title: Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model.
abstract: 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(-/low) TRACP(-) osteomacs and F4/80(+) Mac-2(hi) TRACP(-) 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.
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research, Herston, Australia.
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Alexander
authors.forename: Ming K
authors.initials: MK
authors.lastname: Chang
authors.forename: Erin R
authors.initials: ER
authors.lastname: Maylin
authors.forename: Thomas
authors.initials: T
authors.lastname: Kohler
authors.forename: Ralph
authors.initials: R
authors.lastname: Müller
authors.forename: Andy C
authors.initials: AC
authors.lastname: Wu
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: Liza J
authors.initials: LJ
authors.lastname: Raggatt
authors.forename: Allison R
authors.initials: AR
authors.lastname: Pettit
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001857:Bone Matrix / Q000187:drug effects / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D007249:Inflammation / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008566:Membranes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000494:pharmacology; D013499:Surface Properties / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase; D013977:Tibia / Q000187:drug effects / Q000293:injuries* / Q000473:pathology*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D007527:Isoenzymes; D008081:Liposomes; D053244:Osteoprotegerin; D004002:Clodronic Acid; D016173:Macrophage Colony-Stimulating Factor; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase