H-Ras as a new regulator of bone integrity

Introduction:

Osteoporosis is characterized by a low bone mass and an increased fracture risk and is associated with aging, menopause and long-term steroids use. Also, there are some rare disorders that have osteoporosis as of their pathophenotypic feature. One of these disorders is Costello syndrome (CS), caused by a germline H-Ras mutation and the molecular bases of bone in CS patients are very poorly understood. The aim of our work is to reveal the molecular pathways and bone cells that are affected by a constitutively active H-Ras G12V with the help of a mouse model which harbours a H-Ras G12V germline mutation.

Material and methods:

Using µCT, bone histomorphometry and cell culture among other methods, I aim to dissect these dysregulated mechanisms in detail.

Results:

CS mice started displaying a premature aging-like phenotype characterized by weight loss, reduced subcutaneous fat, premature death, kyphosis, among other features. Our data indicates that constitutively active H-Ras leads to bone loss of both cortical and trabecular bone in CS mice as a result of an increased osteoclastogenesis and an osteoclastic activity. Additionally, we found in in vitro osteoclast differentiation from bone marrow cells that, in contrast to wild type cells, H-Ras mutation leads to an increased differentiation.

Discussion:

Taken together, these results indicate that constitutively active H-Ras G12V mutation leads to bone loss via an osteoclast-dependent mechanism. The understanding of Ras pathways involvement in bone homeostasis could pave the way for future therapeutical perspectives for osteoporosis not only in CS and other RASopathies, but also in other pathologies.