title: Actin and ERK1/2-CEBPβ signaling mediates phagocytosis-induced innate immune response of osteoprogenitor cells.
abstract: Wear particles at the host bone-implant interface are a major challenge for successful bone implant arthoplasties. Current understanding of aseptic loosening consists of macrophage-mediated inflammatory responses and increasing osteoclastogenesis, which lead to an imbalance between bone formation and resorption. Despite its significant role in bone regeneration and implant osteointegration, the osteoprogenitor response to wear particles has been examined recent years. More specifically, the intracellular mechanism of osteoprogenitor mediated inflammation has not been fully elucidated. In this study, we examined the role of osteoprogenitors and the cellular mechanism by which metal wear particles elicit an inflammatory cascade. Through both in vivo and in vitro experiments, we have demonstrated that osteoprogenitor cells are capable of initiating inflammatory responses by phagocytosing wear particles, which lead to subsequent accumulation of macrophages and osteoclastogenesis, and the ERK_CEBP/β intracellular signaling is a key inflammatory pathway that links phagocytosis of wear particles to inflammatory gene expression in osteoprogenitors. AZD6244 treatment, a potent inhibitor of the ERK pathway, attenuated particle mediated inflammatory osteolysis both in vivo and in vitro. This study advances our understanding of the mechanisms of osteoprogenitor-mediated inflammation, and provides further evidence that the ERK_CEBP/β pathway may be a suitable therapeutic target in the treatment of inflammatory osteolysis.
authors: Department of Orthopaedic Surgery, Columbia University College of Physicians and Surgeons, NY 10032, USA.
authors: Heon Goo
authors: HG
authors: Lee
authors: Hiroshi
authors: H
authors: Minematsu
authors: Kyung Ok
authors: KO
authors: Kim
authors: Ayse B
authors: AB
authors: Celil Aydemir
authors: Mike J
authors: MJ
authors: Shin
authors: Saqib A
authors: SA
authors: Nizami
authors: Kook Jin
authors: KJ
authors: Chung
authors: Anny C
authors: AC
authors: Hsu
authors: Christopher R
authors: CR
authors: Jacobs
authors: Francis Youngin
authors: FY
authors: Lee
mesh_terms: D000199:Actins / Q000378:metabolism*; D000268:Adhesiveness / Q000187:drug effects; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001842:Bone and Bones / Q000166:cytology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015638:Cytochalasin D / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D012886:Skull / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D013997:Time Factors; D014025:Titanium / Q000633:toxicity
chemical_list: C517975:AZD 6244; D000199:Actins; D001562:Benzimidazoles; D022782:CCAAT-Enhancer-Binding Protein-beta; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D015638:Cytochalasin D; D014025:Titanium; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases