Differentiation and resorption by osteoclasts derived from peripheral blood of symptomatic and asymptomatic carriers of mutations causing cherubism

Cherubism is a disorder that cause abnormality of the jaws, majority of cases are characterized by a mutation at the gene encoding SH3BP2. The factors that contributing to genetic penetrance and severity of clinical symptoms are still unknown. In mice cherubism mutation causes systemic inflammation mediated by increased TNFα levels, however the etiological role of TNFα in humans is still under debate. It has been suggested that the symptom severity can be correlate to enrichment of multinucleated osteoclasts in bone lesions. However, it is unknown whether the level of these cells is intrinsic or derives from environmental factors that control osteoclast formation.We compared the differentiation and resorption of osteoclasts derived from blood of two symptomatic and one asymptomatic carriers to gender and age matched controls.

PBMCs from the carriers formed bigger osteoclasts than matched controls, when cultured with either RANKL or TNFα. Furthermore osteoclasts from mutation carriers cultured with RANKL resorbed significantly more bone than their matched control. However, compared to RANKL, TNFα induced much lower resorption.

Our data show that osteoclasts from cherubism carriers are highly aggressive regardless of patient symptom severity. These data suggest that the appearance and severity of symptoms in cherubism is mediated in an osteoclast non cell autonomous manner and are likely mediated by other cells or environmental factors. Moreover our data shows that as opposed to mice giant cell formation by TNFα is not correlated with enhanced osteoclast aggression in humans which may explain why attempts to target TNFα in cherubism patients were ineffective.