Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages

Prod’homme, Virginie; Boyer, Laurent; Dubois, Nicholas; Mallavialle, Aude; Munro, Patrick; Mouska, Xavier; Coste, Isabelle; Rottapel, Robert; Tartare‐Deckert, Sophie; Deckert, Marcel

doi:10.1172/jci71081

Cited by 25 publications

(37 citation statements)

References 23 publications

(31 reference statements)

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“…(38,39) They also fail to develop an organized actin cytoskeleton, which is required for sealing zone formation of bone-resorbing osteoclasts. (38,54) In addition, it has been shown that deletion of Sh3bp2 in osteoclast progenitors by LysM-Cre suppressed in vitro osteoclast bone resorption capability. (55) These data establish SH3BP2 as a crucial regulator for osteoclast function rather than for differentiation (38) and support our conclusion that lack of SH3BP2 decreases alveolar bone loss by suppressing osteoclast function.…”

Section: Discussionmentioning

confidence: 99%

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Kittaka

Yoshimoto

Schlosser

et al. 2019

Journal of Bone and Mineral Research

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Periodontitis is a bacterially induced chronic inflammatory condition of the oral cavity where tooth-supporting tissues including alveolar bone are destructed. Previously, we have shown that the adaptor protein SH3-domain binding protein 2 (SH3BP2) plays a critical role in inflammatory response and osteoclastogenesis of myeloid lineage cells through spleen tyrosine kinase (SYK). In this study, we show that SH3BP2 is a novel regulator for alveolar bone resorption in periodontitis. Micro-CT analysis of SH3BP2-deficient (Sh3bp2 −/− ) mice challenged with ligature-induced periodontitis revealed that Sh3bp2 −/− mice develop decreased alveolar bone loss (male 14.9% AE 10.2%; female 19.0% AE 6.0%) compared with wild-type control mice (male 25.3% AE 5.8%; female 30.8% AE 5.8%). Lack of SH3BP2 did not change the inflammatory cytokine expression and osteoclast induction. Conditional knockout of SH3BP2 and SYK in myeloid lineage cells with LysM-Cre mice recapitulated the reduced bone loss without affecting both inflammatory cytokine expression and osteoclast induction, suggesting that the SH3BP2-SYK axis plays a key role in regulating alveolar bone loss by mechanisms that regulate the bone-resorbing function of osteoclasts rather than differentiation. Administration of a new SYK inhibitor GS-9973 before or after periodontitis induction reduced bone resorption without affecting inflammatory reaction in gingival tissues. In vitro, GS-9973 treatment of bone marrow-derived M-CSF-dependent macrophages suppressed tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation with decreased mineral resorption capacity even when GS-9973 was added after RANKL stimulation. Thus, the data suggest that SH3BP2-SYK is a novel signaling axis for regulating alveolar bone loss in periodontitis and that SYK can be a potential therapeutic target to suppress alveolar bone resorption in periodontal diseases.

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Section: Discussionmentioning

confidence: 99%

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Kittaka

Yoshimoto

Schlosser

et al. 2019

Journal of Bone and Mineral Research

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“…Syk amplifies signaling by further phosphorylating nearby ITAMs , and also propagates the signal through the recruitment and phosphorylation of adapter proteins. Several adapter proteins including linker of activated T cells (LAT), growth factor receptor‐bound protein 2 (Grb2), Grb2‐associated‐binding protein 2 (Gab2), and the Src homology 3 (SH3) domain‐binding protein 2 (SH3BP2) are recruited to sites of phagocytic receptor signaling in a Syk‐dependent manner ( Fig. ).…”

Section: Stage 1: Particle Engagement Receptor Signaling and Phagosmentioning

confidence: 99%

The life cycle of phagosomes: formation, maturation, and resolution

Levin

Grinstein

Canton

2016

Immunological Reviews

250

329

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Phagocytosis, the regulated uptake of large particles (>0.5 μm in diameter), is essential for tissue homeostasis and is also an early, critical component of the innate immune response. Phagocytosis can be conceptually divided into three stages: phagosome, formation, maturation, and resolution. Each of these involves multiple reactions that require exquisite spatial and temporal orchestration. The molecular events underlying these stages are being unraveled and the current state of knowledge is briefly summarized in this article.

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“…3BP2 missense mutations, associated with the craniofacial dysmorphia syndrome cherubism, uncouple 3BP2 from tankyrase and block 3BP2 ADP ribosylation and subsequent ubiquitylation by RNF146 (15). A knockin mouse model expressing one of the cherubism-associated mutations in Sh3bp2 displays osteopenia due to active osteoclastogenesis, and bone marrow-derived macrophages from cherubism mice are more susceptive to LPS-induced TNF-α production (18,30). We have shown that Rnf146 fl/fl LysM-Cre mice phenocopy cherubism knockin mice with osteopenia and highly activated osteoclasts and that depletion of 3BP2 in Rnf146 fl/fl LysM-Cre mice restores this phenotype, showing that the 3BP2 degradation program controlled by RNF146 is critical for optimal postnatal skeletal remodeling.…”

Section: Loss Of 3bp2 Rescued Osteopenia Observed In Rnf146mentioning

confidence: 99%

“…at a concentration of 1.8 mg/kg. Blood was harvested 4 hours later by cardiac puncture, and TNF-α in the serum was measured by ELISA (eBioscience) as described previously (30).…”

Section: Rankl Integrates the 3bp2 And β-Catenin Signaling Pathways Rmentioning

confidence: 99%