Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor

Autores
Wu, Yingjie; Sun, Hui; Basta Pljakic, Jelena; Cardoso, Luis; Kennedy, Oran D.; Jasper, Hector Guillermo; Domene, Horacio Mario; Karabatas, Liliana Margarita; Guida, María Clara; Schaffler, Mitchell B.; Rosen, Clifford J.; Yakar, Shoshana
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKO-HIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1, allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth.
Fil: Wu, Yingjie. University Of New York; Estados Unidos
Fil: Sun, Hui. University Of New York; Estados Unidos
Fil: Basta Pljakic, Jelena. City College of New York; Estados Unidos
Fil: Cardoso, Luis. City College of New York; Estados Unidos
Fil: Kennedy, Oran D.. City College of New York; Estados Unidos
Fil: Jasper, Hector Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina
Fil: Domene, Horacio Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina
Fil: Karabatas, Liliana Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina
Fil: Guida, María Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina
Fil: Schaffler, Mitchell B.. City College of New York; Estados Unidos
Fil: Rosen, Clifford J.. Maine Medical Center Research Institute; Estados Unidos
Fil: Yakar, Shoshana. University Of New York; Estados Unidos
Materia
IGF-1
growth hormone receptor
bone,
micro-computed tomography,
beta-islet,
glucose tolerance.
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/8142
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/8142
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptorWu, YingjieSun, HuiBasta Pljakic, JelenaCardoso, LuisKennedy, Oran D.Jasper, Hector GuillermoDomene, Horacio MarioKarabatas, Liliana MargaritaGuida, María ClaraSchaffler, Mitchell B.Rosen, Clifford J.Yakar, ShoshanaIGF-1growth hormone receptorbone,micro-computed tomography,beta-islet,glucose tolerance.https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKO-HIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1, allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth.Fil: Wu, Yingjie. University Of New York; Estados UnidosFil: Sun, Hui. University Of New York; Estados UnidosFil: Basta Pljakic, Jelena. City College of New York; Estados UnidosFil: Cardoso, Luis. City College of New York; Estados UnidosFil: Kennedy, Oran D.. City College of New York; Estados UnidosFil: Jasper, Hector Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Domene, Horacio Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Karabatas, Liliana Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Guida, María Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Schaffler, Mitchell B.. City College of New York; Estados UnidosFil: Rosen, Clifford J.. Maine Medical Center Research Institute; Estados UnidosFil: Yakar, Shoshana. University Of New York; Estados UnidosWiley2013-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/8142Wu, Yingjie; Sun, Hui; Basta Pljakic, Jelena; Cardoso, Luis; Kennedy, Oran D.; et al.; Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor; Wiley; Journal Of Bone And Mineral Research; 28; 7; 7-2013; 1575-15861523-4681enginfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843230/info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/jbmr.1920/abstractinfo:eu-repo/semantics/altIdentifier/doi/10.1002/jbmr.1920info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:58:12Zoai:ri.conicet.gov.ar:11336/8142instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:58:13.088CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor
title Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor
spellingShingle Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor
Wu, Yingjie
IGF-1
growth hormone receptor
bone,
micro-computed tomography,
beta-islet,
glucose tolerance.
title_short Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor
title_full Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor
title_fullStr Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor
title_full_unstemmed Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor
title_sort Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor
dc.creator.none.fl_str_mv Wu, Yingjie
Sun, Hui
Basta Pljakic, Jelena
Cardoso, Luis
Kennedy, Oran D.
Jasper, Hector Guillermo
Domene, Horacio Mario
Karabatas, Liliana Margarita
Guida, María Clara
Schaffler, Mitchell B.
Rosen, Clifford J.
Yakar, Shoshana
author Wu, Yingjie
author_facet Wu, Yingjie
Sun, Hui
Basta Pljakic, Jelena
Cardoso, Luis
Kennedy, Oran D.
Jasper, Hector Guillermo
Domene, Horacio Mario
Karabatas, Liliana Margarita
Guida, María Clara
Schaffler, Mitchell B.
Rosen, Clifford J.
Yakar, Shoshana
author_role author
author2 Sun, Hui
Basta Pljakic, Jelena
Cardoso, Luis
Kennedy, Oran D.
Jasper, Hector Guillermo
Domene, Horacio Mario
Karabatas, Liliana Margarita
Guida, María Clara
Schaffler, Mitchell B.
Rosen, Clifford J.
Yakar, Shoshana
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv IGF-1
growth hormone receptor
bone,
micro-computed tomography,
beta-islet,
glucose tolerance.
topic IGF-1
growth hormone receptor
bone,
micro-computed tomography,
beta-islet,
glucose tolerance.
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKO-HIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1, allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth.
Fil: Wu, Yingjie. University Of New York; Estados Unidos
Fil: Sun, Hui. University Of New York; Estados Unidos
Fil: Basta Pljakic, Jelena. City College of New York; Estados Unidos
Fil: Cardoso, Luis. City College of New York; Estados Unidos
Fil: Kennedy, Oran D.. City College of New York; Estados Unidos
Fil: Jasper, Hector Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina
Fil: Domene, Horacio Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina
Fil: Karabatas, Liliana Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina
Fil: Guida, María Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina
Fil: Schaffler, Mitchell B.. City College of New York; Estados Unidos
Fil: Rosen, Clifford J.. Maine Medical Center Research Institute; Estados Unidos
Fil: Yakar, Shoshana. University Of New York; Estados Unidos
description States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKO-HIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1, allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth.
publishDate 2013
dc.date.none.fl_str_mv 2013-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/8142
Wu, Yingjie; Sun, Hui; Basta Pljakic, Jelena; Cardoso, Luis; Kennedy, Oran D.; et al.; Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor; Wiley; Journal Of Bone And Mineral Research; 28; 7; 7-2013; 1575-1586
1523-4681
url http://hdl.handle.net/11336/8142
identifier_str_mv Wu, Yingjie; Sun, Hui; Basta Pljakic, Jelena; Cardoso, Luis; Kennedy, Oran D.; et al.; Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor; Wiley; Journal Of Bone And Mineral Research; 28; 7; 7-2013; 1575-1586
1523-4681
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3843230/
info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/jbmr.1920/abstract
info:eu-repo/semantics/altIdentifier/doi/10.1002/jbmr.1920
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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