title: The relative timing of exposure to phagocytosable particulates and to osteoclastogenic cytokines is critically important in the determination of myeloid cell fate.
abstract: During granulomatous inflammatory reactions, myeloid cells can differentiate into activated phagocytic macrophages, wound-healing macrophages, foreign body giant cells, and bone-resorbing osteoclasts. Although it is appreciated that a variety of stimuli, including cytokines, cell-matrix interactions, and challenge with foreign materials can influence myeloid cell fate, little is known of how these signals integrate during this process. In this study, we have investigated the cross talk between receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis and particle phagocytosis-induced activation of human monocytes. Understanding interconnected signals is of particular importance to disorders, such as periprosthetic osteolysis, in which granulomatous inflammation is initiated by particle phagocytosis in proximity to bone and leads to inflammatory bone loss. Using cell-based osteoclastogenesis and phagocytosis assays together with expression analysis of key regulators of osteoclastogenesis, we show in this study that phagocytosis of disease-relevant particles inhibits RANKL-mediated osteoclastogenesis of human monocytes. Mechanistically, phagocytosis mediates this effect by downregulation of RANK and c-Fms, the receptors for the essential osteoclastogenic cytokines RANKL and M-CSF. RANKL pretreatment of monocytes generates preosteoclasts that are resistant to RANK downregulation and committed to osteoclast formation, even though they retain phagocytic activity. Thus, the relative timing of exposure to phagocytosable particulates and to osteoclastogenic cytokines is critically important in the determination of myeloid cell fate.
authors.affiliation: Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: James
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Nestor
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sculco
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
authors.forename: F Patrick
authors.initials: FP
authors.lastname: Ross
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldring
authors.forename: P Edward
authors.initials: PE
authors.lastname: Purdue
mesh_terms: D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D052638:Particulate Matter / Q000378:metabolism / Q000494:pharmacology*; D010587:Phagocytosis; D019904:Polymethyl Methacrylate / Q000378:metabolism / Q000494:pharmacology; D053245:RANK Ligand / Q000494:pharmacology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012822:Silicon Dioxide / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors; D014025:Titanium / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016207:Cytokines; D052638:Particulate Matter; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; D012822:Silicon Dioxide; D016173:Macrophage Colony-Stimulating Factor; D019904:Polymethyl Methacrylate; D014025:Titanium; D016186:Receptor, Macrophage Colony-Stimulating Factor; D056657:Cathepsin K