Activating transcription factor 4 regulates osteoclast differentiation in mice

Huiling Cao, Shibing Yu, Zhi Yao, Deborah L. Galson, Yu Jiang, Xiaoyan Zhang, Jie Fan, Binfeng Lu, Youfei Guan, Min Luo, Yumei Lai, Yibei Zhu, Noriyoshi Kurihara, Kenneth Patrene, G. David Roodman, Guozhi Xiao

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2755-2766
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number8
DOIs
StatePublished - Aug 2 2010
Externally publishedYes

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Activating Transcription Factor 4
Osteoclasts
Macrophage Colony-Stimulating Factor
Osteogenesis
Transcription Factors
Metabolic Bone Diseases
Bone Diseases
Bone Resorption
Coculture Techniques
Osteoblasts
Phosphatidylinositol 3-Kinases
Monocytes
Bone Marrow
Macrophages
Bone and Bones

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cao, H., Yu, S., Yao, Z., Galson, D. L., Jiang, Y., Zhang, X., ... Xiao, G. (2010). Activating transcription factor 4 regulates osteoclast differentiation in mice. Journal of Clinical Investigation, 120(8), 2755-2766. https://doi.org/10.1172/JCI42106

Activating transcription factor 4 regulates osteoclast differentiation in mice. / Cao, Huiling; Yu, Shibing; Yao, Zhi; Galson, Deborah L.; Jiang, Yu; Zhang, Xiaoyan; Fan, Jie; Lu, Binfeng; Guan, Youfei; Luo, Min; Lai, Yumei; Zhu, Yibei; Kurihara, Noriyoshi; Patrene, Kenneth; Roodman, G. David; Xiao, Guozhi.

In: Journal of Clinical Investigation, Vol. 120, No. 8, 02.08.2010, p. 2755-2766.

Research output: Contribution to journalArticle

Cao, H, Yu, S, Yao, Z, Galson, DL, Jiang, Y, Zhang, X, Fan, J, Lu, B, Guan, Y, Luo, M, Lai, Y, Zhu, Y, Kurihara, N, Patrene, K, Roodman, GD & Xiao, G 2010, 'Activating transcription factor 4 regulates osteoclast differentiation in mice', Journal of Clinical Investigation, vol. 120, no. 8, pp. 2755-2766. https://doi.org/10.1172/JCI42106
Cao, Huiling ; Yu, Shibing ; Yao, Zhi ; Galson, Deborah L. ; Jiang, Yu ; Zhang, Xiaoyan ; Fan, Jie ; Lu, Binfeng ; Guan, Youfei ; Luo, Min ; Lai, Yumei ; Zhu, Yibei ; Kurihara, Noriyoshi ; Patrene, Kenneth ; Roodman, G. David ; Xiao, Guozhi. / Activating transcription factor 4 regulates osteoclast differentiation in mice. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 8. pp. 2755-2766.
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