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Osteoblast-specific expression of the alpha 2(I) collagen promoter in transgenic mice: correlation with the distribution of TGF-beta 1.

To begin to assess the transcriptional mechanisms that regulate type I collagen gene expression in differentiating osteoblasts, we have sought to determine the minimal promoter sequences that confer osteoblast-specific expression to the alpha 2(I) collagen gene during murine development. Transgenic mice were generated harboring DNA constructs in which the -2000, -500, and -350 to +54 regions located upstream of the start of transcription were linked to the Escherichia coli beta-galactosidase reporter gene (LacZ). Histochemical staining using X-gal indicated that the -2000 lacZ transgene was strongly expressed in newly differentiated and fully functional osteoblasts at intramembranous and endochondral sites of ossification. The promoter was also active in osteocytes in regions of bone remodeling within alveolar bone. The temporal and spatial activity of this region of the promoter closely resembled the developmental patterns of expression of the endogenous alpha 2(I) collagen gene as determined by in situ hybridization. The cis-acting elements within the 500 and 350 bp segments of the alpha 2(I) collagen promoter also drove reporter gene expression in forming osteoblasts, although levels of transgene expression were not as marked as that seen with the 2000 bp promoter. Furthermore, the synthesis and secretion of TGF-beta 1 in osteogenic zones coincided with areas where the alpha 2(I) collagen promoter constructs were transcriptionally active. Since a nuclear factor 1 binding site present at -300 has been shown to mediate the effects of TGF-beta 1 on the alpha 2(I) collagen promoter, these data support a role for TGF-beta 1 in the control of this gene during development.