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* Institute for Molecular Bioscience, Cooperative Research Centre for Chronic Inflammatory Diseases, University of Queensland, Brisbane, Queensland, Australia;
Institute of Medical and Veterinary Science and Hanson Institute, Adelaide, South Australia, Australia;
Medical Research Council, Mammalian Genetics Unit, Harwell, United Kingdom; and
Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, United Kingdom
Resident macrophages are an integral component of many tissues and are important in homeostasis and repair. This study examines the contribution of resident tissue macrophages to bone physiology. Using immunohistochemistry, we showed that a discrete population of resident macrophages, OsteoMacs, was intercalated throughout murine and human osteal tissues. OsteoMacs were distributed among other bone lining cells within both endosteum and periosteum. Furthermore, OsteoMacs were coisolated with osteoblasts in murine bone explant and calvarial preparations. OsteoMacs made up 15.9% of calvarial preparations and persisted throughout standard osteoblast differentiation cultures. Contrary to previous studies, we showed that it was OsteoMacs and not osteoblasts within these preparations that responded to pathophysiological concentrations of LPS by secreting TNF. Removal of OsteoMacs from calvarial cultures significantly decreased osteocalcin mRNA induction and osteoblast mineralization in vitro. In a Transwell coculture system of enriched osteoblasts and macrophages, we demonstrated that macrophages were required for efficient osteoblast mineralization in response to the physiological remodeling stimulus, elevated extracellular calcium. Notably, OsteoMacs were closely associated with areas of bone modeling in situ, forming a distinctive canopy structure covering >75% of mature osteoblasts on diaphyseal endosteal surfaces in young growing mice. Depletion of OsteoMacs in vivo using the macrophage-Fas-induced apoptosis (MAFIA) mouse caused complete loss of osteoblast bone-forming surface at this modeling site. Overall, we have demonstrated that OsteoMacs are an integral component of bone tissues and play a novel role in bone homeostasis through regulating osteoblast function. These observations implicate OsteoMacs, in addition to osteoclasts and osteoblasts, as principal participants in bone dynamics.
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1 This work was supported by National Health and Medical Research Council (Grant 455941); Ramaciotti Foundations (Grant RA078/05); and University of Queensland Early Career Grant (Project 2004001479). The following authors received funding from National Health and Medical Research Council: M.K.C., Dora Lush Scholarship (Grant ID 409913); K.A.A., Dora Lush Scholarship (Grant ID 409914); and L.-J.R., Peter Doherty Fellowship (Grant ID 252934).
2 M.K.C and L.J.R contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Allison R. Pettit, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia. E-mail address: a.pettit{at}imb.uq.edu.au
4 Abbreviations used in this paper: PFA, paraformaldehyde; OA, osteoarthritic; DAPI, 4',6-diamidino-2-phenylindole; BMM, bone marrow-derived macrophage; ObS, osteoblast bone surface; eGFP, enhanced GFP; TRAP, tartate-resistant acid phosphatase; MAFIA, macrophage-Fas-induced apoptosis.
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