Second-Generation SYK Inhibitor Entospletinib Ameliorates Fully Established Inflammation and Bone Destruction in the Cherubism Mouse Model.

ABSTRACT: Cherubism is a craniofacial disorder characterized by maxillary and mandibular bone destruction. Gain-of-function mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for the excessive bone resorption caused by fibrous inflammatory lesions. A homozygous knock-in (KI) mouse model for cherubism (Sh3bp2^KI/KI ) develops autoinflammation resulting in systemic bone destruction. Although administration of the TNF-α blocker etanercept to neonatal Sh3bp2^KI/KI mice prevented the disease onset, this therapy was not effective for adult Sh3bp2^KI/KI mice or human cherubism patients who already had lesions. Because genetic ablation of spleen tyrosine kinase (SYK) in myeloid cells rescues Sh3bp2^KI/KI mice from inflammation, we examined whether

SUBMITTER: Yoshimoto T 

PROVIDER: S-EPMC6351076 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature