Imatinib has minimal effects on inflammatory and osteopenic phenotypes in a murine cherubism model

Mukai, Tomoyuki; Akagi, Takahiko; Asano, Sumie Hiramatsu; Tosa, Ikue; Ono, M.; Kittaka, Mizuho; Ueki, Yasuyoshi; Yahagi, Ayano; Iseki, Masanori; Oohashi, Toshitaka; Ishihara, Katsuhiko; Morita, Yoshitaka

doi:10.1111/odi.14073

Cited by 5 publications

(5 citation statements)

References 51 publications

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“… 3 , 7 In support of these facts, a recent study showed that the efficacy of imatinib, a BCR-ABL fusion protein inhibitor, differs between human and mouse cherubism, suggesting that the key signaling mechanisms that cause human cherubism are not identical to those in mice. 41 , 42 SYK has been shown to be a promising therapeutic target for cherubism in our studies with SH3BP2 cherubism mice. 3 , 43 Given the possible differences in cherubism pathogenesis between humans and mice, it may be conceivable that SYK inhibitor treatment for human cherubism may not be as effective as for cherubism in mice.…”

Section: Discussionmentioning

confidence: 69%

Loss-of-function OGFRL1 variants identified in autosomal recessive cherubism families

Kittaka,

Mizuno,

Morino

et al. 2024

JBMR Plus

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Cherubism (OMIM 118400) is a rare craniofacial disorder in children characterized by destructive jawbone expansion due to the growth of inflammatory fibrous lesions. Our previous studies have shown that gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2) are responsible for cherubism and that a knock-in mouse model for cherubism recapitulates the features of cherubism, such as increased osteoclast formation and jawbone destruction. To date, SH3BP2 is the only gene identified to be responsible for cherubism. Since not all patients clinically diagnosed with cherubism had mutations in SH3BP2, we hypothesized that there may be novel cherubism genes and that these genes may play a role in jawbone homeostasis. Here, using whole exome sequencing, we identified homozygous loss-of-function variants in the opioid growth factor receptor like 1 (OGFRL1) gene in two independent autosomal recessive cherubism families from Syria and India. The newly identified pathogenic homozygous variants were not reported in any variant databases, suggesting that OGFRL1 is a novel gene responsible for cherubism. Single cell analysis of mouse jawbone tissue revealed that Ogfrl1 is highly expressed in myeloid lineage cells. We generated OGFRL1 knockout mice and mice carrying the Syrian frameshift mutation to understand the in vivo role of OGFRL1. However, neither mouse model recapitulated human cherubism or the phenotypes exhibited by SH3BP2 cherubism mice under physiological and periodontitis conditions. Unlike bone marrow-derived M-CSF-dependent macrophages (BMMs) carrying the SH3BP2 cherubism mutation, BMMs lacking OGFRL1 or carrying the Syrian mutation showed no difference in TNF-ɑ mRNA induction by LPS or TNF-ɑ compared to wild-type BMMs. Osteoclast formation induced by receptor activator of NF-κB ligand (RANKL) was also comparable. These results suggest that the loss-of-function effects of OGFRL1 in humans differ from those in mice and highlight the fact that mice are not always an ideal model for studying rare craniofacial bone disorders.

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Section: Discussionmentioning

confidence: 69%

Loss-of-function OGFRL1 variants identified in autosomal recessive cherubism families

Kittaka,

Mizuno,

Morino

et al. 2024

JBMR Plus

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“…Clinical outcomes were satisfying with imatinib, a tyrosine kinase inhibitor, as the volume of the lesions decreased ( 39 ). Interestingly, this off-study and off-label treatment efficient to decrease the volume of the patients’ lesions did not have any effect on the cherubism mouse ( 44 ). However, Yoshimoto and colleagues demonstrated that treating with a very new second-generation SYK inhibitor (Entospletinib) rescued the cherubism phenotype ( 45 ).…”

Section: Discussionmentioning

confidence: 89%

Pharmacological management of cherubism: A systematic review

et al. 2023

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ObjectiveThe aim of this systematic review was to determine if there exists an efficacious drug treatment for cherubism, based on published studies.MethodsThis systematic review included observational case studies reporting pharmacological management of cherubism. We developed specific search strategies for PubMed (including Medline), ScienceDirect, Web of Science. We evaluated the methodological quality of the included studies using criteria from the Joanna Briggs Institute’s critical appraisal tools.ResultsAmong the 621 studies initially identified by our search script, 14 were selected for inclusion, of which five were classified as having a low risk of bias, four as having an unclear risk, and five a high risk. Overall, 18 cherubism patients were treated. The sample size in each case study ranged from one to three subjects. This review identified three types of drugs used for cherubism management: calcitonin, immunomodulators and anti-resorptive agents. However, the high heterogeneity in case reports and the lack of standardized outcomes precluded a definitive conclusion regarding the efficacy of any treatment for cherubism.ConclusionsThe present systematic review could not identify an effective treatment for cherubism due to the heterogeneity and limitations of the included studies. However, in response to these shortcomings, we devised a checklist of items that we recommend authors consider in order to standardize the reporting of cherubism cases and specifically when a treatment is given toward identification of an efficacious cherubism therapy.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022351044, identifier CRD42022351044.

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“…Quantitative polymerase chain reaction (qPCR) was performed as previously described (35, 36). Total RNA from cultured cells or spleens was extracted using RNAiso Plus (Takara Bio).…”

Section: Methodsmentioning

confidence: 99%

Epstein-Barr virus induced 3 attributes to TLR7-mediated splenomegaly and bicytopenia

Iseki,

Sakamoto,

Takezaki

et al. 2024

Preprint

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Epstein-Barr virus induced 3 (EBI3) is a gene induced by stimulation of toll-like receptors (TLRs) and functions as a component of a heterodimer cytokine IL-27. IL-27 regulates both innate and acquired immune responses; however, their functionin vivois still largely unknown. Splenomegaly, an enlargement of the spleen, is known to be induced by chronic infectious diseases, including infectious mononucleosis due to EB virus infection. Repeated treatment of imiquimod (IMQ; a TLR7 agonist) has been reported to induce splenomegaly and cytopenia due to increased splenic function. Although immune cell activation is speculated to be involved in the pathogenesis of chronic infection-mediated splenomegaly, the detailed molecular mechanism is unknown. Here, we demonstrated that IMQ induced marked splenomegaly and severe bicytopenia (anemia and thrombocytopenia) in the wild-type mice. Myeloid cells, not lymphoid cells, were increased in the enlarged spleen. Extramedullary hematopoiesis was observed in the enlarged spleen of the IMQ-treated mice. RNA-seq analysis revealed that type I interferon (IFN)-related genes were upregulated in the spleen and peripheral blood in IMQ-treated mice.Ebi3deficiency partially retrieved these IMQ-induced pathological changes. We found thatIl27as well asEbi3genes were elevated by IMQ in the spleen and peripheral blood. Further, IL-27 stimulation upregulated type I IFN-related genes in bone marrow-derived macrophage culture in the absence of type I IFN. Collectively, EBI3 contributes to TLR7-induced splenomegaly and bicytopenia, presumably via IL-27.

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Imatinib has minimal effects on inflammatory and osteopenic phenotypes in a murine cherubism model

Cited by 5 publications

References 51 publications

Loss-of-function OGFRL1 variants identified in autosomal recessive cherubism families

Loss-of-function OGFRL1 variants identified in autosomal recessive cherubism families

Pharmacological management of cherubism: A systematic review

Epstein-Barr virus induced 3 attributes to TLR7-mediated splenomegaly and bicytopenia

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