Treatment with a long-acting chimeric CSF1 molecule enhances fracture healing of healthy and osteoporotic bones

Lena Batoon, Susan M. Millard, Liza J. Raggatt, Cheyenne Sandrock, Edmund Pickering, Kyle Williams, Lucas W.H. Sun, Andy C. Wu, Katharine M. Irvine, Peter Pivonka, Vaida Glatt, Martin E. Wullschleger, David A. Hume, Allison R. Pettit

Research output: Contribution to journalArticlepeer-review

Abstract

Macrophage-targeted therapies, including macrophage colony-stimulating factor 1 (CSF1), have been shown to have pro-repair impacts post-fracture. Preclinical/clinical applications of CSF1 have been expedited by development of chimeric CSF1-Fc which has extended circulating half-life. Here, we used mouse models to investigate the bone regenerative potential of CSF1-Fc in healthy and osteoporotic fracture. We also explored whether combination of CSF1-Fc with interleukin (IL)-4 provided additional fracture healing benefit in osteopenic bone. Micro-computed tomography, in situ histomorphometry, and bone mechanical parameters were used to assess systemic impacts of CSF1-Fc therapy in naive mice (male and female young, adult and geriatric). An intermittent CSF1-Fc regimen was optimized to mitigate undesirable impacts on bone resorption and hepatosplenomegaly, irrespective of age or gender. The intermittent CSF1-Fc regimen was tested in a mid-diaphyseal femoral fracture model in healthy bones with treatment initiated 1-day post-fracture. Weekly CSF1-Fc did not impact osteoclasts but increased osteal macrophages and improved fracture strength. Importantly, this treatment regimen also improved fracture union and strength in an ovariectomy-model of delayed fracture repair. Combining CSF1-Fc with IL-4 initiated 1-week post-fracture reduced the efficacy of CSF1-Fc. This study describes a novel strategy to specifically achieve bone regenerative actions of CSF1-Fc that has the potential to alleviate fragility fracture morbidity and mortality.

Original languageEnglish (US)
Article number120936
JournalBiomaterials
Volume275
DOIs
StatePublished - Aug 2021
Externally publishedYes

Keywords

  • Bone regeneration
  • Colony stimulating factor 1
  • Fracture repair
  • Osteal macrophages
  • Osteomacs
  • Osteoporotic fracture

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Ceramics and Composites
  • Biomaterials
  • Mechanics of Materials

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