Increased osteoclastogenesis contributes to bone loss in the Costello syndrome mouse model.

RAS GTPases are ubiquitous GDP/GTP-binding proteins that function as molecular switches in cellular signalling and control numerous signalling pathways and biological processes. Pathogenic mutations in genes severely affect cellular homeostasis, leading to cancer when occurring in somatic cells and developmental disorders when the germline is affected. These disorders are generally termed as RASopathies and among them Costello syndrome (CS) is a distinctive entity that is caused by specific germline mutations. The majority of these mutations affect residues 12 and 13, the same sites as somatic oncogenic mutations. The hallmarks of the disease include congenital cardiac anomalies, impaired thriving and growth, neurocognitive impairments, distinctive craniofacial anomalies, and susceptibility to cancer. Adult patients often present signs of premature aging including reduced bone mineral density and osteoporosis. Using a CS mouse model harbouring a germline mutation, we aimed at determining whether this model recapitulates the patients' bone phenotype and which bone cells are driving the phenotype when mutated. Our data revealed that mutation induces bone loss in mice at certain ages. In addition, we identified that bone loss correlated with an increased number of osteoclasts and mutations increased osteoclastogenesis . Last, but not least, mutant osteoclast differentiation was reduced by treatment with MEK and PI3K inhibitors, respectively. These results indicate that Hras is a novel regulator of bone homeostasis and an increased osteoclastogenesis due to mutation contributes to bone loss in the Costello syndrome.