Grant: Operating Grant

Our ultimate goal is to understand the molecular and cellular mechanisms that regulate bone homeostasis. Throughout life, equilibrium between two opposite phenomena, bone formation and bone resorption, has to be maintained. When osteoclast activity is affected severe diseases as osteoporosis and osteopetrosis can occur. Particularly, osteopetrosis is observed when osteoclast cells are deficient or absent, thereby causing an excess of bone mass and a severe reduction of the bone marrow cavity, leading to death. To gain insights into osteopetrosis, we study the grey-lethal Ostm1 null mouse model that reproduces the human infantile and most severe form of this disorder. As in human, mice with loss of the Ostm1 in neurons also display major neurodegeneration due to defect in protein degradation mechanism. Recently, we determined that the mouse and human Ostm1 protein responsible for this disease is a trans-membrane protein. Our studies will focus on the characterization of Ostm1 intracellular function in osteoclast differentiation, maturation and activation mechanisms. We will dissect in vivo the intracellular role(s) and molecular mechanism(s) of Ostm1 in osteoclast lysosomal biogenesis, intracellular trafficking and fusion leading to proper osteoclast secretory and bone resorption functions. Understanding these mechanisms associated with osteoclast activation is fundamental and will lead to future development of potential therapeutic strategies.