scholarly journals Regulation of Insulin-Like Growth Factor-Binding Protein-5 by Insulin-Like Growth Factor I and Interleukin-1α in Ovine Articular Chondrocytes*

Endocrinology ◽  
1998 ◽  
Vol 139 (5) ◽  
pp. 2356-2362 ◽  
Author(s):  
Damir Sunic ◽  
Julian D. McNeil ◽  
Timothy E. Rayner ◽  
Dennis L. Andress ◽  
David A. Belford
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Articular Chondrocytes ◽  
Critical Role ◽  
Limited Proteolysis ◽  
Cartilage Matrix ◽  
Proteoglycan Synthesis ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Igf I

Abstract Insulin-like growth factors (IGFs) contribute to the maintenance of the cartilage matrix by stimulating proteoglycan synthesis. In contrast, interleukin-1 (IL-1), an inflammatory cytokine, suppresses the synthesis of proteoglycans. In pathological conditions the chondrocytes’ responsiveness to IGF-I is decreased, and elevated levels of IGF-binding proteins (IGFBPs) have been implicated as a possible cause. The aim of this study was to investigate the effects of IGF-I and IL-1 on IGFBP production by ovine articular chondrocytes (OAC) and the roles of these IGFBPs in the regulation of proteoglycan synthesis. As revealed by Western ligand and immunoblotting, OACs secreted IGFBP-2 and a 24-kDa IGFBP in culture medium under basal conditions. Exposure of the cells to IGF-I for 48 h resulted in the appearance of IGFBP-5 in the medium. Des(1–3)IGF-I, an IGF-I analog with reduced affinity for IGFBPs, also increased the level of IGFBP-5, but to a lesser extent than IGF-I, whereas LR3IGF-I, which has virtually no affinity for IGFBPs, had no effect on IGFBP-5. Furthermore, IGFBP-5 underwent a time-dependent limited proteolysis when incubated with OAC-conditioned medium, degrading into 22- and 16-kDa fragments. The degradation of IGFBP-5 was significantly inhibited by IGF-I, but not by des(1–3)IGF-I or LR3IGF-I. Basic fibroblast growth factor, transforming growth factor-β, and platelet-derived growth factor had no effect on OAC IGFBPs. However, IL-1α increased the IGFBP-5 level in a dose-dependent manner, showing maximum activity at 200 U/ml. Furthermore, IL-1α, but not IGF-I, induced IGFBP-5 messenger RNA expression, as assessed by Northern blot analysis. Coincubation of IGF-I with IL-1α resulted in a substantially increased IGFBP-5 protein level, suggesting a synergism between the mechanisms of action of these two factors. Des(1–3)IGF-I and LR3IGF-I were 10 times more potent than IGF-I in stimulating proteoglycan synthesis, indicating inhibition of IGF-I activity by endogenous IGFBPs. IL-1α reduced the IGF-I bioactivity, but had no effect on the activities of the IGF-I analogs, thus implying that locally produced IGFBPs, particularly IGFBP-5, which was substantially increased when IGF-I and IL-1α were coincubated, mediated the reduction of the IGF-I activity. Our results demonstrate that IGF-I and IL-1α synergistically increase the level of IGFBP-5 in OAC by inhibiting the proteolysis and stimulating the expression of IGFBP-5, respectively. Furthermore, the attenuation of IGF-I-stimulated proteoglycan synthesis by IL-1α in OAC appears to be mediated by chondrocyte IGFBPs. We conclude that locally produced IGFBPs, in particular IGFBP-5, may play a critical role in the regulation of cartilage matrix degradation in inflammatory and degenerative arthritides.

Insulin-like growth factor II and transforming growth factor β1 regulate insulin-like growth factor I secretion in mouse bone cells

1991 ◽  
Vol 125 (5) ◽  
pp. 538-546 ◽  
Author(s):  
Florence A. Tremollieres ◽  
Donna D. Strong ◽  
David J. Baylink ◽  
Subburaman Mohan
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Bone Cells ◽  
Transforming Growth Factor Β1 ◽  
Component Part ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Igf I

Abstract. Bone cells in culture produce and respond to growth factors, suggesting that local as well as systemic factors regulate bone volume. Previous studies have shown that IGF-I is the major mitogen produced by mouse bone cells and that its production is regulated by systemic agents such as PTH and estrogen. Because IGF-II and transforming growth factor β1 have been shown, respectively, to increase and decrease MC3T3-E1 cell proliferation, we tested the hypothesis that these two growth factors modulate the production of IGF-I in this cell line. In order to eliminate artifacts owing to IGF binding proteins, conditioned media samples were pretreated with IGF-II before measurement of IGF-I by RIA. After 24 h treatment at a density of 2.5× 104 cells/cm2, IGF-II (10 μg/l) induced a 2.2-fold increase compared with untreated control (9.5±1.5 vs 4.2±0.44 pg/μg protein, p<0.001), whereas transforming growth factor β1 (1 μg/l) caused a 66% decrease in IGF-I production (1.5±0.3 vs 4.2±0.44 pg/μg protein, p<0.001). Both IGF-II and transforming growth factor β1 regulated IGF-I production in a dose-, time- and cell density-dependent manner. The lowest effective doses for IGF-II and transforming growth factor β1 were 1 and 0.01 μg/l, respectively. These results support a role for IGF-II and transforming growth factor β1 as potent modulators of IGF-I secretion in mouse bone cells. Furthermore, regulation of IGF-I production in bone cells by IGF-II and transforming growth factor β1 in an autocrine/paracrine manner could represent a component part of the mechanism whereby the skeleton locally adapts in reponse to external stimuli.

scholarly journals Calcium Input Potentiates the Transforming Growth Factor (TGF)-β1-dependent Signaling to Promote the Export of Inorganic Pyrophosphate by Articular Chondrocyte

2011 ◽  
Vol 286 (22) ◽  
pp. 19215-19228 ◽  
Author(s):  
Frederic Cailotto ◽  
Pascal Reboul ◽  
Sylvie Sebillaud ◽  
Patrick Netter ◽  
Jean-Yves Jouzeau ◽  
...  
Keyword(s):  
Growth Factor ◽  
Promoter Activity ◽  
Transforming Growth Factor ◽  
Articular Chondrocytes ◽  
Specific Protein ◽  
Dependent Manner ◽  
Articular Chondrocyte ◽  
Experimental Conditions ◽  
Inorganic Pyrophosphate ◽  
Tgf Β1

Transforming growth factor (TGF)-β1 stimulates extracellular PPi (ePPi) generation and promotes chondrocalcinosis, which also occurs secondary to hyperparathyroidism-induced hypercalcemia. We previously demonstrated that ANK was up-regulated by TGF-β1 activation of ERK1/2 and Ca2+-dependent protein kinase C (PKCα). Thus, we investigated mechanisms by which calcium could affect ePPi metabolism, especially its main regulating proteins ANK and PC-1 (plasma cell membrane glycoprotein-1). We stimulated articular chondrocytes with TGF-β1 under extracellular (eCa2+) or cytosolic Ca2+ (cCa2+) modulations. We studied ANK, PC-1 expression (quantitative RT-PCR, Western blotting), ePPi levels (radiometric assay), and cCa2+ input (fluorescent probe). Voltage-operated Ca2+-channels (VOC) and signaling pathways involved were investigated with selective inhibitors. Finally, Ank promoter activity was evaluated (gene reporter). TGF-β1 elevated cCa2+ and ePPi levels (by up-regulating Ank and PC-1 mRNA/proteins) in an eCa2+ dose-dependent manner. TGF-β1 effects were suppressed by cCa2+ chelation or L- and T-VOC blockade while being mostly reproduced by ionomycin. In the same experimental conditions, the activation of Ras, the phosphorylation of ERK1/2 and PKCα, and the stimulation of Ank promoter activity were affected similarly. Activation of SP1 (specific protein 1) and ELK-1 (Ets-like protein-1) transcription factors supported the regulatory role of Ca2+. SP1 or ELK-1 overexpression or blockade experiments demonstrated a major contribution of ELK-1, which acted synergistically with SP1 to activate Ank promoter in response to TGF-β1. TGF-β1 promotes input of eCa2+ through opening of L- and T-VOCs, to potentiate ERK1/2 and PKCα signaling cascades, resulting in an enhanced activation of Ank promoter and ePPi production in chondrocyte.

scholarly journals Evidence for modulation of osteocalcin containing gamma-carboxyglutamic acid residues synthesis by insulin-like growth factor-I and vitamin K2 in human osteosarcoma cell line MG-63

1998 ◽  
pp. 443-448 ◽  
Author(s):  
Y Kudo ◽  
M Iwashita ◽  
Y Takeda ◽  
T Muraki
Keyword(s):  
Growth Factor ◽  
Vitamin K2 ◽  
Osteosarcoma Cell ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Concentration Dependent Manner ◽  
Factor I ◽  
Carboxyglutamic Acid ◽  
Igf I ◽  
Growth Factor I

The effect of insulin-like growth factor-I (IGF-I) and 2-methyl-3-all-trans-tetraphenyl-1,4-naphtoquinone (vitamin K2) on the synthesis of osteocalcin containing gamma-carboxyglutamic acid (Gla) residues which is the physiologically relevant form in bone metabolism was studied in cultured human osteoblast-like (MG-63) cells. Both IGF-I and vitamin K2 stimulated 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-induced osteocalcin containing Gla secretion in a concentration-dependent manner. This stimulatory effect of IGF-I and vitamin K2 was additive. Vitamin K2-enhanced osteocalcin containing Gla secretion was selectively suppressed by 3-(alpha-acetonyl-benzyl)-4-hydroxy-coumarin (warfarin). The stimulatory effect of IGF-I was completely abolished by the presence of cycloheximide; in contrast the effect of vitamin K2 was still observed in the presence of cycloheximide. Treatment of MG-63 cells with IGF-I caused an approximately 2.2-fold increase in osteocalcin mRNA levels (determined by reverse transcription-polymerase chain reaction). Vitamin K2 had no effect on either the stimulation of mRNA level by IGF-I or the basal level. IGF-I-stimulated osteocalcin containing Gla secretion was inhibited by one of its binding proteins (insulin-like growth factor binding protein-4) in a concentration-dependent manner. These findings suggest that the modes of action of IGF-I and vitamin K2 on 1.25(OH)2D3-induced osteocalcin containing Gla secretion in MG-63 cells are different.

Effects of insulin-like growth factor-I and insulin on the in-vitro uptake of sulphate by eel branchial cartilage: evidence for the presence of independent hepatic and pancreatic sulphation factors

1992 ◽  
Vol 133 (2) ◽  
pp. 211-219 ◽  
Author(s):  
C. Duan ◽  
T. Hirano
Keyword(s):  
Growth Factor ◽  
Coho Salmon ◽  
Bovine Insulin ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Cartilage Growth ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

ABSTRACT The possible roles of insulin-like growth factor-I (IGF-I) and insulin in regulating cartilage growth were studied in the teleost Anguilla japonica. Significant sulphation activity was found in the extracts of pancreas, liver and muscle, but not in those of kidney, intestine or spleen. The hepatic sulphation activity was significantly decreased by hypophysectomy or by fasting for 14 days, suggesting that this activity is regulated by pituitary function and nutritional status. Northern blot analysis revealed that the hepatic IGF-I mRNA in the eel consists of a major 4·0 kb band. This mRNA was GH-dependent and was significantly decreased by fasting for 14 days. On the other hand, fasting for 14 days had no significant effect on pancreatic sulphation activity. Pancreatic extracts from both intact and hypophysectomized eels exhibited equally significant stimulating activity. Addition of bovine or human insulin (1–250 ng/ml) to the culture medium significantly stimulated sulphate uptake in a dose-dependent manner. Teleost (coho salmon) insulin was as effective as bovine insulin. Bovine insulin was more effective than IGF-I at lower concentrations (1–4 ng/ml) but less effective at higher concentrations (10–250 ng/ml). These results indicate that not only IGF-I but also insulin are likely to be involved in the regulation of cartilage growth in the eel. Journal of Endocrinology (1992) 133, 211–219

The effect of insulin-like growth factor (IGF) and of human serum on steps in proteoglycan synthesis

1981 ◽  
Vol 97 (4) ◽  
pp. 503-507 ◽  
Author(s):  
Avivah Silbergeld ◽  
Rivka Mamet ◽  
Zvi Laron ◽  
Zvi Nevo
Keyword(s):  
Growth Factor ◽  
Human Serum ◽  
Chondroitin Sulphate ◽  
Proteoglycan Synthesis ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Intact Cartilage ◽  
Normal Human ◽  
Sugar Chains ◽  
Dose Dependent

Abstract. Embryonic chick pelvic cartilages were incubated in the presence of insulin like growth factor (IGF) (1–100 μU/ml), as well as normal human serum (5%), with radiolabelled precursors of proteoglycan (PG) synthesis: L-[3-3H]serine, D-[6-3H]glucosamine and [35S]Na2SO4. IGF alone (1–15 μU/ml), stimulated in a dose-dependent manner D-[6-3H]glucosamine incorporation into tissue-bound and soluble isolated glycosaminoglycan (GAG) chains. L-[3-3H]serine incorporation into PG molecules was not stimulated by IGF (1–100 μU/ml), despite the increase in the uptake of this precursor into intact cartilage. [35S]Na2SO4 incorporation was unaffected by IGF. Serum promoted the uptake of all three precursors into tissue-bound glycosaminoglycans. It was postulated that IGF could stimulate proteoglycan synthesis not only by elongating existing chondroitin sulphate chains but also by increased synthesis of other sugar chains e.g. keratan sulphate and oligosaccharides.

scholarly journals Local versus systemic control of bone and skeletal muscle mass by components of the transforming growth factor-β signaling pathway

2021 ◽  
Vol 118 (33) ◽  
pp. e2111401118
Author(s):  
Yewei Liu ◽  
Adam Lehar ◽  
Renata Rydzik ◽  
Harshpreet Chandok ◽  
Yun-Sil Lee ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Muscle Mass ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
The Body ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Mineral Density

Skeletal muscle and bone homeostasis are regulated by members of the myostatin/GDF-11/activin branch of the transforming growth factor-β superfamily, which share many regulatory components, including inhibitory extracellular binding proteins and receptors that mediate signaling. Here, we present the results of genetic studies demonstrating a critical role for the binding protein follistatin (FST) in regulating both skeletal muscle and bone. Using an allelic series corresponding to varying expression levels of endogenous Fst, we show that FST acts in an exquisitely dose-dependent manner to regulate both muscle mass and bone density. Moreover, by employing a genetic strategy to target Fst expression only in the posterior (caudal) region of the animal, we show that the effects of Fst loss are mostly restricted to the posterior region, implying that locally produced FST plays a much more important role than circulating FST with respect to regulation of muscle and bone. Finally, we show that targeting receptors for these ligands specifically in osteoblasts leads to dramatic increases in bone mass, with trabecular bone volume fraction being increased by 12- to 13-fold and bone mineral density being increased by 8- to 9-fold in humeri, femurs, and lumbar vertebrae. These findings demonstrate that bone, like muscle, has an enormous inherent capacity for growth that is normally kept in check by this signaling system and suggest that the extent to which this regulatory mechanism may be used throughout the body to regulate tissue mass may be more significant than previously appreciated.

scholarly journals Insulin-like growth factor I and insulin induce adipogenic-related gene expression in fetal brown adipocyte primary cultures

1996 ◽  
Vol 319 (2) ◽  
pp. 627-632 ◽  
Author(s):  
Teresa TERUEL ◽  
Angela M VALVERDE ◽  
Manuel BENITO ◽  
Margarita LORENZO
Keyword(s):  
Growth Factor ◽  
Fatty Acid Synthase ◽  
Brown Adipocyte ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Brown Adipocytes ◽  
Factor I ◽  
Fetal Rat ◽  
Igf I ◽  
Growth Factor I

Fetal rat brown adipocytes show high-affinity binding sites for both insulin-like growth factor I (IGF-I) and insulin. Cell culture for 24 h in the presence of IGF-I or insulin, independently, up-regulated the mRNA expression of adipogenic-related genes, such as fatty acid synthase (FAS), glycerol-3-phosphate dehydrogenase and insulin-regulated glucose transporter Glut4, and down-regulated the expression of phosphoenolpyruvate carboxykinase mRNA in a dose-dependent manner. Moreover, both IGF-I and insulin increased the FAS gene transcription rate at 2 h, producing a time-dependent accumulation of FAS mRNA. Furthermore IGF-I or insulin increased glucose uptake and lipid content throughout the 24 h culture period. Our results suggest that both IGF-I and insulin are major signals involved in initiating and/or maintaining the expression of adipogenic-related genes in fetal rat brown adipocytes.

Transforming growth factor β1, pituitary-specifi c transcriptional factor 1 and insulin-like growth factor I gene polymorphisms in the population of the Poltava clay chicken breed: association with productive traits

2015 ◽  
Vol 2 (1) ◽  
pp. 67-72
Author(s):  
R. Kulibaba ◽  
A. Tereshchenko
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Transcriptional Factor ◽  
Meat Production ◽  
Insulin Like Growth Factor ◽  
Chicken Breed ◽  
Igf I ◽  
Productive Traits ◽  
Tgf Β1

Aim. To investigate the gene polymorphisms of transforming growth factor β1 (TGF-β1), pituitary-specifi c transcriptional factor 1 (PIT-1) and insulin-like growth factor I (IGF-I) in the population of Poltava clay chicken breed, used for egg and meat production, and to analyze the association of different genotypes for each locus with productive traits. Methods. Genotyping of the chickens was performed using the polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP). Results. Transforming growth factor TGF-β1, pituitary-specifi c transcriptional factor PIT-1, and insulin-like growth factor IGF-I were shown to be polymorphic in the studied populations. The association between genotypes by the loci TGF-β1 and PIT-1 and the indices of egg and meat production of chickens was demonstrated. Conclusions. The data on the genetic structure of the population of Poltava clay chicken breed by loci TGF-β1 and PIT-1 is recommended for the targeted selection of chickens to produce offspring with desirable genotypes, which will, in addition to classical breeding methods, reveal the productive potential of chickens as effi ciently as possible.

Cytokines modulate the sensitivity of human fibroblasts to stimulation with insulin-like growth factor-I (IGF-I) by altering endogenous IGF-binding protein production

1993 ◽  
Vol 137 (1) ◽  
pp. 151-159 ◽  
Author(s):  
M. E. Yateman ◽  
D. C. Claffey ◽  
S. C. Cwyfan Hughes ◽  
V. J. Frost ◽  
J. A. H. Wass ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Human Fibroblasts ◽  
Dermal Fibroblasts ◽  
Insulin Like Growth Factor ◽  
Tnf Α ◽  
Igf I ◽  
Dose Dependent ◽  
Tgf Β1 ◽  
Igfbp 3

ABSTRACT Human dermal fibroblasts produce a number of insulin-like growth factor-binding proteins (IGFBPs) including the main circulating form, IGFBP-3. It has been suggested that the regulation of IGFBP secretion may play a major role in modulating insulin-like growth factor (IGF) bioactivity. We have quantified the effects of two cytokines, transforming growth factor-β1 (TGF-β1) and tumour necrosis factor-α (TNF-α) which have opposing actions on fibroblast IGFBP-3 production, and examined their subsequent role in IGF-I mitogenesis. TGF-β1 caused a dose-dependent increase in IGFBP-3 in serum-free fibroblast-conditioned media. TGF-β1 (1 μg/l) resulted in immunoreactive IGFBP-3 levels reaching 286·5 ± 22·4% of control after 20 h, the increase being confirmed by Western ligand blot. TNF-α caused a dose-dependent decrease in fibroblast IGFBP-3 secretion, 1 μg TNG-α/l reducing IGFBP-3 levels to 32·1 ± 11·% of control. This effect was not due to cytotoxicity and was not cell-density-dependent. Fibroblast proliferation was examined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric cytochemical bioassay. The addition of IGF-I resulted in dose-dependent growth stimulation after 48 h, the effective range being 20–100 μg/l. The IGF-I analogue Long-R3-IGF-I which has little affinity for the IGFBPs was approximately 20-fold more potent in this assay, and was unaffected by exogenous IGFBP-3. While the addition of 1 μg TGF-β1/l to increasing doses of IGF-I resulted in a fourfold decrease in mitogenic sensitivity to the IGF-I, no such effect was seen with Long-R3-IGF-I. Conversely, 1 μg TNF-α/l increased fibroblast IGF-I sensitivity five-fold, an effect not observed with the IGF-I analogue. Such data suggest that endogenous IGFBP-3 inhibits IGF-I bioactivity and that the regulation of IGF mitogenesis by TGF-β1 and TNF-α can occur via local IGFBP modulation. This may represent a mechanism by which complex growth signals are co-ordinated in vivo. Journal of Endocrinology (1993) 137, 151–159

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