Effects of over-expressing Dlx5 on bone development in transgenic mice

Date of Completion

January 2005

Keywords

Biology, Molecular|Biology, Genetics

Degree

Ph.D.

Abstract

The Dlx5 gene encodes a DNA-binding homeobox protein, which acts as a transcription factor and is expressed in all developing bones. Previous in vitro and in vivo studies have suggested a positive regulatory role for Dlx5 in both osteoblast differentiation and chondrocyte maturation. To explore the role of Dlx5 in regulating osteoblast and chondrocyte differentiation in vivo, we generated transgenic mice over-expressing Dlx5 in osteoblast or chondrocyte lineages. ^ Rat Col1a1 and mouse Col2a1 promoters were used to direct Dlx5 expression into osteoblast and chondrocyte lineages respectively. Phenotypic analysis of these Dlx5 over-expressing transgenic mice revealed multiple bone developmental defects in axial and craniofacial portions of the skeletons. Studies of the Dlx5 over-expressing mice driven by the 3.6kb Col1a1 promoter revealed a severe osteopenic phenotype in long bones. Long bone histology and micro-CT analysis both showed significantly reduced trabecular numbers and cortical bone thickness, and significantly increased bone porosity in mutant femurs. Osteoid is profoundly increased in both calvarias and long bones in the mutants. In addition, an increased number of bright GFP cells, which indicated more active osteoblasts, was found in the pre-osteoblast population. Real-time RNA analysis by gPCR using primary calvarial cultures from transgenic mice suggested that Dlx5 plays a role in accelerating osteoblast differentiation, which is consistent with previous in vitro data. Our data therefore demonstrates that Dlx5 might play different roles during different stages of osteoblast differentiation. Over-expressing Dlx5 in the early osteoblast lineage may lead to premature induction of osteoblast differentiation. However, over-expressing Dlx5 at later stages might compromise late stage osteoblast functions and lead to increased osteoid and delayed mineralization. ^

Link to Full Text

Share

COinS