Date of Completion

7-27-2018

Embargo Period

6-27-2020

Advisors

Kamran Safavi, D.M.D., M.Ed. / Qiang Zhu, D.D.S., Ph.D. / Kyle Baumbauer, Ph.D.

Field of Study

Dental Science

Degree

Master of Dental Science

Open Access

Open Access

Abstract

Cherubism (CBM) is characterized by multiple fibro-osseous lesions in jawbones and caused by mutations in the SH3-domain binding protein 2 (SH3BP2). CBM patients also suffer from dental abnormalities. Biochemical analyses showed that mutations in CBM lead to SH3BP2 gain-of-function because mutant SH3BP2 is protected from tankyrase-mediated proteasomal degradation. A knock-in (KI) mouse model expressing a CBM substitution mutation (P416R) in Sh3bp2 has been generated. Homozygous mice (Sh3bp2KI/KI) show increased systemic inflammation and osteopenia phenotype with high serum TNF-α level, increased numbers of macrophages and enhanced osteoclastogenesis. Heterozygous mice (Sh3bp2+/KI) exhibit intermediate phenotype with increased bone resorption without significant elevation of TNF-α. Here, we utilized CBM mice to study whether CBM-causing SH3BP2 mutant protein potentiates the development of apical periodontitis. Sh3bp2+/+, Sh3bp2+/KI and Sh3bp2KI/KI male and female mice (8 week-old) were analyzed 3, 7, 14 and 21 days after pulp exposure of the right mandibular first molars. Left molars from the same mice without pulp exposure were used as controls. While Sh3bp2+/+ and Sh3bp2+/KI mice recovered after initial significant weight loss for 7 days, Sh3bp2KI/KI mice continued to lose weight through 21 days after pulp exposure. Sh3bp2KI/KI mice without receiving dental procedures did not have significant weight loss suggesting the weight loss is caused by the development of apical periodontitis. Radiographs by Faxitron and micro-CT showed 1) periapical bone destruction can be observed as early as day 3 in Sh3bp2KI/KI mice; 2) significantly increased bone destruction in Sh3bp2KI/KI mice; 3) Sh3bp2+/KI mice exhibited intermediate sizes of apical lesions. H&E staining of paraffin sections showed the most severe periapical inflammatory bone loss in Sh3bp2KI/KI mice. Sh3bp2KI/KI mice showed significantly higher percentage of cathepsin K-positive (+) area normalized to the bone perimeter on days 7 and 14 compared to other groups. Our study suggests that Sh3bp2 gain-of-function in CBM potentiates the development of apical periodontitis. Increased bony destruction associated with apical periodontitis may occur in CBM patients thus close monitoring the oral health of CBM patients is recommended as part of standard care.

Major Advisor

I-Ping Chen, D.D.S., Ph.D.

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