Tlr2/4-Mediated Hyperinflammation Promotes Cherubism-Like Jawbone Expansion in Sh3bp2 (P416R) Knockin Mice.
| Title: | Tlr2/4-Mediated Hyperinflammation Promotes Cherubism-Like Jawbone Expansion in Sh3bp2 (P416R) Knockin Mice. |
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| Authors: | Fujii Y; Department of Oral Health and Diagnostic Sciences, School of Dental Medicine University of Connecticut Health Farmington CT USA.; Monteiro N; Department of Oral Health and Diagnostic Sciences, School of Dental Medicine University of Connecticut Health Farmington CT USA.; Sah SK; Department of Oral Health and Diagnostic Sciences, School of Dental Medicine University of Connecticut Health Farmington CT USA.; Javaheri H; Department of Oral Health and Diagnostic Sciences, School of Dental Medicine University of Connecticut Health Farmington CT USA.; Ueki Y; Department of Biomedical Sciences and Comprehensive Care Indiana University School of Dentistry Indianapolis IN USA.; Indiana Center for Musculoskeletal Health Indiana University, School of Medicine Indianapolis IN USA.; Fan Z; Department of Immunology, School of Medicine University of Connecticut Health Farmington CT USA.; Reichenberger EJ; Center for Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences University of Connecticut Health Farmington CT USA.; Chen IP; Department of Oral Health and Diagnostic Sciences, School of Dental Medicine University of Connecticut Health Farmington CT USA. |
| Source: | JBMR plus [JBMR Plus] 2021 Oct 30; Vol. 6 (1), pp. e10562. Date of Electronic Publication: 2021 Oct 30 (Print Publication: 2022). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Oxford University Press Country of Publication: England NLM ID: 101707013 Publication Model: eCollection Cited Medium: Internet ISSN: 2473-4039 (Electronic) Linking ISSN: 24734039 NLM ISO Abbreviation: JBMR Plus Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Publication: 2024- : Oxford : Oxford University Press; Original Publication: [Chichester, West Sussex, UK] : John Wiley & Sons, [2017]- |
| Abstract: | Cherubism (CBM), characterized by expansile jawbones with multilocular fibrocystic lesions, is caused by gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2; mouse orthologue Sh3bp2). Loss of jawbone and dental integrity significantly decrease the quality of life for affected children. Treatment for CBM is limited to multiple surgeries to correct facial deformities. Despite significant advances made with CBM knockin (KI) mouse models (Sh3bp2 KI/KI ), the activation mechanisms of CBM lesions remain unknown because mutant mice do not spontaneously develop expansile jawbones. We hypothesize that bony inflammation of an unknown cause triggers jawbone expansion in CBM. To introduce jawbone inflammation in a spatiotemporally controlled manner, we exposed pulp of the first right mandibular molar of 6-week-old Sh3bp2 +/+ , Sh3bp2 KI/+ , and Sh3bp2 KI/KI mice. Bacterial invasion from the exposed pulp into root canals led to apical periodontitis in wild-type and mutant mice. The pathogen-associated molecular patterns (PAMPs)-induced inflammation of alveolar bone resulted in jawbone expansion in Sh3bp2 KI/+ and Sh3bp2 KI/KI mice. CBM-like lesions developed exacerbated inflammation with increased neutrophil, macrophage, and osteoclast numbers. These lesions displayed excessive neutrophil extracellular traps (NETs) compared to Sh3bp2 +/+ mice. Expression levels of IL-1β, IL-6, and TNF-α were increased in periapical lesions of Sh3bp2 +/+ , Sh3bp2 KI/+ , and Sh3bp2 KI/KI mice and also in plasma and the left untreated mandibles (with no pulp exposure) of Sh3bp2 KI/KI mice, suggesting a systemic upregulation. Ablation of Tlr2/4 signaling or depletion of neutrophils by Ly6G antibodies ameliorated jawbone expansion induced by PAMPs in Sh3bp2 KI/KI mice. In summary, successful induction of CBM-like lesions in jaws of CBM mice is important for studying initiating mechanisms of CBM and for testing potential therapies. Our findings further emphasize a critical role of host immunity in the development of apical periodontitis and the importance of maintaining oral health in CBM patients. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.; (© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.) |
| Competing Interests: | All authors declare that they have no conflicts of interest. |
| References: | Cell. 2007 Jan 12;128(1):71-83. (PMID: 17218256); Int J Oral Maxillofac Surg. 2005 Jun;34(4):350-6. (PMID: 16053841); Am J Hum Genet. 2001 Jun;68(6):1321-6. (PMID: 11326338); Arch Oral Biol. 2005 Mar;50(3):333-40. (PMID: 15740712); Science. 2004 Mar 5;303(5663):1532-5. (PMID: 15001782); Br J Oral Surg. 1978 Jul;16(1):47-56. (PMID: 280370); Nat Rev Rheumatol. 2014 Oct;10(10):593-601. (PMID: 24914698); Nat Rev Rheumatol. 2011 Sep 27;7(12):691-9. (PMID: 21947176); Int J Pediatr Otorhinolaryngol. 2003 Sep;67(9):1005-12. (PMID: 12907058); PLoS One. 2014 Aug 21;9(8):e105518. (PMID: 25144740); Front Immunol. 2016 Nov 22;7:513. (PMID: 27920776); Cell. 2011 Dec 9;147(6):1324-39. (PMID: 22153076); Nat Immunol. 2010 May;11(5):373-84. (PMID: 20404851); Arch Oral Biol. 1999 Jan;44(1):55-66. (PMID: 10075151); J Bone Miner Res. 2014 Dec;29(12):2618-35. (PMID: 24916406); J Rheumatol. 2019 Dec;46(12):1560-1569. (PMID: 31043551); J Immunol. 2012 Sep 1;189(5):2138-50. (PMID: 22815290); Nature. 2015 Jun 18;522(7556):349-53. (PMID: 25985180); Immunity. 2015 Jun 16;42(6):1143-58. (PMID: 26070485); J Clin Pathol. 1998 Nov;51(11):831-7. (PMID: 10193324); Ann Plast Surg. 2007 Jun;58(6):645-51. (PMID: 17522488); Oral Surg Oral Med Oral Pathol. 1965 Sep;20:340-9. (PMID: 14342926); Nature. 2015 Jun 18;522(7556):345-348. (PMID: 25822788); J Clin Invest. 2015 Apr;125(4):1396-400. (PMID: 25705883); J Endod. 1985 Nov;11(11):479-88. (PMID: 3913729); Anticancer Res. 2016 Jun;36(6):3109-15. (PMID: 27272835); Cell. 2011 Dec 9;147(6):1340-54. (PMID: 22153077); Nat Rev Immunol. 2010 Dec;10(12):826-37. (PMID: 21088683); J Oral Maxillofac Surg. 1998 Nov;56(11):1336-42. (PMID: 9820222); Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2353-2366. (PMID: 31644352); Nat Rev Immunol. 2008 Apr;8(4):279-89. (PMID: 18340345); Oral Surg Oral Med Oral Pathol. 1965 Nov;20(5):648-53. (PMID: 5213235); BMC Musculoskelet Disord. 2020 Aug 21;21(1):564. (PMID: 32825821); Nat Med. 2009 Jun;15(6):623-5. (PMID: 19448636); J Oral Maxillofac Surg. 1991 May;49(5):535-42. (PMID: 2019904); Cell Rep. 2014 Sep 25;8(6):1752-1766. (PMID: 25220465); Nat Med. 2016 Dec;22(12):1402-1410. (PMID: 27775706); Orphanet J Rare Dis. 2012 May 24;7 Suppl 1:S6. (PMID: 22640403) |
| Grant Information: | R01 HL145454 United States HL NHLBI NIH HHS; R01 DE025870 United States DE NIDCR NIH HHS; R21 DE030561 United States DE NIDCR NIH HHS; R01 DE025664 United States DE NIDCR NIH HHS; R01 DE020835 United States DE NIDCR NIH HHS |
| Contributed Indexing: | Keywords: CHERUBISM; GENETIC ANIMAL MODELS; JAW ABNORMALITIES; NEUTROPHIL EXTRACELLULAR TRAPS; OSTEOIMMUNOLOGY |
| Entry Date(s): | Date Created: 20220126 Latest Revision: 20240611 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC8771001 |
| DOI: | 10.1002/jbm4.10562 |
| PMID: | 35079675 |
| Database: | MEDLINE |
Journal Article