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 domain-binding protein 2 (SH3BP2), yet factors influencing genetic penetrance and clinical severity remain unclear. In mice, this mutation induces tumor necrosis factor alpha (TNF-α)-mediated systemic inflammation, though its role in human cherubism is debated. Multinucleated osteoclasts (OCs), rather than macrophages, are linked to symptom severity, but whether this results from progenitor differentiation or environmental factors is unknown. To elucidate this, OC differentiation and resorption were compared in PBMCs from two symptomatic and one asymptomatic carrier of the same cherubism mutation. All carriers exhibited larger OCs than healthy controls when cultured with RANKL or TNF-α. On bone slices, OCs from carriers resorbed more bone than controls, with TNF-α 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 OCs. Additionally, while TNF-α promotes giant cell formation in cherubism OCs, its impact on resorption is limited. These findings may explain why TNF-α inhibition reduces giant cell numbers in cherubism lesions without improving clinical outcomes.