A zinc finger protein controls two stages of bone formation by opposing the master regulator of osteogenesis, Hesse et al. report.
Runx2 is a transcription factor essential for the differentiation of mesenchymal precursors into bone-forming osteoblasts. Mutations in human Runx2 cause the skeletal disorder cleidocranial dysplasia, in which certain bones are underdeveloped. The zinc finger protein Zfp521 also controls bone formation and is a binding partner of Runx2. Hesse et al. examined how the two proteins combine to regulate osteogenesis in vivo.
Mice lacking one copy of Runx2 have underdeveloped bones similar to cleidocranial dysplasia patients. This phenotype was largely rescued by removing one copy of Zfp521, whereas overexpressing the zinc finger protein exacerbated the bone defects. Accordingly, Hesse et al. found that Zfp521 inhibits Runx2 to limit the differentiation of mesenchymal cells into osteoblasts. Zfp521 blocked Runx2 by recruiting the histone deacetylase HDAC3 to switch off Runx2-mediated transcription. Zfp521 was unable to inhibit Runx2 activity in the absence of HDAC3.
Some evidence suggests that Runx2 itself has an inhibitory function at later stages of bone development, preventing osteoblasts from reaching their fully mature state. Indeed, overexpressing Runx2 in adult mice resulted in reduced bone density and the accumulation of immature osteoblasts. This was reversed by simultaneously overexpressing Zfp521, suggesting that the zinc finger protein antagonizes Runx2 at this stage of bone development as well.
Zfp521 therefore maintains the correct balance of Runx2 activity for osteoblast commitment and maturation. The authors now want to identify other transcription factors regulated by Zfp521.
