Age-related bone fragility in type 1 diabetes – the role of bone cell senescence

Overview:

Patients with type 1 diabetes are living much longer due to advances in treatment. While this represents remarkable progress in overcoming this disease, it is becoming apparent that people with type 1 are at high risk of bone fractures as they age Sugar-dependent changes in bone structure make the bone become less flexible and more liable to fracture. If patients do suffer a broken bone, they do not heal as easily as healthy people of the same age Bones are constantly renewed through breaking down old bone and making new bone; balancing breakdown and reformation is important in keeping bones healthy. This balance is controlled by a master regulator cell-type, the osteocyte. Osteocytes show signs of premature ageing in type 1 diabetes, undergoing a process called cell senescence. Senescent cells behave differently to normal cells; they can break down surrounding tissues and force other cells to become senescent, making the damage worse.

The overall aim of this research is to understand bone fragility in ageing patients with type 1 diabetes who are currently at high risk of bone fracture and premature death, and to develop new treatments to combat this. To do this, Professor Cox and Professor Dresner Pollak will first find out which type of bone cells are senescent and what makes them different from normal bone cells, and then they will identify ways of either killing the senescent cells or make them behave more like normal cells, as a first step in developing a new treatment for patients with type 1 diabetes.

The research teams will compare bone cell senescence in mice with type 1 diabetes and healthy mice. The bones from mice at different ages will be studied by micro CT scan analysis and modern molecular biology techniques to measure strength and senescence. Bone cells will also be grown in the laboratory. They will identify drugs that act on senescence and test them for their ability to kill cultured senescent cells to make the cells behave normally again. If successful, the next step will test if these drugs can improve bone strength in diabetic mice as they age.

Outcomes

Understanding how quickly bone cells age in type 1 diabetes, how many senescent cells are present, and what drives senescence is important as this should help us to highlight new treatments. By treating the root cause of bone fragility in type 1 diabetes, this project will assist towards preventing much of the disability and premature death of type 1 diabetic patients who sustain a fracture. 

The partnership 

The project will be carried out jointly in Jerusalem and in Oxford. The Israeli team will perform the work in mice as they have extensive expertise in studying bone biology in mice, while the Oxford Cell Senescence team will perform the cell culture work and initial drug discovery and testing