BoneKEy Reports | BoneKEy Watch
Osterix and Runx2 cooperate to induce expression of the Col1a1 promoter
As mice that lack the ability to produce the transcription factors Runx2 or Osterix are unable to produce mature osteoblasts, both factors are viewed as master controllers of the process of osteogenesis. In this study, Ortuño et al. investigated the interactions between Osterix, Runx2 and the Col1a1 promoter.
The addition of bone morphogenetic protein 2 (BMP-2) to several mesenchymal and osteoblastic cell types increased expression of both Osterix and Col1a1. Furthermore, overexpression of either BMP-2 or Osterix enhanced Col1a1 transcription. Osterix and BMP-2 were found to regulate Col1a1 through two evolutionarily conserved regions (Sp1 boxes), the bone enhancer region and a portion of the proximal promoter region.
Col1a1 expression was also found to be regulated by p38 and Erk MAPK signaling. Further experiments confirmed that Osterix binds to both Sp1 boxes in vivo, regulating transcription of Col1a1 through p38-dependent phosphorylation. Two isoforms of Osterix (one short, one long) cooperate with Runx2 to activate the Col1a1 promoter, but they showed different levels of Osterix-induced reporter activity (× 1.6 and × 2.6, respectively).
Editor’s comment: The authors’ sequence analysis of the Osterix-responsive Sp1 boxes in the Col1a1 promoter is consistent with consensus Sp1 sequences in other Osterix-responsive genes, such as Col11a2, Dkk1, Fmod and Ibsp. The interplay between Runx2, Osterix and Col1a1 through p38 and Erk MAPK signaling may exert pivotal control of the osteoblastic phenotype.
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