Skeletal development and physiological ER stress: dissecting the role of SUCO in osteoblastogenesis

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022

The low bone mass diseases, either rare as osteogenesis imperfecta (OI), or common as osteoporosis, represent a serious burden for patient quality of life and health care. Our project will tackle the role of SUCO in osteoblast maturation, a crucial event in bone formation, still not completely understood. SUCO is a membrane protein of the endoplasmic reticulum (ER), the organelle where proteins are synthesized, and its function to date is unknown. Mutations in SUCO were identified in a patient with OI phenotype. The murine model lacking SUCO shows osteopenia and fractures and a reduced level of osteoblast proteins such as collagen I. The expression of these proteins during osteoblastogenesis is driven by the cell response to a mild ER stress activated by the cytokine BMP2. We will investigate the role of SUCO in the activation of BMP2-induced ER stress and collagen synthesis during osteoblastogenesis. In vitro and in vivo models lacking SUCO will be generated. The activation of the cell response to mild ER stress is driven by specific ER membrane proteins, OASIS and ATF6, whose expression and activation will be investigated together with collagen synthesis. The protein associated to SUCO will be identified to clarify its mechanism of function. The osteoblast development and skeletal properties will be studied in a  Suco knock out zebrafish model. The project success will clarify the pathological mechanisms of a new OI form, likely identifying a novel target for innovative treatments and will provide a unique animal model for future therapeutic trials.