CD169<sup>+</sup>Mac-2<sup>+</sup> osteomacs promote bone regeneration via intramembranous and endochondral ossification — ASN Events
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CD169+Mac-2+ osteomacs promote bone regeneration via intramembranous and endochondral ossification (#61)

Lena Batoon 1 , Susan Millard 1 , Martin Wullschleger 2 3 4 , Corina Preda 5 , Andy Wu 1 , Simranpreet Kaur 1 6 , Hsu-Wen Teng 1 , David Hume 2 7 , Jean-Pierre Levesque 1 2 , Liza Raggatt 1 2 , Allison Pettit 1 2
  1. Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, QUEENSLAND, Australia
  2. The University of Queensland, Faculty of Medicine, Herston, Queensland, Australia
  3. Griffith University, School of Medicine, Southport, Queensland, Australia
  4. Gold Coast University Hospital, Southport, Queensland, Australia
  5. Redcliffe Hospital, Queensland Health, Redcliffe, Queensland, Australia
  6. The University of Queensland, Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
  7. The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, Scotland

Macrophages contribute to multiple processes required for successful fracture repair. Several different macrophage subsets accumulate at sites of bone repair that likely have distinct functional roles. Identifying and characterizing the specific macrophage subsets that drive pro-regenerative responses will aid discovery of new bone anabolic molecules/mechanisms. Using a refined in vivo macrophage depletion model, we demonstrated that CD169+ osteal tissue resident macrophages (osteomacs) are critical for optimal bone regeneration following bone injury whether healing progresses via intramembranous (tibial injury) or endochondral (internally-plated femoral full thickness osteotomy model) ossification. In the tibial injury model CD169+ osteomac/macrophage depletion caused a significant 52.8% reduction in collagen type 1 regenerative woven bone deposition but a 54.5% increase in fibrotic tissue, suggesting loss of this macrophage subset impacted commitment toward a regenerative versus scar response. CD169+ osteomac/macrophage depletion in the femoral fracture model also significantly impaired bone regeneration by 57.7%. Mac-2 is highly expressed on pro-healing alternatively activated macrophages. F4/80+Mac-2+ and F4/80+Mac-2- osteomacs/macrophages were abundant within normally healing bone injuries sites where they were associated with osteoblasts and woven bone surfaces. In CD169+ osteomac/macrophage depleted mice, residual osteomacs/macrophages in the injury site were predominantly F4/80+Mac-2-. Thus, CD169+ ostemac/macrophage depletion selectively reduced the number of pro-regenerative osteomacs/macrophages within the injury site, conforming with the impaired regenerative response. Anecdotally, F4/80+Mac-2+ osteomacs/macrophages also predominate at the metaphyseal corticalisation zone in actively growing mice, which is a site of elevated anabolic generation. Overall, these findings provide evidence that a CD169+Mac-2+ subset of osteomacs drive pro-regenerative bone anabolic functions which are mandatory for successful bone repair.