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Fracture Healing Requires Proliferation of Callus Cells at Early and Mature Stages of Osteoblast Differentiation

ABSTRACT: Fractures heal by rapid formation of mineralized callus, a process requiring periosteal cell proliferation. To dissect the role of cell proliferation in fracture healing, we asked: How are callus cellular and tissue composition altered when proliferation of osteolineage cells is blocked? Does proliferation of osteolineage cells contribute to callus formation? First, mice expressing thymidine kinase (TK) driven by the 3.6Col1a1 promoter were treated with ganciclovir (GCV) to ablate proliferating osteolineage cells for 5 or 10 days. Single-cell RNA-seq of callus cells revealed that GCV-treated Col1-TK mice had fewer osteoblasts and chondrocytes than controls, with more myofibroblasts and immune cells, consistent with fibrous nonunion. In controls, 15-30% of callus cells expressing the early osteoblast markers osterix (Sp7) and the late marker osteocalcin (Bglap) were in the cell cycle. Next, we targeted proliferating osteolineage cells at different stages of differentiation by crossing Osx-CreERT2, Ocn-Cre and Dmp1-CreERT2 mice with ROSA-TK mice. Following fracture, each Cre;ROSA-TK mouse line exhibited decreased callus bone volume and a shift from callus bone to fibrous tissue. Therefore, during fracture repair, proliferation of callus cells at early and mature stages of osteoblast differentiation is a key step in the formation of a mineralized callus that is essential for healing.

ORGANISM(S): Mus musculus

PROVIDER: GSE343272 | GEO | 2026/08/18

REPOSITORIES: GEO

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