ABSTRACT
Interleukin-34 (IL-34) has been recently identified as a novel cytokine, substituting for the function of macrophage colony-stimulating factor (M-CSF), a pivotal osteoclastogenic factor involved in bone-related diseases (e.g., osteomyelitis of the jaws). However, the molecular mechanisms are not fully understood. This study aimed to explore the potential mechanism of IL-34 in receptor activator of NF-kB ligand (RANKL)-induced osteoclast formation. We found that IL-34 alone significantly maintained the survival of bone marrow macrophages (BMMs) and enhanced the expression of the osteoclast-related genes TRAP, Ctsk, and NFATc1, as well as TRAP-positive multinucleated cells combined with RANKL, which can be reversed by AG490. Conversely, AG490 did not affect the M-CSF-mediated osteoclastogenesis in the presence of RANKL. The protein expression of p-STAT3 in BMMs was enhanced by IL-34 combined with RANKL compared with RANKL alone, and AG490 inhibited the expression of p-SATA3 at protein level in the IL-34 plus RANKL group, resulting in significantly increased Smad7 expression. This study demonstrated for the first time that IL-34 may play a crucial role in RANKL-induced osteoclastogenesis by promoting the proliferation and differentiation of BMMs, stimulating p-STAT3 expression, and inhibiting the expression of Smad7 in the absence of M-CSF.
Subject(s)
Osteogenesis/drug effects , Tyrphostins/pharmacology , Animals , Bone Marrow/metabolism , Bone Marrow Cells/metabolism , Cell Differentiation/drug effects , Interleukins/metabolism , Macrophages/metabolism , Mice , NF-kappa B/metabolism , Osteoclasts/drug effects , Osteoclasts/metabolism , RANK Ligand/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effectsABSTRACT
Enhanced osteoclast formation increases bone resorption, which triggers bone remodeling. Platelet-derived growth factor BB (PDGF-BB) enhances precursor cell homing, angiogenesis, and bone healing, and thereby could also treat osteoporosis. However, the effect of PDGF-BB on osteoclast formation is not fully understood. We investigated whether exogenous recombinant PDGF-BB directly affects osteoclast formation and osteoclast precursor cell chemotaxis. The murine monocyte-macrophage cell line RAW264.7 and bone-marrow-derived macrophages were cultured with recombinant mouse PDGF-BB with or without a platelet-derived growth factor receptor ß inhibitor (AG-1295) or a Janus kinase 2 inhibitor (AG-490) to analyze the effect on osteoclastogenesis in vitro. PDGF-BB with or without AG-490 or AG-1295 was locally administrated in the mandibular fracture of 16-week-old Sprague Dawley rats (n = 18) for 1-2 weeks to analyze the effect on osteoclastogenesis in vivo. The effect of the treatments on osteoclast formation, osteoclast precursor cell migration, and expression of osteoclastogenic signaling molecules was analyzed. PDGF-BB enhanced osteoclast formation both in vitro and in vivo, but AG-490 and AG-1295 inhibited this effect. PDGF-BB enhanced phosphorylation of extracellular-signal-regulated kinase 1/2 (ERK1/2), Akt, and signal transducer and activator of transcription 3 (STAT3) in RAW264.7 cells. AG-490 inhibited PDGF-BB-induced STAT3 phosphorylation. PDGF-BB enhanced RAW264.7 cell migration and gene expression of osteoclastogenic signaling molecules (i.e., nuclear factor of activated T cells 1, dendrocyte-expressed seven transmembrane protein, and B-cell lymphoma 2), and treatment with AG-1295, AG-490, or S3I-201 (a STAT3 inhibitor) reduced this effect. PDGF-BB enhanced osteoclast formation, osteoclast precursor cell chemotaxis, and phosphorylation of STAT3, Akt, and ERK1/2. but AG-1295 and AG-490 reduced this effect. These findings reflect the complexity of PDGF-BB in bone biology.
Subject(s)
Chemotaxis/drug effects , Osteoclasts/metabolism , Proto-Oncogene Proteins c-sis/pharmacology , Aminosalicylic Acids/pharmacology , Animals , Becaplermin , Benzenesulfonates/pharmacology , Cells, Cultured , Chemotaxis/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation/drug effects , Macrophages/cytology , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Osteoclasts/drug effects , Osteogenesis/drug effects , Osteogenesis/genetics , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , RAW 264.7 Cells , Rats, Sprague-Dawley , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Tyrphostins/pharmacologyABSTRACT
PURPOSE: The purpose of this study was to describe the application of computer-assisted navigation for the retrieval of accidentally displaced mandibular third molars. PATIENTS AND METHODS: All patients identified as having an accidentally displaced mandibular third molar or root fragment and presented to the authors' department from April 2013 through June 2015 were included in this prospective study. Retrieval of the displaced molar was performed in these patients under the guidance of computer-assisted navigation, in which a registered forceps was used to clamp and retrieve the molar. Postoperative complications were assessed for all patients. RESULTS: Twelve patients were included in this case series. Using computer-assisted navigation, the operation proceeded successfully in all patients. These patients displayed uneventful healing without postoperative complications. CONCLUSION: Computer-assisted navigation is a safe, straightforward, and minimally invasive treatment method that can be applied for the retrieval of accidentally displaced third molars. It is recommended as an intraoperative tool for the retrieval of teeth or tooth fragments displaced into areas that are difficult to access.
