Loss of Cbfβ in bone marrow cells slowed fracture healing in mice

Loss of Cbfβ in bone marrow cells slowed fracture healing in mice

On 10 August, the authors of an article reported that, in a mouse model, deletion of the Cbfb gene in bone marrow adipocytes and their progenitors induced cellular senescence, depleted the pool of cells available for bone repair, and impaired fracture healing.

After a fracture, a temporary cartilage bridge first joins the broken bone, and new bone tissue then replaces it. Skeletal progenitor cells produce this tissue. Mature adipocytes and the cells that give rise to them reside nearby in the bone marrow. The authors tested whether the state of these neighboring cells determines whether enough progenitors remain available for repair.

The focus on Cbfβ builds on a 2017 study from the same line of research, which linked this protein to a skeletal progenitor's choice between bone and fat cell fates. In the current experiment, the researchers deleted the Cbfb gene only in the bone marrow adipocyte lineage of young adult mice. Genetic lineage tracing showed that these cells rarely became osteoblasts, the cells that form bone. After gene deletion, progenitor numbers decreased in both the bone marrow and the periosteum, the membrane covering the bone surface.

Fractures healed less effectively. On day 12, the temporary cartilage bridge was 51,7% smaller. On day 21, the volume of new mineralized tissue was 40,3% lower. By day 35, the fractures had not united. Progenitors cultured in medium previously conditioned by cells lacking Cbfb divided less effectively and formed fewer colonies. These findings indicate that the altered bone marrow cells inhibited progenitor proliferation through substances that they released into the medium.

Together with RUNX proteins, Cbfβ helps activate genes required to repair damaged DNA. After Cbfb deletion, DNA damage accumulated in cells of the adipocyte lineage. The cells entered senescence, a state in which cell division stops and the profile of secreted substances changes. One of the secreted proteins, IGFBP7, weakened IGF–AKT signaling, which supports progenitor proliferation.

The authors tested this sequence of events with two interventions. A combination of dasatinib and quercetin reduced markers of senescence and partially restored progenitor numbers and the cartilage bridge in mice lacking the gene. In middle aged mice, an AAV vector, a viral carrier used for gene delivery, increased Cbfβ levels in cells of the bone marrow adipocyte lineage, increased the number of progenitors at the fracture site, and improved healing. In this mouse model, the state of cells within the bone marrow niche determined how many cells remained available for bone repair.