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Transfer of proα2(I) cDNA into cells of a murine model of human Osteogenesis Imperfecta restores synthesis of type I collagen comprised of α1(I) and α2(I) heterotrimers in vitro and in vivo

✍ Scribed by Christopher Niyibizi; Patrick Smith; Zhibao Mi; Charlotte L. Phillips; Paul Robbins

Publisher
John Wiley and Sons
Year
2001
Tongue
English
Weight
197 KB
Volume
83
Category
Article
ISSN
0730-2312

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✦ Synopsis

Abstract

The oim mouse is a model of human Osteogenesis Imperfecta (OI) that has deficient synthesis of proα2(I) chains. Cells isolated from oim mice synthesize α1(I) collagen homotrimers that accumulate in tissues. To explore the feasibility of gene therapy for OI, a murine proα2(I) cDNA was inserted into an adenovirus vector and transferred into bone marrow stromal cells isolated from oim mice femurs. The murine cDNA under the control of the cytomegalovirus early promoter was expressed by the transduced cells. Analysis of the collagens synthesized by the transduced cells demonstrated that the cells synthesized stable type I collagen comprised of α1(I) and α2(I) heterotrimers in the correct ratio of 2:1. The collagen was efficiently secreted and also the cells retained the osteogenic potential as indicated by the expression of alkaline phosphatase activity when the transduced cells were treated with recombinant human bone morphogenetic protein 2. Injection of the virus carrying the murine proα2(I) cDNA into oim skin demonstrated synthesis of type I collagen comprised of α1 and α2 chains at the injection site. These preliminary data demonstrate that collagen genes can be transferred into bone marrow stromal cells as well as fibroblasts in vivo and that the genes are efficiently expressed. These data encourage further studies in gene replacement for some forms of OI and use of bone marrow stromal cells as vehicles to deliver therapeutic genes to bone. © 2001 Wiley‐Liss, Inc.

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