Skeletal Maturity and Age‐Related Changes in Immune Cells and Circulatory Factors Impair Large‐Scale Bone Regeneration

Large-scale bone defects require complex surgical procedures to repair, but full restoration of the bone is not guaranteed due to the significant tissue loss involved. In contrast, fractures can frequently be treated with conservative techniques. Particularly, ribs have a remarkable ability to spontaneously regenerate large-scale bone defects. However, we show here that skeletal maturity and age are associated with a decrease in the regenerative potential of human ribs. To investigate skeletal maturity and age-related cellular and transcriptional changes during large-scale bone regeneration, we used a mouse model that mimics the regenerative clinical features of human ribs. Unlike immature mice, mature mice lose the ability to regenerate after rib resection, and instead of bone, the resected rib space is repaired with abundant fibronectin cells. In addition, bone repair in mature mice presents reduced immune cell infiltration, which coincides with decreased levels of circulatory pro-inflammatory factors. To address the role of cell-cell communication and test whether skeletal maturity and age-related changes in immune cells and circulatory factors influence bone regeneration, we used immunodeficient mouse strains and performed heterochronic parabiosis. In immature mice, defective immune cell function altered callus composition rather than inhibiting bone regeneration. Remarkably, under parabiosis, a systemic pro-regenerative response is triggered exclusively in resected immature mice and is capable of partially rescuing bone regeneration in mature mice otherwise unable to regenerate spontaneously. Collectively, these findings suggest that therapeutic strategies focused on identifying pro-regenerative immune factors are promising for supporting the regeneration of large bone defects.