SH3BP2 (SH3 domain binding protein 2) is an adapter protein that plays a crucial role in bone homeostasis by regulating both osteoclast and osteoblast function 1. The protein functions in signal transduction pathways and binds to phosphatidylinositols, linking hematopoietic tyrosine kinases to the cytoplasmic membrane in a phosphorylation-dependent mechanism. SH3BP2 is essential for optimal bone formation and osteoblast differentiation, as demonstrated by mouse models showing decreased trabecular bone thickness, reduced osteoblast function, and impaired expression of differentiation markers like collagen type I and osteocalcin when the gene is mutated 1. The protein's expression is transcriptionally regulated by PARP1, which binds to the SH3BP2 promoter and is essential for its expression 2. Gain-of-function mutations in SH3BP2 cause cherubism, a rare autosomal dominant disorder characterized by symmetrical bone resorptive lesions of the jaws in children 34. The pathogenesis involves systemic autoinflammatory responses mediated by innate immune system cells, particularly those of myeloid lineage 5. Clinically, cherubism affects both sexes equally, with lesions typically beginning at ages 2-5 years and often regressing after puberty 3. Recently, gain-of-function PLCG2 variants have also been identified as a novel genetic cause of cherubism 6.