title: HDAC4 integrates PTH and sympathetic signaling in osteoblasts.
abstract: 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.
authors.affiliation: Department of Genetics and Development, Columbia University, New York, NY 10032.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Obri
authors.affiliation: Department of Genetics and Development, Columbia University, New York, NY 10032.
authors.forename: Munevver Parla
authors.initials: MP
authors.lastname: Makinistoglu
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Genetics and Development, Columbia University, New York, NY 10032 gk2172@columbia.edu.
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D064326:MEF2 Transcription Factors / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology; D054875:Ubiquitination
chemical_list: C081452:Atf4 protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D010281:Parathyroid Hormone; D053245:RANK Ligand; C493716:Runx2 protein, mouse; C505689:Tnfsf11 protein, mouse; D051701:Activating Transcription Factor 4; C533325:Smurf2 protein, mouse; D044767:Ubiquitin-Protein Ligases; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases