ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2015
Diacylglycerol Kinase ζ (DGKζ) Is a Critical Regulator of Bone Homeostasis Via Modulation of c-Fos Levels in Osteoclasts.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 25 citations in OpenAlex.
- Modulators of Diacylglycerol Kinase Activity: A Review of Advances and Challenges.Medicinal research reviews · 2026Review
- Macrophage DGKActa pharmaceutica Sinica. B · 2025Article
- Impact of Titanium Plate Fixation on Diacylglycerol and Growth Factor Levels in the Periosteum of the Mandible and Maxilla in Patients with Dentofacial Deformities After Jaw Osteotomies.International journal of molecular sciences · 2025Article
- Metabolomics study of osteopetrosis caused byFrontiers in endocrinology · 2024Article
- Causal relationship between type 2 diabetes mellitus and bone mineral density: a Mendelian randomization study in an East Asian population.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2023Article
- PERK signaling pathway in bone metabolism: Friend or foe?Cell proliferation · 2021Review
- Diacylglycerol Kinase ζ Regulates Macrophage Responses in Juvenile Arthritis and Cytokine Storm Syndrome Mouse Models.Journal of immunology (Baltimore, Md. : 1950) · 2020Article
- Importance of the Conserved Carboxyl-Terminal CNOT1 Binding Domain to Tristetraprolin ActivityMolecular and cellular biology · 2019Article
- A Knock-In Tristetraprolin (TTP) Zinc Finger Point Mutation in Mice: Comparison with Complete TTP Deficiency.Molecular and cellular biology · 2018Article
- DGKZ Acts as a Potential Oncogene in Osteosarcoma Proliferation Through Its Possible Interaction With ERK1/2 and MYC Pathway.Frontiers in oncology · 2018Article
- Phospholipase Cγ1 (PLCγ1) Controls Osteoclast Numbers via Colony-stimulating Factor 1 (CSF-1)-dependent Diacylglycerol/β-Catenin/CyclinD1 Pathway.The Journal of biological chemistry · 2017Article
- Article
- Osteoclasts-Key Players in Skeletal Health and Disease.Microbiology spectrum · 2016Review
- Diacylglycerol Kinases in T Cell Tolerance and Effector Function.Frontiers in cell and developmental biology · 2016Review
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Increased diacylglycerol (DAG) levels are observed in numerous pathologies, including conditions associated with bone loss. However, the effects of DAG accumulation on the skeleton have never been directly examined. Because DAG is strictly controlled by tissue-specific diacylglycerol kinases (DGKs), we sought to examine the biological consequences of DAG accumulation on bone homeostasis by genetic deletion of DGKζ, a highly expressed DGK isoform in osteoclasts (OCs). Strikingly, DGKζ(-/-) mice are osteoporotic because of a marked increase in OC numbers. In vitro, DGKζ(-/-) bone marrow macrophages (BMMs) form more numerous, larger, and highly resorptive OCs. Surprisingly, although increased DAG levels do not alter receptor activator of NF-κB (RANK)/RANK ligand (RANKL) osteoclastogenic pathway, DGKζ deficiency increases responsiveness to the proliferative and pro-survival cytokine macrophage colony-stimulating factor (M-CSF). We find that M-CSF is responsible for increased DGKζ(-/-) OC differentiation by promoting higher expression of the transcription factor c-Fos, and c-Fos knockdown in DGKζ(-/-) cultures dose-dependently reduces OC differentiation. Using a c-Fos luciferase reporter assay lacking the TRE responsive element, we also demonstrate that M-CSF induces optimal c-Fos expression through DAG production. Finally, to demonstrate the importance of the M-CSF/DGKζ/DAG axis on regulation of c-Fos during osteoclastogenesis, we turned to PLCγ2(+/-) BMMs, which have reduced DAG levels and form fewer OCs because of impaired expression of the master regulator of osteoclastogenesis NFATc1 and c-Fos. Strikingly, genetic deletion of DGKζ in PLCγ2(+/-) mice rescues OC formation and normalizes c-Fos levels without altering NFATc1 expression. To our knowledge, this is the first report implicating M-CSF/DGKζ/DAG axis as a critical regulator of bone homeostasis via its actions on OC differentiation and c-Fos expression.
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