Osteoblast-specific expression of insulin-like growth factor-1 in bone of transgenic mice induces insulin-like growth factor binding protein-5

Meilan M. Rutter, Edith Markoff, Lisa Clayton, Nagako Akeno, Guisheng Zhao, Thomas Clemens, Steven D. Chernausek

Research output: Contribution to journalArticle

Abstract

The activities of insulin-like growth factors (IGFs) in bone are modulated by a family of binding proteins (IGFBPs) whose physiological roles remain poorly understood. We have previously shown that targeted overexpression of IGF-I in osteoblasts of transgenic (OC-IGF-I) mice stimulates bone formation. In this model, bone formation is markedly but transiently increased in an age-dependent manner, raising the possibility that IGF-I may be influencing IGFBPs to in turn modulate its paracrine actions within bone. We sought to characterize the IGFBPs in normal mouse bone during development and to determine whether osteoblast-targeted overexpression of IGF-I influenced bone IGFBP abundance in vivo. Femoral bone IGFBP content was assessed in control nontransgenic and OC-IGF-I mice by I125-IGF-I ligand and immunoblotting. Bone IGFBP-5 and IGF-I mRNA abundance was determined using real-time reverse transcription (RT)-PCR. Ligand blot of bone extract showed a 30-kDa band, identified as IGFBP-5 by immunoblot, predominated. The abundance of IGFBP-5 declined with age in both control and transgenic bone. Ligand and immunoblot analysis revealed a 5-fold increase in IGFBP-5 protein levels at 3 weeks in transgenic bone (P <0.0001). The elevated IGFBP-5 protein levels were associated with a similar increase in IGF-I mRNA abundance (4-fold, P <0.01) and a significant increase in IGFBP-5 mRNA abundance (1.5-fold). Despite the age-related decline at 6 weeks, IGFBP-5 remained significantly (P <0.01) more abundant in transgenic bone compared to controls. In contrast, bone IGFBP-4 abundance was relatively unchanged by either age or IGF-I overexpression. These studies demonstrate a distinctive developmental pattern of IGFBP-5 content in mouse bone and show that osteoblast-derived IGF-I determines skeletal IGFBP-5 abundance, at least in part by inducing its synthesis. In that IGFBP-5 is thought to stimulate bone formation, directly or via IGF-I action, such changes in bone IGFBP-5 may be important to ensure robust bone acquisition in the early postnatal period.

Original languageEnglish (US)
Pages (from-to)224-231
Number of pages8
JournalBone
Volume36
Issue number2
DOIs
StatePublished - Feb 2005
Externally publishedYes

Fingerprint

Insulin-Like Growth Factor Binding Protein 5
Somatomedins
Osteoblasts
Transgenic Mice
Insulin-Like Growth Factor I
Bone and Bones
Insulin-Like Growth Factor Binding Proteins
Osteogenesis
Ligands
Messenger RNA
Insulin-Like Growth Factor Binding Protein 4
Bone Development
Thigh
Immunoblotting

Keywords

  • Bone formation
  • Insulin-like growth factor (IGF-I)
  • Insulin-like growth factor binding protein (IGFBP)
  • Paracrine regulation
  • Transgenic mice

ASJC Scopus subject areas

  • Physiology
  • Hematology

Cite this

Osteoblast-specific expression of insulin-like growth factor-1 in bone of transgenic mice induces insulin-like growth factor binding protein-5. / Rutter, Meilan M.; Markoff, Edith; Clayton, Lisa; Akeno, Nagako; Zhao, Guisheng; Clemens, Thomas; Chernausek, Steven D.

In: Bone, Vol. 36, No. 2, 02.2005, p. 224-231.

Research output: Contribution to journalArticle

Rutter, Meilan M. ; Markoff, Edith ; Clayton, Lisa ; Akeno, Nagako ; Zhao, Guisheng ; Clemens, Thomas ; Chernausek, Steven D. / Osteoblast-specific expression of insulin-like growth factor-1 in bone of transgenic mice induces insulin-like growth factor binding protein-5. In: Bone. 2005 ; Vol. 36, No. 2. pp. 224-231.
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abstract = "The activities of insulin-like growth factors (IGFs) in bone are modulated by a family of binding proteins (IGFBPs) whose physiological roles remain poorly understood. We have previously shown that targeted overexpression of IGF-I in osteoblasts of transgenic (OC-IGF-I) mice stimulates bone formation. In this model, bone formation is markedly but transiently increased in an age-dependent manner, raising the possibility that IGF-I may be influencing IGFBPs to in turn modulate its paracrine actions within bone. We sought to characterize the IGFBPs in normal mouse bone during development and to determine whether osteoblast-targeted overexpression of IGF-I influenced bone IGFBP abundance in vivo. Femoral bone IGFBP content was assessed in control nontransgenic and OC-IGF-I mice by I125-IGF-I ligand and immunoblotting. Bone IGFBP-5 and IGF-I mRNA abundance was determined using real-time reverse transcription (RT)-PCR. Ligand blot of bone extract showed a 30-kDa band, identified as IGFBP-5 by immunoblot, predominated. The abundance of IGFBP-5 declined with age in both control and transgenic bone. Ligand and immunoblot analysis revealed a 5-fold increase in IGFBP-5 protein levels at 3 weeks in transgenic bone (P <0.0001). The elevated IGFBP-5 protein levels were associated with a similar increase in IGF-I mRNA abundance (4-fold, P <0.01) and a significant increase in IGFBP-5 mRNA abundance (1.5-fold). Despite the age-related decline at 6 weeks, IGFBP-5 remained significantly (P <0.01) more abundant in transgenic bone compared to controls. In contrast, bone IGFBP-4 abundance was relatively unchanged by either age or IGF-I overexpression. These studies demonstrate a distinctive developmental pattern of IGFBP-5 content in mouse bone and show that osteoblast-derived IGF-I determines skeletal IGFBP-5 abundance, at least in part by inducing its synthesis. In that IGFBP-5 is thought to stimulate bone formation, directly or via IGF-I action, such changes in bone IGFBP-5 may be important to ensure robust bone acquisition in the early postnatal period.",
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AU - Clemens, Thomas

AU - Chernausek, Steven D.

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N2 - The activities of insulin-like growth factors (IGFs) in bone are modulated by a family of binding proteins (IGFBPs) whose physiological roles remain poorly understood. We have previously shown that targeted overexpression of IGF-I in osteoblasts of transgenic (OC-IGF-I) mice stimulates bone formation. In this model, bone formation is markedly but transiently increased in an age-dependent manner, raising the possibility that IGF-I may be influencing IGFBPs to in turn modulate its paracrine actions within bone. We sought to characterize the IGFBPs in normal mouse bone during development and to determine whether osteoblast-targeted overexpression of IGF-I influenced bone IGFBP abundance in vivo. Femoral bone IGFBP content was assessed in control nontransgenic and OC-IGF-I mice by I125-IGF-I ligand and immunoblotting. Bone IGFBP-5 and IGF-I mRNA abundance was determined using real-time reverse transcription (RT)-PCR. Ligand blot of bone extract showed a 30-kDa band, identified as IGFBP-5 by immunoblot, predominated. The abundance of IGFBP-5 declined with age in both control and transgenic bone. Ligand and immunoblot analysis revealed a 5-fold increase in IGFBP-5 protein levels at 3 weeks in transgenic bone (P <0.0001). The elevated IGFBP-5 protein levels were associated with a similar increase in IGF-I mRNA abundance (4-fold, P <0.01) and a significant increase in IGFBP-5 mRNA abundance (1.5-fold). Despite the age-related decline at 6 weeks, IGFBP-5 remained significantly (P <0.01) more abundant in transgenic bone compared to controls. In contrast, bone IGFBP-4 abundance was relatively unchanged by either age or IGF-I overexpression. These studies demonstrate a distinctive developmental pattern of IGFBP-5 content in mouse bone and show that osteoblast-derived IGF-I determines skeletal IGFBP-5 abundance, at least in part by inducing its synthesis. In that IGFBP-5 is thought to stimulate bone formation, directly or via IGF-I action, such changes in bone IGFBP-5 may be important to ensure robust bone acquisition in the early postnatal period.

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