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
Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice
Wei Jin, … , Jun You, Shao-Cong Sun
Wei Jin, … , Jun You, Shao-Cong Sun
Published April 1, 2008
Citation Information: J Clin Invest. 2008;118(5):1858-1866. https://doi.org/10.1172/JCI34257.
View: Text | PDF
Research Article Bone biology

Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice

  • Text
  • PDF
Abstract

Osteoclastogenesis is a tightly regulated biological process, and deregulation can lead to severe bone disorders such as osteoporosis. The regulation of osteoclastic signaling is incompletely understood, but ubiquitination of TNF receptor–associated factor 6 (TRAF6) has recently been shown to be important in mediating this process. We therefore investigated the role of the recently identified deubiquitinating enzyme CYLD in osteoclastogenesis and found that mice with a genetic deficiency of CYLD had aberrant osteoclast differentiation and developed severe osteoporosis. Cultured osteoclast precursors derived from CYLD-deficient mice were hyperresponsive to RANKL-induced differentiation and produced more and larger osteoclasts than did controls upon stimulation. We assessed the expression pattern of CYLD and found that it was drastically upregulated during RANKL-induced differentiation of preosteoclasts. Furthermore, CYLD negatively regulated RANK signaling by inhibiting TRAF6 ubiquitination and activation of downstream signaling events. Interestingly, we found that CYLD interacted physically with the signaling adaptor p62 and thereby was recruited to TRAF6. These findings establish CYLD as a crucial negative regulator of osteoclastogenesis and suggest its involvement in the p62/TRAF6 signaling axis.

Authors

Wei Jin, Mikyoung Chang, Emmanuel M. Paul, Geetha Babu, Andrew J. Lee, William Reiley, Ato Wright, Minying Zhang, Jun You, Shao-Cong Sun

×

Figure 3

Enhanced OC differentiation from Cyld–/– bone marrow cells.

Options: View larger image (or click on image) Download as PowerPoint
Enhanced OC differentiation from Cyld–/– bone marrow cells.
   
(A) Bone...
(A) Bone marrow cells derived from age-matched Cyld+/+ and Cyld–/– mice were cultured in M-CSF media either in the absence (NT) or presence of 100 ng/ml of GST-RANKL for 4 days and then subjected to TRAP staining. The images of RANKL-stimulated cells are presented as lower (×20) and higher (×100) magnifications. (B) Average number of nuclei per OC calculated based on counting in 15 Cyld+/+ and 15 Cyld–/– OCs. (C) Bone marrow cells derived from CYLD+/+ and CYLD–/– mice were cultured in M-CSF media supplemented with the indicated amounts of GST-RANKL. After 7 days, OCs were detected by TRAP staining. Note that this experiment used a longer differentiation time (7 days) than that shown in Figure 3A in order to detect OCs in the wild-type cell culture at low doses of GST-RANKL. (D) Real-time RT-PCR was performed using RNA isolated from BMDMs or BMDMs cultured in the presence of both M-CSF and 100 ng/ml GST-RANKL for the indicated times. The relative mRNA level of individual genes was expressed as fold induction compared with NT Cyld+/+ cells. Data represent mean values of 3 independent experiments, with error bars indicating SD.

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

Sign up for email alerts