The mechanism behind trimeric intracellular cation channel B function in Osteogenesis Imperfecta skeleton

Osteogenesis imperfecta (OI) is a rare skeletal disease characterized by bone fragility and fractures and caused by defects in over 20 proteins related to collagen synthesis. The investigation of the molecular mechanisms behind OI forms is necessary to clarify the disease pathophysiology and to identify potential new pharmacological targets for a yet untreatable disorder. Moreover, the findings of altered pathways, potentially common to other diseases, could extend the relevance of the study results to a larger patient population. Our proposal focuses on the identification of a druggable target for the OI form caused by loss-of-function mutations in the trimeric intracellular cation channel B (TRIC-B), an endoplasmic reticulum potassium channel that modulates calcium flux. How mutations in an ion channel are responsible for a heritable bone disease is puzzling the field. To understand TRIC-B function in bone, we generated a transgenic model that reproduces patients’ skeletal outcome. We will investigate bone properties and matrix composition taking advantage of histology, high-resolution tomography and microscopy. The bone cell precursor commitment and differentiation ability in absence of TRIC-B will be evaluated in vivo by specific assays that allow to mimic the processes of bone formation. Ions are indispensable for several cell activities including signal transduction pathways that regulate differentiation and function of osteoblasts, the bone making cells. Among them, we will investigate the TGF-β and WNT pathways, well known to be Ca²⁺ dependent. Advanced molecular, biochemical and high-resolution imaging techniques will be employed. The findings will be validated in patients’ cells.