Insulin-like growth factor-I regulates proliferation and osteoblastic differentiation of calcifying vascular cells via extracellular signal-regulated protein kinase and phosphatidylinositol 3-kinase pathways

Circ Res. 2005 Mar 4;96(4):398-400. doi: 10.1161/01.RES.0000157671.47477.71. Epub 2005 Feb 3.

Abstract

Vascular calcification develops within atherosclerotic lesions and results from a process similar to osteogenesis. One of the paracrine regulators of bone-derived osteoblasts, insulin-like growth factor-I (IGF-I), is also present in atherosclerotic lesions. To evaluate its possible role in vascular calcification, we assessed its in vitro effects on proliferation and differentiation in calcifying vascular cells (CVCs), a subpopulation of bovine aortic medial cells. Results showed that IGF-I inhibited spontaneous CVC differentiation and mineralization as evidenced by decreased alkaline phosphatase (AP) activity and decreased matrix calcium incorporation, respectively. Furthermore, IGF-I inhibited the AP activity induced by bacterial lipopolysaccharide, TNF-alpha, or H2O2. It also induced CVC proliferation based on 3H-thymidine incorporation. Results from Northern analysis and tests using IGF-I analogs suggest that IGF-I effects are mediated through the IGF-I receptor. IGF-I also activated both the extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) pathways. Inhibition of either the ERK or PI3K pathway reversed IGF-I effects on CVC proliferation and AP activity, suggesting a common downstream target. Overexpression of ERK activator also mimicked IGF-I inhibition of lipopolysaccharide-induced AP activity. These results suggest that IGF-I promotes proliferation and inhibits osteoblastic differentiation and mineralization of vascular cells via both ERK and PI3K pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkaline Phosphatase / analysis
  • Animals
  • Aorta / cytology*
  • Aortic Diseases / physiopathology*
  • Becaplermin
  • Calcinosis / physiopathology*
  • Calcium / metabolism
  • Cattle
  • Cell Differentiation / drug effects
  • Cell Division / drug effects
  • Cells, Cultured / drug effects
  • Chromones / pharmacology
  • DNA-Binding Proteins / physiology
  • Extracellular Matrix / metabolism
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / physiology*
  • Flavonoids / pharmacology
  • Humans
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / pharmacology*
  • Insulin-Like Growth Factor I / physiology
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / physiology
  • Morpholines / pharmacology
  • Osteoblasts / drug effects*
  • Osteoblasts / pathology
  • Phosphatidylinositol 3-Kinases / physiology*
  • Platelet-Derived Growth Factor / pharmacology
  • Protein Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-sis
  • Receptor, IGF Type 1 / drug effects
  • Receptor, IGF Type 1 / physiology
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Transcription Factors / physiology
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tunica Media / cytology*
  • ets-Domain Protein Elk-1

Substances

  • Chromones
  • DNA-Binding Proteins
  • Flavonoids
  • Lipopolysaccharides
  • Morpholines
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-sis
  • Recombinant Proteins
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • ets-Domain Protein Elk-1
  • Becaplermin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases
  • Alkaline Phosphatase
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Calcium