Lamin B1 deficiency impairs bone formation in stem cells

In an experiment using bone marrow-derived mesenchymal stem cells linked to senile osteoporosis, researchers examined how aging impairs bone formation. They found that an age-related loss of lamin B1 caused detachment of lamina-associated domains. This led to the formation of super-enhancers, clusters of regulatory DNA that drove production of the transporter protein SLC7A11. Elevated SLC7A11 activated disulfidptosis, a form of cell death that formed abnormal chemical bonds in actin fibres and collapsed the internal skeleton of the cell. This structural collapse disrupted binding with DRP1, a protein needed for mitochondrial division. Intercepting mitochondrial division caused dysfunction in cellular energy generation and impaired osteogenesis, the process by which stem cells build bone. Using virtual molecular screening, the team also identified the drug naldemedine as an inhibitor of this pathway.