Plenary Poster 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2020

Treatment with a chimeric long-acting CSF1 molecule enhances fracture healing of healthy and osteoporotic bones (#23)

Lena Batoon 1 , Susan Millard 1 , Kyle Williams 1 , Wenhao Sun 1 , Cheyenne Sandrock 1 , Andy Wu 2 , Katharine Irvine 1 3 , Vaida Glatt 4 , Liza Raggatt 1 3 , Martin Wullschleger 3 5 6 , David Hume 1 3 , Allison Pettit 1 3
  1. Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, QUEENSLAND, Australia
  2. Translational Research Institute, Woolloongabba, Queensland, Australia
  3. The University of Queensland, Faculty of Medicine, Herston, Queensland, Australia
  4. University of Texas Health Science Center, San Antonio, Texas, United States of America
  5. Griffith University, School of Medicine, Southport, Queensland, Australia
  6. Gold Coast University Hospital, Southport, Queensland, Australia

Macrophage colony-stimulating factor 1 (CSF1) controls osteoclast and macrophage proliferation, differentiation and function. Pharmacokinetic limitations of recombinant CSF1 that constrained clinical application and pre-clinical experimentation have been overcome by engineering a potent, long acting chimeric CSF1-Fc. Exogenous CSF1 has been shown to have anabolic effects on multiple tissues, including bone, and we have previously reported that it can enhance fracture callus formation. However, bone catabolic actions of CSF1, particularly in osteoporotic bone is a potential contraindication of CSF1-Fc use for promoting fracture repair. We tested weekly and biweekly systemic CSF1-Fc treatment regimens over a 4-week period in adult 12-16-week-old mice. Histomorphometric analysis showed F4/80+ osteal macrophage number was unchanged after either regimen, while TRAP+ osteoclasts were significantly increased only after biweekly CSF1-Fc treatment (p=0.0071), irrespective of gender. Hence, weekly CSF1-Fc treatment had minimal impact on bone-related myeloid cell populations under homeostatic conditions. To assess whether this non-myeloproliferative CSF1-Fc regimen primed regenerative mechanisms, we investigated the fracture therapeutic potential using the MouseFix internally plated femoral fracture model. Torsional strength testing of the fractured femora in healthy adult mice revealed CSF1-Fc treatment significantly increased fracture maximum torque (+44%). To determine whether a similar treatment strategy can improve osteoporotic fracture healing, ovariectomised (OVX) C3H/HeJ mice that had confirmed trabecular (p<0.0001) and cortical bone loss (p<0.01) were fractured using the MouseScrew intramedullary screw fixation system. Micro-CT assessment of fracture sites showed a 50% reduction in cortical bridging at 5 weeks post-fracture in OVX mice compared to sham controls, indicative of delayed bone repair associated with OVX. Importantly, weekly CSF1-Fc treatment of OVX mice post-fracture corrected this delayed healing phenotype. Collectively, our results demonstrate that a low dose CSF1-Fc treatment regimen is a promising fracture therapeutic to promote regeneration in healthy and osteoporotic bones.