H-Ras, a new regulator of bone integrity - the mechanistic base of osteoporosis triggered by a constitutive active H-Ras GTPase

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Bone homeostasis is a dynamic process that is regulated by the bone forming and bone resorbing cells. An increase in bone resorption triggers osteoporosis, that is characterized by a low bone mass and an increased fracture risk. Osteoporosis is generally associated with increased aging, post-menopause and long-term steroid use, but there are some rare diseases that have osteoporosis as phenotypic feature. One of these rare disorders is the Costello syndrome (CS), triggered by germline mutations in the H-Ras oncogene. Adult patients are characterized by a premature aging phenotype, with osteoporosis as one prominent phenotypic pathology. Our preliminary work demonstrated that in a CS mouse model harbouring an H-Ras G12V constitutive active mutation, bone mass is reduced and osteoclastogenesis and osteoclast activity are increased. In vitro osteoclasts differentiation in response to recombinant M-CSF and RANKL showed that hyperactive H-Ras increases osteoclasts number in a cell autonomous manner, confirming our in vivo studies. At the same time, we cannot exclude the effects of cell non-autonomous mechanisms induced by the imbalance in the cross-talk between osteoclasts and osteoblasts, osteocytes and stromal cells. Hyperactive H-Ras is a known senescence inducer in various cell types, therefore osteoblasts, osteocytes and stromal cells may undergo senescence Through their secreted phenotype, senescent osteoblasts, osteocytes and stromal cells may enhance osteoclasts differentiation and activity, thus contributing to the bone loss observed in CS mice. To this end, we plan (I) to characterize in detail the osteoporotic phenotype in CS mice in order to identify the early onset of osteoporosis, (II) to reveal H-Ras-controlled signalling pathways and dysregulated biological processes in CS mouse- and CS patients-derived osteoclasts and (III) to study the cross-talk between osteoclasts and osteoblasts, osteocytes and stromal cells and understand whether it contributes to the increased osteoclastogenesis detected in CS mouse. The expected results will provide insights into H-Ras-controlled molecular mechanisms that are responsible for osteoporosis in CS patients and other Ras-MAPK developmental syndromes (RASopathies) and will enhance our general understanding of osteoclast biology.