Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Activating transcription factor 4 regulates osteoclast differentiation in mice
Huiling Cao, … , G. David Roodman, Guozhi Xiao
Huiling Cao, … , G. David Roodman, Guozhi Xiao
Published July 12, 2010
Citation Information: J Clin Invest. 2010;120(8):2755-2766. https://doi.org/10.1172/JCI42106.
View: Text | PDF
Research Article Bone biology

Activating transcription factor 4 regulates osteoclast differentiation in mice

  • Text
  • PDF
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.

Authors

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

×

Figure 1

OCL differentiation is dramatically diminished in Atf4–/– BMM cultures and bones.

Options: View larger image (or click on image) Download as PowerPoint
OCL differentiation is dramatically diminished in Atf4–/– BMM cultures a...
(A) Western blot. Whole cell extracts (20 μg) from primary BMMs were incubated with or without 1 unit calf intestinal phosphatase (CIP) at room temperature for 30 minutes. (B) IHC. Differentiated BMMs were stained with an ATF4 antibody or control IgG. (C) Tibial sections were stained for TRAP activity for 30 minutes at 37°C. TRAP activity in both metaphyseal (top) and epiphyseal (bottom) regions of tibias is shown. (D) TRAP+ OCLs (arrows) on trabecular surfaces of WT and Atf4–/– tibiae. Oc.S/BS and Oc.Nb/BPm values for primary and secondary spongiosa are shown in Table 1. (E–G) WT and Atf4–/– BMMs were maximally differentiated for 9 days, followed by TRAP staining. TRAP+ MNCs (F) and the number of nuclei per OCL (G) were scored. (H and I) Bone resorption pit assay on dentin slices. BMMs were differentiated on dentin slices for 9 days. (H) Bone resorption pits were stained with hematoxylin solution. (I) Pit area versus total bone area on each dentin slice was measured as described in Methods. (J) Time course of TRAP+ mononuclear OCL differentiation. BMMs were differentiated for the indicated times followed by TRAP staining, and percent TRAP+ mononuclear cells was measured. *P < 0.01 versus WT. Original magnification, ×100 (C, E, and H), ×200 (B and D).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts