Comparative Analysis of Osteoclast Function in Symptomatic and Asymptomatic Individuals with Cherubism-Causing SH3BP2 Mutation

Cherubism is a rare autosomal dominant bone disease of the maxilla and mandible with variable severity. Most patients harbor a mutation in SH3 binding protein 2 (SH3BP2), yet factors influencing genetic penetrance and clinical severity remain unclear. In mice, this mutation induces TNFα-mediated systemic inflammation, though its role in human cherubism is debated. Multinucleated osteoclasts, rather than macrophages, are linked to symptom severity, but whether this results from progenitor differentiation or environmental factors is unknown. To elucidate this, osteoclast differentiation and resorption were compared in PBMCs from two symptomatic and one asymptomatic carrier of the same cherubism mutation. All carriers exhibited larger osteoclasts than healthy controls when cultured with RANKL or TNFα. On bone slices, osteoclasts from carriers resorbed more bone than controls, with TNFα exerting a weaker effect than RANKL. No significant differences were observed between symptomatic and asymptomatic carriers, suggesting that symptom severity is influenced by microenvironmental factors external to osteoclasts. Additionally, while TNFα promotes giant cell formation in cherubism osteoclasts, its impact on resorption is limited. These findings may explain why TNFα inhibition reduces giant cell numbers in cherubism lesions without improving clinical outcomes. Lay abstract Cherubism is a rare genetic bone disorder affecting the jaw, caused by mutations in the SH3BP2 gene. This study compared bone-resorbing cells (osteoclasts) from two symptomatic sisters and their asymptomatic father, all carrying the same mutation. The osteoclasts of all carriers were larger and more active than those from healthy individuals, but symptom severity did not correlate with osteoclast behavior, suggesting external factors influence disease progression. The study found that one of the body’s natural signals that breaks down bone was more active than another, helping to explain why treatments that block this specific signal may work better than other anti-inflammatory drugs for managing cherubism.