4.8 Article

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

Journal

BIOMATERIALS
Volume 275, Issue -, Pages -

Publisher

ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2021.120936

Keywords

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

Funding

  1. Mater Foundation
  2. National Health and Medical Research Council [APP1143802]
  3. University of Queensland Postgraduate Scholarship
  4. Mater Research Frank Clair Scholarship
  5. Australian Research Council Future Fellowship [FT150100335]
  6. Australian Government

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Research using mouse models investigated the bone regenerative potential of CSF1-Fc in healthy and osteoporotic fractures, revealing an effective treatment regimen that improves fracture union and strength.
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.

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