Activating transcription factor 4 regulates osteoclast differentiation in mice
Open Access
- 2 August 2010
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 120 (8), 2755-2766
- https://doi.org/10.1172/JCI42106
Abstract
Activating transcription factor 4 (ATF4) is a critical transcription factor for osteoblast (OBL) function and bone formation; however, a direct role in osteoclasts (OCLs) has not been established. Here, we targeted expression of ATF4 to the OCL lineage using the Trap promoter or through deletion of Atf4 in mice. OCL differentiation was drastically decreased in Atf4–/– bone marrow monocyte (BMM) cultures and bones. Coculture of Atf4–/– BMMs with WT OBLs or a high concentration of RANKL failed to restore the OCL differentiation defect. Conversely, Trap-Atf4-tg mice displayed severe osteopenia with dramatically increased osteoclastogenesis and bone resorption. We further showed that ATF4 was an upstream activator of the critical transcription factor Nfatc1 and was critical for RANKL activation of multiple MAPK pathways in OCL progenitors. Furthermore, ATF4 was crucial for M-CSF induction of RANK expression on BMMs, and lack of ATF4 caused a shift in OCL precursors to macrophages. Finally, ATF4 was largely modulated by M-CSF signaling and the PI3K/AKT pathways in BMMs. These results demonstrate that ATF4 plays a direct role in regulating OCL differentiation and suggest that it may be a therapeutic target for treating bone diseases associated with increased OCL activity.Keywords
This publication has 68 references indexed in Scilit:
- CCAAT/Enhancer-binding Protein β Promotes Osteoblast Differentiation by Enhancing Runx2 Activity with ATF4Molecular Biology of the Cell, 2008
- Activating transcription factor 4 is critical for proliferation and survival in primary bone marrow stromal cells and calvarial osteoblastsJournal of Cellular Biochemistry, 2008
- Parathyroid Hormone Increases Activating Transcription Factor 4 Expression and Activity in Osteoblasts: Requirement for Osteocalcin Gene ExpressionEndocrinology, 2008
- General Transcription Factor IIA-γ Increases Osteoblast-specific Osteocalcin Gene Expression via Activating Transcription Factor 4 and Runt-related Transcription Factor 2Published by Elsevier BV ,2008
- Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget diseaseJCI Insight, 2007
- ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiaeCell Metabolism, 2006
- Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1–haploinsufficient osteoclast functionsJCI Insight, 2006
- Osteoclast differentiation and activationNature, 2003
- NFAT Signaling: Choreographing the Social Lives of CellsCell, 2002
- Generic Signals and Specific Outcomes: Signaling through Ca2+, Calcineurin, and NF-ATCell, 1999