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Studies on the Role of Insulin Like Growth Factor-I on Bone Formation and Mineralization

by Mukherjee, Aditi

Abstract (Summary)
The insulin-like growth factor-I (IGF-I) controls somatic growth and exerts profound anabolic effects in most tissues, including the skeleton. In this study, I investigated interactions between the IGF-I system and several important pathways involved in growth and differentiation of cartilage and bone. In the first study, I explored the mechanisms responsible for transforming growth factor beta (TGF-beta)induced inhibition of chondrocyte proliferation and hypertrophic differentiation in mouse metatarsal organ cultures. Specifically, I sought to determine the involvement and fibroblast growth factor (FGF), and IGF-I as mediators of TGF-beta’s effects. My results demonstrate that IGF-I increases chondrocyte proliferation and hypertrophic differentiation whereas FGF-2, decreases these parameters, in a perichondrium dependent manner. In addition, TGF-beta interacts with components of both the IGF and FGF systems but seems to exert most of its inhibitory effects by upregulating FGF signaling.To study the action of IGF-I in different phases of osteoblast differentiation, I developed an in vitro system to disrupt the type I IGF receptor (IGF-IR) by introducing adenoviral Cre vector in primary osteoblast cultures prepared from IGF-IR fl/fl mice. This study demonstrates that disruption of IGF-IR at onset of osteoblast differentiation inhibits differentiation and calcified nodule formation in association with decreased expression of Runx-2, osteopontin and osteocalcin. Knockdown of the IGF-IR in mature, differentiated osteoblast resulted in decreased calcified nodule formation accompanied by a significant decrease in the expression of several factors known to be involved in the process of mineralization including, phosphate transporter Pit-1, Phex, alkaline phosphatase and dentin matrix protein-1. Sodium dependent phosphate (Pi) uptake, an initial and essential event in mineralization, was also decreased in the absence of IGF-I signaling in the differentiated osteoblasts. However, restoration of Pi uptake in the osteoblasts by re-expressing Pit-1 was unable to correct the mineralized nodule formation. Nevertheless, these findings indicate that IGF-I signaling is critical for normal expression of several factors required for matrix mineralization.
Bibliographical Information:

Advisor:

School:University of Cincinnati

School Location:USA - Ohio

Source Type:Master's Thesis

Keywords:igf i cartilage bone mineralization

ISBN:

Date of Publication:01/01/2005

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