| First Author | Prod'Homme V | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 4 | Pages | 1396-400 |
| PubMed ID | 25705883 | Mgi Jnum | J:221901 |
| Mgi Id | MGI:5641813 | Doi | 10.1172/JCI71081 |
| Citation | Prod'Homme V, et al. (2015) Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages. J Clin Invest 125(4):1396-400 |
| abstractText | Cherubism is a rare autoinflammatory bone disorder that is associated with point mutations in the SH3-domain binding protein 2 (SH3BP2) gene, which encodes the adapter protein 3BP2. Individuals with cherubism present with symmetrical fibro-osseous lesions of the jaw, which are attributed to exacerbated osteoclast activation and defective osteoblast differentiation. Although it is a dominant trait in humans, cherubism appears to be recessively transmitted in mice, suggesting the existence of additional factors in the pathogenesis of cherubism. Here, we report that macrophages from 3BP2-deficient mice exhibited dramatically reduced inflammatory responses to microbial challenge and reduced phagocytosis. 3BP2 was necessary for LPS-induced activation of signaling pathways involved in macrophage function, including SRC, VAV1, p38MAPK, IKKalpha/beta, RAC, and actin polymerization pathways. Conversely, we demonstrated that the presence of a single Sh3bp2 cherubic allele and pathogen-associated molecular pattern (PAMP) stimulation had a strong cooperative effect on macrophage activation and inflammatory responses in mice. Together, the results from our study in murine genetic models support the notion that infection may represent a driver event in the etiology of cherubism in humans and suggest limiting inflammation in affected individuals may reduce manifestation of cherubic lesions. |
