Mice formed less new bone after a second injury, even though the bone marrow already appeared to have recovered
Mice formed less new bone after a second injury, even though the bone marrow already appeared to have recovered
In a paper published on 19 August in Nature Communications, researchers tested whether bone marrow cells could participate in bone repair again after an earlier injury. Following the second injury, their descendants were less likely to become osteoblasts, and less new bone formed.
Stromal cells support the environment within the bone marrow. After an injury, some of these cells can become osteoblasts, the cells that build bone. To track this change, the authors genetically labeled cells in mice and compared the responses to one and two operations that initiated bone marrow repair.
After the second operation, micro-CT, an X-ray imaging method that reveals the internal structure of bone, showed that less new trabecular, or spongy, bone had formed. The labeled cells were less likely to become osteoblasts, while their descendants were more likely to become bone marrow fat cells. A separate repeat fracture model produced the same pattern: less new bone and fewer osteoblasts, with more fat cell descendants.
The researchers initially allowed about four weeks between operations. By the time of the next injury, the bone marrow appeared comparable under the microscope to uninjured marrow. They then extended the interval to 12 weeks. Before the new injury, the bone marrow cavity had largely regained its usual appearance, but the second response still produced less trabecular bone, fewer osteoblasts, and more fat cell descendants. The visible structure recovered before these cells regained their capacity to build bone in response to another injury.
The experiment built on a 2020 study from the same line of research. That study showed that injury causes stromal cells to become osteoblast progenitors through the Wnt/β-catenin signaling pathway, which directs them toward a bone-forming fate. The new study tested whether this transition could be activated again after a second injury. Signaling pathway activity was lower following the second injury. Deleting β-catenin from the labeled cell lineage after one injury reduced osteoblast formation and promoted differentiation into fat cells. Genetically or pharmacologically increasing the signal after a repeat injury partially restored bone formation.
The authors describe this condition as stromal exhaustion. In the mouse experiments, after a previous injury, the descendants of these cells were more likely to become fat cells and less likely to become osteoblasts when another injury occurred. Bone marrow structure recovered before the cells regained their capacity to build bone in response to another injury.