page 1261 that the inducible transcription factor NFATc1 must turn on its own expression for bone-resorbing osteoclasts to form.
NFATc1 drives osteoclast-specific gene expression and is essential for the development of these cells in vitro. But whether NFATc1 is required in vivo was unknown, as deletion of the NFATc1 gene is lethal in mice. Another open questions was whether NFATc2—NFATc1's closest relative—can drive osteoclast formation in the absence of NFATc1.
Asagiri and colleagues now show that NFATc1 is indeed essential for osteoclast formation in vivo, as only NFATc1-expressing stem cells rescued osteoclast development when transferred into osteoclast-deficient mice. NFATc1-deficient stem cells failed at this task, despite having normal expression of NFATc2.
Transcriptional regulation explained why only NFATc1 could do the job. Stimulation of bone marrow cells with the osteoclast growth factor RANKL (receptor activator of NF-κB ligand) caused the NFATc2 protein in the cell—along with RANKL-induced NF-κB proteins—to pile onto the NFATc1 promoter at the expense of the NFATc2 promoter. This binding induced the expression of NFATc1, which then bound back to its own promoter, thus amplifying NFATc1 production. The NFATc1 promoter also hoarded histone acetylases, whose DNA modifications facilitate transcription. The authors are now analyzing the chromatin structure of the two promoters, which might help explain why these proteins avoid the NFATc2 promoter.