kidney:body weight ratio. This was associated with an increase in 5-bromo-2-deoxyuridine incorporation (marker for hyperplastic cell growth) at day 2, which returned to baselines levels by day 4, and an increase in the protein:DNA ratio (marker for hypertrophic cell growth), which was clearly evident by day 10. Thus, diabetes-induced proximal tubule growth involved an initial hyperplastic, followed by a hypertrophic, growth period. During the hyperplastic growth period, both cdk4/cyclin D (cyclin D) and cdk2/cyclin E (cyclin E) kinase activities were increased. The switch between the growth periods was associated with continued activation of cyclin D, but inhibition of cyclin E kinase. The reduction in cyclin E kinase activity correlated with a reduction in cdk2/cyclin E complex abundance and an increased abundance of cyclin kinase inhibitors in cdk2/cyclin E complexes that did form. Also associated with the switch in growth patterns was a change in transforming growth factor-beta (TGF-beta) receptor expression. During the hyperplastic growth period, TGF-beta receptor II expression was decreased, while during the hypertrophic growth period, there was both a return of receptor II expression to baseline levels and increased expression of receptor I. Consistent with an increase in TGF-beta signaling during hypertrophy, there was an increase in Smad 2/3 protein expression and an increase in the abundance of Smad 2/4 complexes. CONCLUSIONS: Diabetes-induced proximal tubule growth involves an initial hyperplastic growth period that switches to a hypertrophic growth period within a couple of days. The pattern of G1 kinase activity associated with the growth pattern switch demonstrates that the hypertrophy is mediated by a cell cycle-dependent mechanism. Regulation of TGF-beta receptor expression and signaling activity through the Smad protein cascade possibly plays a role in the growth pattern switch.

Animals↗
PubMed1999

Growth hormone and insulin-like growth factor-I therapy promote protein deposition and growth in dexamethasone-treated piglets.

BACKGROUND: Dexamethasone treatment facilitates the weaning of premature infants from mechanical ventilation but impairs protein homeostasis, lean tissue deposition, and growth. The current study was conducted to investigate whether dexamethasone mediates these effects by reducing protein synthesis or elevating protein breakdown, and whether adjuvant growth hormone+/-insulin-like growth factor-I therapy can attenuate such effects. METHODS: Piglets (n = 24) were randomized to placebo, a tapered course of dexamethasone (0.5, 0.3, 0.2 mg/kg per day for 5, 5 and 4 days each, respectively), dexamethasone + growth hormone 0.1 mg/kg per day, or dexamethasone + growth hormone + insulin-like growth factor-I 0.1 mg/kg per day for 14 days. On day 13, 15N-glycine was administered as a single oral dose, and urine was collected at timed intervals during the subsequent 48 hours. RESULTS: Total urinary N and cumulative 15N excretion were higher in all dexamethasone groups than in control subjects. Protein synthesis was suppressed, whereas protein breakdown was unaltered by dexamethasone. Adjunctive growth hormone+/-insulin-like growth factor-I therapy enhanced protein synthesis, but only combined therapy improved net protein gain compared with dexamethasone alone. Higher circulating insulin-like growth factor-I may have mediated the greater net protein gain. Blood urea nitrogen was elevated in all dexamethasone-treated groups at days 6 and 11 but was normalized by day 15 with adjunctive growth hormone+/-insulin-like growth factor-I. From a functional perspective, both adjunctive growth hormone and growth hormone+/-insulin-like growth factor-I partially attenuated the dexamethasone-induced reduction in weight and length gain but not in whole body lean and fat mass. CONCLUSION: Adjunctive growth hormone+/-insulin-like growth factor-I therapy partially reverses the dexamethasone-induced reduction in protein synthesis, resulting in improved growth when given concurrently with a low tapering dose of dexamethasone.

Animals↗
PubMed1983

Circulating growth factor studies in growth plate versus resting cartilage in vitro. II. Recognition of growth factors in rat serum.

The growth-promoting effects of GH can be explained in part by the mediation of somatomedins/insulin-like growth factors (IGFs). However, large quantities of the IGFs are required to stimulate growth in vivo, and in some conditions, IGF levels may correlate poorly with GH levels and growth status. These observations suggest that other circulating factors may also be important for growth. We have examined the growth-promoting activity in rat serum, as assessed by stimulation of sulfate and/or thymidine uptake by resting and growth plate cartilage (osteochondral junction) from hypophysectomized rats in vitro. Although stimulation by a low molecular weight somatomedin fraction (approximately 5,000-12,000) accounted for about 90% of serum stimulation of sulfate uptake by resting cartilage, it explained only about 60% of stimulation of the growth plate. Growth plate and resting cartilage appeared equally insensitive to insulin, but the growth plate exhibited reduced sensitivity to inhibitor(s) in diabetic rat serum. Fractionation of normal rat serum by gel filtration at neutral pH revealed comparable stimulation of growth plate and resting cartilage by high molecular weight factors, presumably somatomedins bound to carrier proteins. After gel filtration at acid pH, both growth plate and resting cartilage responded to somatomedins with molecular weights from 5,000-12,000. However, the growth plate also responded to a 12,000-22,000 mol wt factor [Sephadex G-75; 5 X 120 cm; sulfate uptake, 68 +/- 16% above buffer (mean +/- SEM); P less than 0.01] which did not affect resting cartilage (sulfate uptake, 27 +/- 21% above buffer; P = NS). Levels of both the low and higher molecular weight factors were reduced in the serum of hypophysectomized rats. We conclude that circulating growth-promoting activity includes both the low molecular weight somatomedins and a higher molecular weight growth plate growth factor which is not recognized by resting cartilage. Use of the osteochondral junction assay system may permit elucidation of the regulation and nature of this growth factor.

Animals↗
PubMed1989

Inhibition of epidermal growth factor/transforming growth factor-alpha-stimulated cell growth by a synthetic peptide.

Estrogen-stimulated growth of the human mammary adenocarcinoma cell line MCF-7 is significantly inhibited by monoclonal antibodies to the epidermal growth factor (EGF) receptor that act as antagonists of EGF's mitogenic events by competing for high-affinity EGF receptor binding sites. These antibodies likewise inhibit the EGF or transforming growth factor-alpha (TGF-alpha)-stimulated growth of these MCF-7 cells. An analogous pattern of specific EGF or TGF-alpha growth inhibitory activity was obtained using a synthetic peptide analog encompassing the third disulfide loop region of TGF-alpha, but containing additional modifications designed for increased membrane affinity [( Ac-D-hArg(Et)2(31),Gly32,33]HuTGF-alpha(31-43)NH2). The growth factor antagonism by this synthetic peptide was specific in that it inhibited EGF, TGF-alpha, or estrogen-stimulated growth of MCF-7 cells but did not inhibit insulin-like growth factor-1 (IGF-1)-stimulated cell growth. Altogether, these results suggest that a significant portion of the estrogen-stimulated growth of these MCF-7 cells is mediated in an autocrine/paracrine manner by release of EGF or TGF-alpha-like growth factors. The TGF-alpha peptide likewise inhibited EGF- but not fibroblast growth factor (FGF)- or platelet-derived growth factor (PDGF)-stimulated growth of NIH-3T3 cells in completely defined media; but had no effect on growth or DNA synthesis of G0-arrested cells, nor did it effect growth of NR-6 cells, which are nonresponsive to EGF. Although this synthetic peptide did not directly compete with EGF for cell surface receptor binding, it exhibited binding to a cell surface component (followed by internalization), which likewise was not competed by EGF. The peptide did not directly inhibit EGF-stimulated phosphorylation of the EGF receptor, nor did it inhibit phosphorylation of an exogenous substrate, angiotensin II, by activated EGF receptor. The TGF-alpha peptide did, however, affect the structure of laminin as manifested by laminin self-aggregation; this affect on laminin may, in turn, have a modulatory effect on EGF-mediated cell growth.

Adenocarcinoma↗
PubMed1994

Keratinocyte growth factor receptor ligands induce transforming growth factor alpha expression and activate the epidermal growth factor receptor signaling pathway in cultured epidermal keratinocytes.

Epidermal growth factor receptor (EGFR) ligands are fundamental regulators of epithelial growth, differentiation, and neoplastic transformation. In addition to being potent mitogens for murine epidermal keratinocytes in vitro, transforming growth factor alpha (TGF alpha) and EGF elicit distinctive changes in keratin expression: Ca(2+)-mediated induction of the differentiation-specific keratins K1 and K10 is blocked, while simple epithelial keratins K8 and K18 are expressed aberrantly (C. Cheng et al., Cell Growth, & Differ., 4: 317-327, 1993). We have evaluated several additional growth factors to determine the specificity of this response for EGFR ligands. TGF alpha, keratinocyte growth factor (KGF), and acidic fibroblast growth factor (aFGF), but not basic fibroblast growth factor (bFGF) or insulin-like growth factor type I, block Ca(2+)-mediated expression of K1 while inducing K8. Since KGF and aFGF (but not bFGF) are ligands for the KGF receptor (KGFR), we explored the possibility that the TGF alpha/EGFR pathway is an intermediary in signaling through the KGFR. TGF alpha mRNA was increased in cells treated with KGF, aFGF, or TGF alpha but not bFGF or insulin-like growth factor type I. Similar changes were detected at the protein level; TGF alpha in conditioned medium (CM) from control, KGF-, TGF alpha-, and aFGF-treated cultures was 54 (+/- 8, SEM), 365 (+/- 50), 146 (+/- 20), and 120 (+/- 50) pg/ml, respectively. KGF and TGF alpha also increased expression of cell-associated TGF alpha measured in keratinocyte lysates. KGF increased TGF alpha secretion and mRNA levels in human as well as mouse keratinocytes. CM from KGF-treated cultures stimulated cell growth when added to cultures of normal keratinocytes. Preincubation with neutralizing antibodies to both TGF alpha and KGF, but not KGF antibody alone, blocked cell growth in cultures treated with KGF CM, suggesting that the predominant keratinocyte mitogen in KGF CM is TGF alpha. In support of this hypothesis, treatment of keratinocytes for 5 min with either KGF CM or purified TGF alpha resulted in EGFR autophosphorylation. Furthermore, after approximately 24 h, KGF as well as TGF alpha induced EGFR down-regulation based on Western blot analysis and 125I-EGF binding. Induction of TGF alpha in KGF-treated keratinocytes, coupled to activation and down-modulation of the EGFR, suggests that TGF alpha may be a proximal effector of KGF action for at least certain aspects of epidermal growth and differentiation.

Animals↗
PubMedDate not supplied

Epidermal growth factor and keratinocyte growth factor differentially regulate epidermal migration, growth, and differentiation.

Various growth factors such as epidermal growth factor and keratinocyte growth factor have been reported to promote wound closure and epidermal regeneration. In the present study epidermis reconstructed on de-epidermized dermis was used to investigate the effects of epidermal growth factor and keratinocyte growth factor on keratinocyte proliferation, migration and differentiation. Our results show that epidermal growth factor supplemented cultures share many of the features which are observed during regeneration of wounded epidermis: a thickening of the entire epidermis, an enhanced rate of proliferation and migration, and an increase in keratin 6, keratin 16, skin-derived antileukoproteinase, involucrin and transglutaminase 1 expression. The increase in transglutaminase 1 protein is accompanied by an increase in the amount of active transglutaminase 1 enzyme. Surprisingly no increase in keratin 17 is observed. Prolonging the culture period for more than two weeks results in rapid senescence and aging of the cultures. In contrast, keratinocyte growth factor supplemented cultures have a tissue architecture that is similar to healthy native epidermis and remains unchanged for at least 4 weeks of air-exposure. The rate of proliferation and the expression of keratins 6, 16 and 17, skin-derived antileukoproteinase, involucrin and transglutaminase 1 is similar to that found in healthy epidermis and furthermore keratinocyte migration does not occur. When the culture medium is supplemented with a combination of keratinocyte growth factor and a low concentration of epidermal growth factor, skin-derived antileukoproteinase, involucrin and keratins 6, 16 and 17 expression is similar to that found in cultures supplemented with keratinocyte growth factor alone and in healthy epidermis. Only high transglutaminase 1 expression remains similar to that observed in cultures supplemented with epidermal growth factor alone. Our results show that the regulation of keratinocyte growth, migration and differentiation depends on the availability of these growth factors. Epidermal growth factor may play a dominant early role in wound healing by stimulating keratinocyte proliferation and migration while keratinocyte growth factor may play a role later in the repair process by stabilizing epidermal turnover and barrier function.

Cell Division↗
PubMed2005

Gene transfers of vascular endothelial growth factor-A, vascular endothelial growth factor-B, vascular endothelial growth factor-C, and vascular endothelial growth factor-D have no effects on atherosclerosis in hypercholesterolemic low-density lipoprotein-receptor/apolipoprotein B48-deficient mice.

BACKGROUND: The role of vascular endothelial growth factors (VEGFs) in large arteries has been proposed to be either vasculoprotective or proatherogenic. Because VEGF family members are used for human therapy, it is important to know whether they could enhance atherogenesis. We tested the effects of the members of the VEGF gene family on atherogenesis in LDL-receptor/apolipoprotein (apo) B48 double-knockout (LDLR/apoB48) mice using systemic adenoviral gene transfer. METHODS AND RESULTS: Six groups of LDLR/apoB48-deficient mice (n=110) were kept 3 months on a Western-type diet. After 6 weeks of diet, mice were injected via tail vein with recombinant adenoviruses expressing VEGF-A, -B, -C, or -D or LacZ (1 x 10(9) PFU) or rhVEGF-A protein (2 microg/kg) and euthanized 6 weeks later. Also, older mice (n=36) were injected after 4 months on the diet and euthanized 6 weeks later (total time on the diet, 22 weeks) to evaluate the effects of gene transfers on the development of more mature lesions. Aortas were analyzed for the presence of macroscopic lesions, cross-sectional lesion areas, neovascularization, and cellular composition of the lesions. All groups had equivalent plasma cholesterol and triglyceride levels. Gene transfers with recombinant adenoviruses or administration of rhVEGF-A protein had no statistically significant effects on en face atherosclerotic lesions in the aorta, cross-sectional lesion area, neovascularization, or cellular composition of the lesions. CONCLUSIONS: This study shows no proatherogenic effects of adenovirus-mediated gene transfers of VEGF-A, -B, -C, or -D in the LDLR/apoB48-deficient hypercholesterolemic mice, in which lipoprotein profile and atherosclerosis closely resemble those in human disease.

Adenoviridae↗
PubMed1994

Several insulin-like growth factor-I analogues and complexes of insulin-like growth factors-I and -II with insulin-like growth factor-binding protein-3 fail to mimic the effect of growth hormone upon lactation in the rat.

Lactation was suppressed in rats using a combined treatment of bromocriptine (to reduce prolactin concentrations) and a specific antiserum to rat GH administered twice daily for 2 days. When milk production had ceased, as determined by litter weight loss and the absence of milk in the stomachs of pups, attempts were made to reinitiate lactation using prolactin, GH, insulin-like growth factor-I (IGF-I) precomplexed to recombinant human IGF-binding protein-3 (hIGFBP-3) or IGF-I plus IGF-II precomplexed to hIGFBP-3. Despite the fact that all treatments except prolactin led to increases in serum IGFs and IGFBP-3, only prolactin and GH provoked the reinitiation of milk production as determined by increased litter weight gain, milk in the stomach of pups and a significant increase in the weight of the mammary glands. Since the mammary gland has been shown to produce IGFBPs which may inhibit IGF action we also tested three IGF-I analogues, R3-IGF-I, Long-IGF-I and Long-R3-IGF-I. R3-IGF-I has a single amino acid substitution (Glu to Arg) at position 3 whereas Long-IGF-I has a 13 amino acid N-terminal extension. These modifications dramatically reduce the ability of these analogues to bind to IGFBPs although they remain active at the IGF-I receptor. Such IGF analogues would therefore be expected to be active irrespective of the production of inhibitory IGFBPs. However, none was effective in reinitiating lactation, even at doses which have been shown to be biologically effective in terms of nitrogen retention.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Insulin-like growth factors, insulin-like growth factor-binding proteins, insulin-like growth factor-binding protein-3 protease, and growth hormone-binding protein in lipodystrophic human immunodeficiency virus-infected patients.

Human immunodeficiency virus (HIV)-lipodystrophy is associated with impaired growth hormone (GH) secretion. It remains to be elucidated whether insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), IGFBP-3 protease, and GH-binding protein (GHBP) are abnormal in HIV-lipodystrophy. These parameters were measured in overnight fasting serum samples from 16 Caucasian males with HIV-lipodystrophy (LIPO) and 15 Caucasian HIV-infected males without lipodystrophy (NONLIPO) matched for age, weight, duration of HIV infection, and antiretroviral therapy. In LIPO, abdominal fat mass and insulin concentration were increased (>90%, P < .01) and insulin sensitivity (Log10ISI(composite)) was decreased (-50%, P < .001). Total and free IGF-I, IGF-II, IGFBP-3, and IGFBP-3 protease were similar between groups (all P > .5), whereas, in LIPO, IGFBP-1 and IGFBP-2 were reduced (-36%, P < .05 and -50%, P < .01). In pooled groups, total IGF-I, free IGF-I, total IGF-II, and IGFBP-3, respectively, correlated inversely with age (all P < .01). In pooled groups, IGFBP-1 and IGFBP-2 correlated positively with insulin sensitivity (age-adjusted all P < .05). IGFBP-3 protease correlated with free IGF-I in pooled groups (r(p) = 0.47, P < .02), and in LIPO (r(p) = 0.71, P < .007) controlling for age, total IGF-I, and IGFBP-3. GHBP was increased, whereas GH was decreased in LIPO (all P < .05). GH correlated inversely with GHBP in pooled groups (P < .05). Taken together the similar IGFs and IGFBP-3 concentrations between study groups, including suppressed GH, and increased GHBP in LIPO, argue against GH resistance of GH-sensitive tissues in LIPO compared with NONLIPO; however, this notion awaits examination in dose-response studies. Furthermore, our data suggest that IGFBP-3 protease is a significant regulator of bioactive IGF-I in HIV-lipodystrophy.

Age Factors↗
PubMed1991

Expression of insulin-like growth factor II and receptors for insulin-like growth factor II, insulin-like growth factor I and insulin in isolated and cultured rat hepatocytes.

Insulin-like growth factor II is believed to play an important role in fetal growth and development. The insulin-like growth factor II gene expression is tissue specific and developmentally regulated. We have previously shown an enhanced level of insulin-like growth factor II messenger RNA and protein in human hepatocellular carcinomas. This led to the suggestion that hepatocytes might be involved in insulin-like growth factor II expression. However, previous studies based on in situ hybridization only showed insulin-like growth factor II messenger RNA in liver sinusoidal cells. This paper reports on the analysis of the expression of insulin-like growth factor II and insulin-like growth factor II, insulin-like growth factor I and insulin receptor messenger RNAs in vivo in isolated rat hepatocytes at various stages of development and in vitro in adult rat hepatocytes primary culture. Our study indicates that isolated rat hepatocytes synthesize insulin-like growth factor II messenger RNA with a switch between fetal and adult messenger RNA profiles occurring 21 days after birth. In addition, adult rat hepatocytes in culture expressed insulin-like growth factor II messenger RNA and protein. Insulin-like growth factor II, insulin-like growth factor I and insulin receptor messenger RNAs were also detected. Therefore these results are consistent with the hypothesis that insulin-like growth factor II acts as an autocrine growth factor for hepatocytes in addition to having a paracrine effect. They also indicate that primary culture of hepatocytes is a good model for further studies on insulin-like growth factor II gene regulation.

Animals↗
PubMed1993

Localization of acidic fibroblast growth factor, basic fibroblast growth factor, and heparan sulphate proteoglycan in rat lens: implications for lens polarity and growth patterns.

PURPOSE: Previous research in this laboratory has shown that fibroblast growth factor stimulates lens epithelial explants to proliferate, migrate, and differentiate into fibers in a progressive dose-dependent manner. The lens has distinct compartments where cells proliferate (germinative zone), migrate, or get displaced (equator) and differentiate into fibers (transitional zone). These compartments occur in an anteroposterior spatial sequence and the authors hypothesized that fibroblast growth factor plays a critical role in determining these spatial patterns of lens growth and lens polarity. To investigate this hypothesis the distribution of fibroblast growth factor in the lens was analyzed. METHODS: Immunohistochemistry was used to localize acidic fibroblast growth factor and basic fibroblast growth factor in the cells and capsule of lenses from neonatal, weanling, and adult rats. Because of its functional relationship with fibroblast growth factor, heparan sulphate proteoglycan was also localized in the lens. RESULTS: In all ages examined, cytoplasmic acidic fibroblast growth factor is present in the germinative and transitional zones of the lens and both acidic fibroblast growth factor and basic fibroblast growth factor are present in the capsule. A major finding is the co-localization of fibroblast growth factor and heparan sulphate proteoglycan reactivity in the lens capsule in the form of laminae. These laminae become more prominent as the capsule thickens and differences in arrangement of laminae between anterior, equatorial, and posterior regions of the capsule also become apparent. CONCLUSIONS: The presence of fibroblast growth factor in lens cells and capsule in neonatal, weanling, and adult rats indicates an important role for fibroblast growth factor in lens cell biology. Moreover, the regional distribution of fibroblast growth factor, particularly in the lens cells, indicates that it may influence determination of lens polarity and growth patterns.

Animals↗
PubMedDate not supplied

Effects of androgen, fibroblast growth factors or other various growth factors on growth of Shionogi carcinoma cells in a protein-free medium.

Shionogi carcinoma 115 (SC115) has been accepted for 20 years as an androgen-responsive mouse mammary tumor. We have recently established an androgen-dependent cloned cell line (SC-3) from a SC115 tumor. We found in the present study that the growth of SC-3 cells can be stimulated by 10(-8) M testosterone (up to 100-fold) even in a protein-free medium beginning from plating [Ham's F-12: Eagle's minimum essential medium (1:1, v/v)]. In the protein-free culture, the proliferation of SC-3 cells was also found to be stimulated by acidic or basic fibroblast growth factor (FGF) alone (up to 50-fold) among various growth factors examined such as FGFs, insulin, insulin-like growth factor (IGF)-I, IGF-II, nerve growth factor, platelet-derived growth factor, epidermal growth factor, transforming growth factor (TGF)-alpha and TGF-beta. The testosterone (10(-8) M)- or FGF (10 ng/ml)-induced growth of SC-3 cells was abolished only by TGF-beta (greater than or equal to 1 ng/ml) among various growth factors examined. We show for the first time in this study an androgen-dependent growth of cancer cells (SC-3) in a protein-free medium. In the protein-free medium, growth of SC-3 cells is also stimulated by FGFs, and the androgen- or FGF-induced growth is inhibited only by TGF-beta.

Animals↗
PubMed1995

Transforming growth factor-beta 1 and fibroblast growth factors in rat growth plate.

Chondrocytes in the growth plate progress in an orderly fashion from resting through proliferating to hypertrophic cells. In the region of hypertrophic chondrocytes, the cartilage is invaded by capillary loops and endochondral ossification is initiated. It is currently believed that growth factors may regulate the proliferation and maturation of chondrocytes and the synthesis of extracellular matrix in the growth plate. The ordered sequence of proliferation and differentiation observed in the growth plate provides a unique opportunity to study the role of acidic fibroblast growth factor, basic fibroblast growth factor, and transforming growth factor-beta 1 in the regulation of these processes. In this study, expression of the mRNA of these growth factors was examined using total RNA extracted from the physis and epiphysis of rat tibias. Transforming growth factor-beta 1 mRNA was detected by Northern hybridization. Expression of the genes encoding acidic and basic fibroblast growth factors was demonstrated by polymerase chain reaction amplification. In addition, using polyclonal antibodies against these growth factors, we localized them by immunohistochemical analysis. Strong intracellular staining with a predominantly nuclear pattern was observed in chondrocytes from the proliferating and upper hypertrophic zones. In contrast, chondrocytes in the resting zone stained only faintly for the presence of these growth factors. Some chondrocytes in the resting zone adjacent to the proliferating zone stained with these antibodies, and the antibodies also stained cells in the zone of Ranvier, which regulates latitudinal bone growth. Lastly, the location of transforming growth factor-beta 1 was examined further with use of a polyclonal antipeptide antibody specific for its extracellular epitope.(ABSTRACT TRUNCATED AT 250 WORDS)

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