Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model

• Published in: Journal of bone and mineral research 2011-07, Vol.26 (7), p.1517-1532
• Main Authors: Alexander, Kylie A, Chang, Ming K, Maylin, Erin R, Kohler, Thomas, Müller, Ralph, Wu, Andy C, Van Rooijen, Nico, Sweet, Matthew J, Hume, David A, Raggatt, Liza J, Pettit, Allison R
• Format: Article
• Language: English
• Subjects: Acid Phosphatase - metabolism; Animals; Biological and medical sciences; Bone Formation; Bone Matrix - drug effects; Bone Matrix - metabolism; Calcification, Physiologic - drug effects; Clodronic Acid - administration & dosage; Clodronic Acid - pharmacology; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Inflammation - pathology; Isoenzymes - metabolism; Liposomes - administration & dosage; Macrophage; Macrophage Colony-Stimulating Factor - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Membranes - drug effects; Membranes - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Osteoblast; Osteoblasts - drug effects; Osteoblasts - pathology; Osteoclast; Osteogenesis - drug effects; Osteomac; Osteoprotegerin - pharmacology; Skeleton and joints; Surface Properties - drug effects; Tartrate-Resistant Acid Phosphatase; Tibia - drug effects; Tibia - injuries; Tibia - pathology; Vertebrates: osteoarticular system, musculoskeletal system; Wound Healing - drug effects
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.354

Bone‐lining tissues contain a population of resident macrophages termed osteomacs that interact with osteoblasts in vivo and control mineralization in vitro. The role of osteomacs in bone repair was investigated using a mouse tibial bone injury model that heals primarily through intramembranous ossification and progresses through all major phases of stabilized fracture repair. Immunohistochemical studies revealed that at least two macrophage populations, F4/80+Mac‐2−/lowTRACP− osteomacs and F4/80+Mac‐2hiTRACP− inflammatory macrophages, were present within the bone injury site and persisted throughout the healing time course. In vivo depletion of osteomacs/macrophages (either using the Mafia transgenic mouse model or clodronate liposome delivery) or osteoclasts (recombinant osteoprotegerin treatment) established that osteomacs were required for deposition of collagen type 1+ (CT1+) matrix and bone mineralization in the tibial injury model, as assessed by quantitative immunohistology and micro–computed tomography. Conversely, administration of the macrophage growth factor colony‐stimulating factor 1 (CSF‐1) increased the number of osteomacs/macrophages at the injury site significantly with a concurrent increase in new CT1+ matrix deposition and enhanced mineralization. This study establishes osteomacs as participants in intramembranous bone healing and as targets for primary anabolic bone therapies. © 2011 American Society for Bone and Mineral Research.