Murine Progeria Model Exhibits Delayed Fracture Healing With Senescent Phenotype and Dysregulated Immune Response

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ABSTRACT An estimated 189 million bone fractures occurred in 2019 making it one of the most globally prevalent injuries. Delayed union or nonunion occurs in up to 15% of normal fractures with higher rates in aged individuals. Preclinical testing supports the translation of novel strategies to promote improved fracture repair, but there is a paucity of small animal models that recapitulate delayed fracture healing. Here, we evaluated the Zmpste24 − / − (Z24 − / − ) murine model of Hutchinson‐Gilford progeria syndrome as a model of delayed fracture healing. Leveraging the previously characterized Z24 − / − phenotype of genomic instability, epigenetic changes, and fragility, we hypothesize that progeria mice will present with significantly delayed fracture healing relative to age‐matched wild type (WT) controls. Mice received intramedullary‐fixed tibia fractures with healing and immunosenescence evaluated throughout repair. Z24 − / − mice demonstrated significantly delayed healing with smaller fracture calli containing more cartilage and less bone relative to WT mice. The fracture healing phenotype of the Z24 − / − phenocopied naturally aged mice with increased systemic senescence noted in animals relative to adult WT. Unlike naturally aged mice, Z24 − / − also presented with frail bones. Z24 − / − showed a dysregulated immune composition, with decreased lymphopoiesis, increased myelopoiesis and neutrophil accumulation. Aspects of the macrophage phenotype in Z24 − / − reflected changes in natural aging, but with different systemic T cell responses. Given the Z24 − / − progeria mouse model demonstrates the delayed fracture healing phenotype of naturally aged animal at 3 rather than 20 months of age, we suggest this model provides an accelerated model of age‐related delayed fracture healing.

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