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PLCγ2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2
Open accessAbstract
Excessive bone loss in arthritic diseases is mostly due to abnormal activation of the immune system leading to stimulation of osteoclasts. While phospholipase Cgamma (PLCgamma) isoforms are known modulators of T and B lymphocyte-mediated immune responses, we found that blockade of PLCgamma enzymatic activity also blocks early osteoclast development and function. Importantly, targeted deletion of Plcg2 in mice led to an osteopetrotic phenotype. PLCgamma2, independent of PLCgamma1, was required for receptor activator of NF-kappaB ligand-induced (RANKL-induced) osteoclastogenesis by differentially regulating nuclear factor of activated T cells c1 (NFATc1), activator protein-1 (AP1), and NF-kappaB. Specifically, we show that NFATc1 upregulation is dependent on RANKL-mediated phosphorylation of PLCgamma2 downstream of Dap12/Fc receptor gamma (Dap12/FcRgamma) receptors and is blocked by the PLCgamma inhibitor U73122. In contrast, activation of JNK and NF-kappaB was not affected by U73122 or Dap12/FcRgamma deletion. Interestingly, we found that in osteoclasts, PLCgamma2 formed a complex with the regulatory adapter molecule GAB2, was required for GAB2 phosphorylation, and modulated GAB2 recruitment to RANK. Thus, PLCgamma2 mediates RANKL-induced osteoclastogenesis and is a potential candidate for antiresorptive therapy.
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“Moreover, PLCγ2-deficient mouse studies showed that blocking PLCγ2 impedes the early development and function of osteoclasts, thereby preventing bone loss in arthritis (99, 100).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [99]
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“PLCγ2 is necessary for separation of blood and lymphatic vessels in mice (29) and osteoclastogenesis (42), and PLCγ2 outside of the brain has roles in immune deficiencies, autoimmunity, and cancer (18).”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [42]
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“PLCG2 is highly expressed in the hematopoietic system.”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [11]
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“RANKL-induced osteoclastogenesis requires PLCγ2, which controls downstream functions including NFATc1, AP1, and NF-κB (99).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [99]
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Metadata
- Authors
- Mao, D., Epple, H., Uthgenannt, B., Novack, D. V., & Faccio, R.
- Affiliations
- Washington University in St. Louis (US)
- Barnes-Jewish Hospital (US)
- Corresponding author
- Faccio, Roberta
- Venue
- Journal of Clinical Investigation
- Published
- 2006-11-01
- Volume
- 116
- Issue
- 11
- Pages
- 2869-2879
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1616195
- OpenAlex
- W2166456614
- Cited by
- 214
- References
- 49
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 11 · 2020: 13 · 2019: 10 · 2018: 8 · 2017: 15 · 2016: 9 · 2015: 11 · 2014: 12 · 2013: 15 · 2012: 15
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- Arthritis Foundation
- Cancer Research UK
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR47846, AR 48335, AR52921, P30AR048335, K08AR047846)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- PLCγ2, osteoclastogenesis, RANKL, ITAM, Gab2, NFATc1, NF-κB, JNK, osteopetrosis, bone resorption, arthritis, antiresorptive therapy, U73122
- MeSH terms
- Actins, Animals, Cell Differentiation, Cells, Cultured, Mice, Inbred C57BL, Osteoclasts, Osteogenesis, Phosphoproteins, Protein Binding, Receptors, Immunologic, Tyrosine, Signal Transduction, Bone Density, NF-kappa B, Phosphorus Compounds, Mice, Knockout, Transcription Factor AP-1, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, Mice, I-kappa B Kinase, Phospholipase C gamma, RANK Ligand
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