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

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 Syk Inhibitor administration can improve fully developed cherubism symptoms in adult Sh3bp2^KI/KI mice. Entospletinib (GS-9973) was intraperitoneally injected into 10-week-old Sh3bp2^KI/KI mice every day for 6 weeks. Treatment with GS-9973 improved facial swelling and histomorphometric analysis of lung and liver tissue showed that GS-9973 administration significantly reduced inflammatory infiltrates associated with decreased levels of serum TNF-α. Micro-computed tomography (μCT) analysis showed that GS-9973 treatment reduced bone erosion in mandibles, calvariae, and ankle and elbow joints of Sh3bp2^KI/KI mice compared to Sh3bp2^KI/KI mice treated with dimethyl sulfoxide (DMSO). Taken together, the results demonstrate that administration of the Syk Inhibitor ameliorates an already established cherubism phenotype in mice, suggesting that pharmacological inhibition of Syk may be a treatment option for cherubism patients with active disease progression. © 2018 American Society for Bone and Mineral Research.