PLCγ2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2

Mao, Dailing; Epple, Holly; Uthgenannt, Brian; Novack, Deborah V.; Faccio, Roberta

doi:10.1172/jci28775

Cited by 214Bone Metabolism and DiseasesRheumatoid Arthritis Research and TherapiesOsteomyelitis and Bone Disorders Research

PLCγ2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2

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Mao, Dailing, Epple, Holly, Uthgenannt, Brian, Novack, Deborah V., Faccio, Roberta·2006·Journal of Clinical Investigation

DOI 10.1172/jci28775PMC PMC1616195

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Abstract

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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Blocking PLCγ2 impedes the early development and function of osteoclasts, thereby preventing bone loss in arthritis.
“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]
The section on inhibition of PLCγ enzymatic activity reports that an inhibitor blocked osteoclast development and bone resorption in culture. The bone-mass results show increased bone volume in PLCγ2-deficient mice, but the Discussion describes preventing arthritis-related bone loss as a potential therapeutic application, not an outcome demonstrated in arthritic mice. (LLM, conf=0.88)
Experimental — accuracy not yet measured
PLCγ2 is necessary for separation of blood and lymphatic vessels in mice and osteoclastogenesis, and PLCγ2 outside of the brain has roles in immune deficiencies, autoimmunity, and cancer.
“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]
PLCγ2 is predominantly expressed in the hematopoietic system, including bone marrow and lymphoid organs.
“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]
RANKL-induced osteoclastogenesis requires PLCγ2, which controls downstream functions including NFATc1, AP1, and NF-κB.
“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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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
ORCID: Novack, Deborah V.
Faccio, Roberta
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2006-11-01
Volume: 116
Issue: 11
Pages: 2869-2879
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci28775
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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PLCγ2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2

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