UMMS Affiliation

Department of Cell and Developmental Biology

Publication Date


Document Type



Activating Transcription Factor 4; Animals; Cell Differentiation; Core Binding Factor Alpha 1 Subunit; Gene Expression Regulation; Histone Deacetylases; MEF2 Transcription Factors; Mice; Models, Biological; Osteoblasts; Parathyroid Hormone; RANK Ligand; *Signal Transduction; Ubiquitin-Protein Ligases; Ubiquitination


Cell and Developmental Biology | Cell Biology | Cellular and Molecular Physiology


Parathyroid hormone (PTH) and the sympathetic tone promote Rankl expression in osteoblasts and osteoclast differentiation by enhancing cyclic adenosine monophosphate production through an unidentified transcription factor for PTH and through ATF4 for the sympathetic tone. How two extracellular cues using the same second messenger in the same cell elicit different transcriptional events is unknown. In this paper, we show that PTH favors Rankl expression by triggering the ubiquitination of HDAC4, a class II histone deacetylase, via Smurf2. HDAC4 degradation releases MEF2c, which transactivates the Rankl promoter. Conversely, sympathetic signaling in osteoblasts favors the accumulation of HDAC4 in the nucleus and its association with ATF4. In this context, HDAC4 increases Rankl expression. Because of its ability to differentially connect two extracellular cues to the genome of osteoblasts, HDAC4 is a critical regulator of osteoclast differentiation.

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DOI of Published Version



J Cell Biol. 2014 Jun 23;205(6):771-80. doi: 10.1083/jcb.201403138. Link to article on publisher's site. Epub 2014 Jun 16.

Journal/Book/Conference Title

The Journal of cell biology

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PubMed ID


Creative Commons License

Creative Commons Attribution-Noncommercial-Share Alike 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.