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Comparative analysis of osteoclast function in symptomatic and asymptomatic individuals with cherubism-causing SH3BP2
Chen Abramovitch-Dahan1, Svetlana Katchkovsky1, Yuval Zur2
1Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 8410500, Israel.
JBMR Plus
|September 29, 2025
Summary
Cherubism, a rare bone disease, involves SH3BP2 mutations. This study found that while carriers have larger osteoclasts, symptom severity may depend on external factors, not just the mutation itself.
Area of Science:
- Genetics
- Immunology
- Bone Biology
Background:
- Cherubism is a rare autosomal dominant disorder affecting the jawbones, often linked to SH3BP2 mutations.
- Factors influencing cherubism's variable severity and genetic penetrance are not fully understood.
- The role of tumor necrosis factor alpha (TNF-α) in human cherubism and its effect on osteoclast activity remain debated.
Purpose of the Study:
- To investigate the role of osteoclast (OC) differentiation and resorption in cherubism.
- To compare OC behavior in symptomatic and asymptomatic carriers of the same cherubism mutation.
- To determine the influence of RANKL and TNF-α on OC characteristics in cherubism.
Main Methods:
- Peripheral blood mononuclear cells (PBMCs) were isolated from cherubism carriers and healthy controls.
- Osteoclast differentiation and resorption assays were performed using RANKL and TNF-α.
- Osteoclast size and bone resorption activity were quantified.
Main Results:
- Cherubism carriers exhibited larger osteoclasts compared to controls when stimulated with RANKL or TNF-α.
- Carrier-derived OCs showed increased bone resorption activity on bone slices.
- No significant differences in OC behavior were found between symptomatic and asymptomatic carriers.
- TNF-α promoted giant cell formation but had a limited effect on resorption compared to RANKL.
Conclusions:
- Osteoclast size and function are altered in cherubism, but symptom severity appears independent of these intrinsic OC characteristics.
- Microenvironmental factors external to osteoclasts likely influence cherubism's clinical presentation.
- While TNF-α affects giant cell formation, its limited impact on resorption may explain why TNF-α inhibition doesn't improve clinical outcomes in cherubism.
