UMMS Affiliation

Department of Cell and Developmental Biology



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


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.

Rights and Permissions

Citation: 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.


This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at

Related Resources

Link to Article in PubMed

Journal Title

The Journal of cell biology

Creative Commons License

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



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.