Vav/Phospholipase Cγ2–mediated control of a neutrophil‐dependent murine model of rheumatoid arthritis

Cremasco, Viviana; Graham, Daniel B.; Novack, Deborah V.; Swat, Wojciech; Faccio, Roberta

doi:10.1002/art.23757

Cited by 51 publications

(62 citation statements)

References 49 publications

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“…In vivo immune phenotypes caused by genetic alterations of Plc␥2 have been described. We and others (12)(13)(14) have shown that PLC␥2 regulates inflammation and autoimmunity, specifically within the bone microenvironment. Plc␥2 Ϫ/Ϫ mice are protected from immune activation in serum transfer arthritis and antigen-induced arthritis (13,14).…”

Section: Discussionmentioning

confidence: 93%

“…We and others (12)(13)(14) have shown that PLC␥2 regulates inflammation and autoimmunity, specifically within the bone microenvironment. Plc␥2 Ϫ/Ϫ mice are protected from immune activation in serum transfer arthritis and antigen-induced arthritis (13,14). In humans, a dominantly inherited disease called PLAID (PLC␥2-associated antibody deficiency and immune dysregulation) is caused by mutant alleles of PLC␥2 in which small, in-frame genomic deletions eliminate part or all of the C-terminal SH2 domain of PLC␥2.…”

Section: Discussionmentioning

confidence: 93%

“…However, the major limitation of these inhibitors is lack of specificity. Using a genetic model consisting of Plc␥2-deficient mice, we previously showed that PLC␥2 is required for the maintenance of basal bone mass and for protection from inflammatory arthritis (13)(14)(15). Thus, the goal of the current study was to identify a specific approach to target endogenous PLC␥2 function.…”

Section: Discussionmentioning

confidence: 99%

“…Plc␥2 Ϫ/Ϫ mice have increased bone mass (osteopetrosis) due to reduced differentiation of BMMs into OCs (15). Additionally, Plc␥2 Ϫ/Ϫ mice are protected from serum transfer-induced arthritis and antigen-induced arthritis due to functional defects in neutrophils and dendritic cells, respectively (13,14). Therefore, PLC␥2 is a promising target for therapeutic design in the context of inflammatory osteolysis.…”

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confidence: 99%

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Targeted Inhibition of Phospholipase C γ2 Adaptor Function Blocks Osteoclastogenesis and Protects from Pathological Osteolysis

Decker¹,

Hesker²,

Zhang

et al. 2013

Journal of Biological Chemistry

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Background: Genetic deletion of PLC␥2 prevents osteoclast differentiation and reduces bone resorption in vitro and in vivo. Results: Ectopic expression of the tandem SH2 domains of PLC␥2 impairs osteoclastogenesis and protects from bone loss in wild-type mice. Conclusion: Targeting PLC␥2 adaptor function is an efficient strategy to block osteoclast differentiation. Significance: This work provides a framework to design specific PLC␥2 inhibitors.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Targeted Inhibition of Phospholipase C γ2 Adaptor Function Blocks Osteoclastogenesis and Protects from Pathological Osteolysis

Decker¹,

Hesker²,

Zhang

et al. 2013

Journal of Biological Chemistry

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“…We have reported that ablation of PLCγ2 results in a blockade of osteoclastogenesis owing to defective NFATc1 induction (11,22). PLCγ2-deficient mice are osteopetrotic and are also protected from inflammatory osteolysis (23,24). Therefore, we sought to identify novel PLCγ2-dependent signaling mediators that could inform therapeutic design for disorders caused by OC overactivity, such as osteoporosis and RA.…”

Section: Resultsmentioning

confidence: 99%

Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass

Decker

Yang

Rimer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Phospholipase C gamma-2 (PLCγ2)-dependent calcium (Ca 2+ ) oscillations are indispensable for nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) activation and downstream gene transcription driving osteoclastogenesis during skeletal remodeling and pathological bone loss. Here we describe, to our knowledge, the first known function of transmembrane protein 178 (Tmem178), a PLCγ2 downstream target gene, as a critical modulator of the NFATc1 axis. In surprising contrast to the osteopetrotic phenotype of PLCγ2 −/− mice, Tmem178 −/− mice are osteopenic in basal conditions and are more susceptible to inflammatory bone loss, owing to enhanced osteoclast formation. Mechanistically, Tmem178 localizes to the ER membrane and regulates RANKL-induced Ca 2+ fluxes, thus controlling NFATc1 induction. Importantly, down-regulation of Tmem178 is observed in human CD14 + monocytes exposed to plasma from systemic juvenile idiopathic arthritis patients. Similar to the mouse model, reduced Tmem178 expression in human cells correlates with excessive osteoclastogenesis. In sum, these findings identify an essential role for Tmem178 to maintain skeletal mass and limit pathological bone loss.

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A novel N‐ethyl‐N‐nitrosourea–induced mutation in phospholipase Cγ2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model

Abe¹,

Fuchs²,

Boersma³

et al. 2011

Arthritis & Rheumatism

138

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Objective. It is difficult to identify a single causative factor for inflammatory arthritis because of the multifactorial nature of the disease. This study was undertaken to dissect the molecular complexity of systemic inflammatory disease, utilizing a combined approach of mutagenesis and systematic phenotype screening in a murine model.Methods. In a large-scale N-ethyl-N-nitrosourea mutagenesis project, the Ali14 mutant mouse strain was established because of dominant inheritance of spontaneous swelling and inflammation of the hind paws. Genetic mapping and subsequent candidate gene sequencing were conducted to find the causative gene, and systematic phenotyping of Ali14/؉ mice was performed in the German Mouse Clinic. Results.A novel missense mutation in the phospholipase C␥2 gene (Plcg2) was identified in Ali14/؉ mice. Because of the hyperreactive external entry of calcium observed in cultured B cells and other in vitro experiments, the Ali14 mutation is thought to be a novel gain-of-function allele of Plcg2. Findings from systematic screening of Ali14/؉ mice demonstrated various phenotypic changes: an abnormally high T cell:B cell

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Vav/Phospholipase Cγ2–mediated control of a neutrophil‐dependent murine model of rheumatoid arthritis

Cited by 51 publications

References 49 publications

Targeted Inhibition of Phospholipase C γ2 Adaptor Function Blocks Osteoclastogenesis and Protects from Pathological Osteolysis

Targeted Inhibition of Phospholipase C γ2 Adaptor Function Blocks Osteoclastogenesis and Protects from Pathological Osteolysis

Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass

A novel N‐ethyl‐N‐nitrosourea–induced mutation in phospholipase Cγ2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model

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