Akt promotes BMP2-mediated osteoblast differentiation and bone development

Aditi Mukherjee, Peter Rotwein

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

Signaling through the IGF-I receptor by locally synthesized IGF-I or IGF-II is crucial for normal skeletal development and for bone remodeling. Osteogenesis is primarily regulated by bone morphogenetic proteins (BMPs), which activate gene expression programs driven by bone-specific transcription factors. In a mesenchymal stem cell model of osteoblast commitment and differentiation controlled by BMP2, we show that an inhibitor of PI3-kinase or a dominant-negative Akt were as potent in preventing osteoblast differentiation as the IGF binding protein IGFBP5, whereas a Mek inhibitor was ineffective. Conversely, an adenovirus encoding an inducible-active Akt was able to overcome the blockade of differentiation caused by IGFBP5 or the PI3-kinase inhibitor, and could restore normal osteogenesis. Inhibition of PI3-kinase or Akt did not block BMP2-mediated signaling, because the Smad-responsive genes Sox9 and JunB were induced normally under all experimental conditions. When activated during different stages of osteoblast maturation, dominant-negative Akt prevented accumulation of bone-specific alkaline phosphatase and reduced mineralization, and more significantly inhibited the longitudinal growth of metatarsal bones in primary culture by interfering with both chondrocyte and osteoblast development and function. We conclude that an intact IGF-induced PI3-kinase-Akt signaling cascade is essential for BMP2-activated osteoblast differentiation and maturation, bone development and growth, and suggest that manipulation of this pathway could facilitate bone remodeling and fracture repair.

Original languageEnglish (US)
Pages (from-to)716-726
Number of pages11
JournalJournal of Cell Science
Volume122
Issue number5
DOIs
StatePublished - Mar 1 2009

Fingerprint

Bone Development
Osteoblasts
Phosphatidylinositol 3-Kinases
Bone Remodeling
Osteogenesis
Bone and Bones
Insulin-Like Growth Factor Binding Proteins
IGF Type 1 Receptor
Bone Morphogenetic Proteins
Insulin-Like Growth Factor II
Metatarsal Bones
Bone Fractures
Chondrocytes
Mesenchymal Stromal Cells
Insulin-Like Growth Factor I
Adenoviridae
Alkaline Phosphatase
Transcription Factors
Gene Expression
Growth

Keywords

  • Akt
  • Bone development
  • Bone morphogenetic factors
  • Insulin-like growth factors
  • Osteoblast
  • PI3-kinase-Akt pathway

ASJC Scopus subject areas

  • Cell Biology

Cite this

Akt promotes BMP2-mediated osteoblast differentiation and bone development. / Mukherjee, Aditi; Rotwein, Peter.

In: Journal of Cell Science, Vol. 122, No. 5, 01.03.2009, p. 716-726.

Research output: Contribution to journalArticle

Mukherjee, Aditi ; Rotwein, Peter. / Akt promotes BMP2-mediated osteoblast differentiation and bone development. In: Journal of Cell Science. 2009 ; Vol. 122, No. 5. pp. 716-726.
@article{704b72ef2ad14598be57f0c6fe78df32,
title = "Akt promotes BMP2-mediated osteoblast differentiation and bone development",
abstract = "Signaling through the IGF-I receptor by locally synthesized IGF-I or IGF-II is crucial for normal skeletal development and for bone remodeling. Osteogenesis is primarily regulated by bone morphogenetic proteins (BMPs), which activate gene expression programs driven by bone-specific transcription factors. In a mesenchymal stem cell model of osteoblast commitment and differentiation controlled by BMP2, we show that an inhibitor of PI3-kinase or a dominant-negative Akt were as potent in preventing osteoblast differentiation as the IGF binding protein IGFBP5, whereas a Mek inhibitor was ineffective. Conversely, an adenovirus encoding an inducible-active Akt was able to overcome the blockade of differentiation caused by IGFBP5 or the PI3-kinase inhibitor, and could restore normal osteogenesis. Inhibition of PI3-kinase or Akt did not block BMP2-mediated signaling, because the Smad-responsive genes Sox9 and JunB were induced normally under all experimental conditions. When activated during different stages of osteoblast maturation, dominant-negative Akt prevented accumulation of bone-specific alkaline phosphatase and reduced mineralization, and more significantly inhibited the longitudinal growth of metatarsal bones in primary culture by interfering with both chondrocyte and osteoblast development and function. We conclude that an intact IGF-induced PI3-kinase-Akt signaling cascade is essential for BMP2-activated osteoblast differentiation and maturation, bone development and growth, and suggest that manipulation of this pathway could facilitate bone remodeling and fracture repair.",
keywords = "Akt, Bone development, Bone morphogenetic factors, Insulin-like growth factors, Osteoblast, PI3-kinase-Akt pathway",
author = "Aditi Mukherjee and Peter Rotwein",
year = "2009",
month = "3",
day = "1",
doi = "10.1242/jcs.042770",
language = "English (US)",
volume = "122",
pages = "716--726",
journal = "Journal of Cell Science",
issn = "0021-9533",
publisher = "Company of Biologists Ltd",
number = "5",

}

TY - JOUR

T1 - Akt promotes BMP2-mediated osteoblast differentiation and bone development

AU - Mukherjee, Aditi

AU - Rotwein, Peter

PY - 2009/3/1

Y1 - 2009/3/1

N2 - Signaling through the IGF-I receptor by locally synthesized IGF-I or IGF-II is crucial for normal skeletal development and for bone remodeling. Osteogenesis is primarily regulated by bone morphogenetic proteins (BMPs), which activate gene expression programs driven by bone-specific transcription factors. In a mesenchymal stem cell model of osteoblast commitment and differentiation controlled by BMP2, we show that an inhibitor of PI3-kinase or a dominant-negative Akt were as potent in preventing osteoblast differentiation as the IGF binding protein IGFBP5, whereas a Mek inhibitor was ineffective. Conversely, an adenovirus encoding an inducible-active Akt was able to overcome the blockade of differentiation caused by IGFBP5 or the PI3-kinase inhibitor, and could restore normal osteogenesis. Inhibition of PI3-kinase or Akt did not block BMP2-mediated signaling, because the Smad-responsive genes Sox9 and JunB were induced normally under all experimental conditions. When activated during different stages of osteoblast maturation, dominant-negative Akt prevented accumulation of bone-specific alkaline phosphatase and reduced mineralization, and more significantly inhibited the longitudinal growth of metatarsal bones in primary culture by interfering with both chondrocyte and osteoblast development and function. We conclude that an intact IGF-induced PI3-kinase-Akt signaling cascade is essential for BMP2-activated osteoblast differentiation and maturation, bone development and growth, and suggest that manipulation of this pathway could facilitate bone remodeling and fracture repair.

AB - Signaling through the IGF-I receptor by locally synthesized IGF-I or IGF-II is crucial for normal skeletal development and for bone remodeling. Osteogenesis is primarily regulated by bone morphogenetic proteins (BMPs), which activate gene expression programs driven by bone-specific transcription factors. In a mesenchymal stem cell model of osteoblast commitment and differentiation controlled by BMP2, we show that an inhibitor of PI3-kinase or a dominant-negative Akt were as potent in preventing osteoblast differentiation as the IGF binding protein IGFBP5, whereas a Mek inhibitor was ineffective. Conversely, an adenovirus encoding an inducible-active Akt was able to overcome the blockade of differentiation caused by IGFBP5 or the PI3-kinase inhibitor, and could restore normal osteogenesis. Inhibition of PI3-kinase or Akt did not block BMP2-mediated signaling, because the Smad-responsive genes Sox9 and JunB were induced normally under all experimental conditions. When activated during different stages of osteoblast maturation, dominant-negative Akt prevented accumulation of bone-specific alkaline phosphatase and reduced mineralization, and more significantly inhibited the longitudinal growth of metatarsal bones in primary culture by interfering with both chondrocyte and osteoblast development and function. We conclude that an intact IGF-induced PI3-kinase-Akt signaling cascade is essential for BMP2-activated osteoblast differentiation and maturation, bone development and growth, and suggest that manipulation of this pathway could facilitate bone remodeling and fracture repair.

KW - Akt

KW - Bone development

KW - Bone morphogenetic factors

KW - Insulin-like growth factors

KW - Osteoblast

KW - PI3-kinase-Akt pathway

UR - http://www.scopus.com/inward/record.url?scp=66149119052&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66149119052&partnerID=8YFLogxK

U2 - 10.1242/jcs.042770

DO - 10.1242/jcs.042770

M3 - Article

VL - 122

SP - 716

EP - 726

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - 5

ER -