PMID- 26369790 OWN - NLM STAT- MEDLINE DCOM- 20160308 LR - 20211203 IS - 1478-811X (Electronic) IS - 1478-811X (Linking) VI - 13 DP - 2015 Sep 14 TI - Pasteurella multocida toxin- induced osteoclastogenesis requires mTOR activation. PG - 40 LID - 10.1186/s12964-015-0117-7 [doi] LID - 40 AB - BACKGROUND: Pasteurella multocida toxin (PMT) is a potent inducer of osteoclast formation. Pigs suffering from an infection with toxigenic Pasteurella multocida strains develop atrophic rhinitis characterised by a loss of turbinate bones and conchae. However, on the molecular level the process of bone loss remains largely uncharacterised. RESULTS: Recently it was found that PMT activates the serine/threonine kinase mammalian target of rapamycin (mTOR) in fibroblasts. Using RAW264.7 macrophages, we investigated the role of the mTOR complex 1 (mTORC1) in PMT-mediated osteoclast formation. PMT induces the differentiation of RAW264.7 macrophages into multinucleated, tartrate resistant acid phosphatase (TRAP) positive osteoclasts that are capable to resorb bone. In the presence of the mTORC1 inhibitor rapamycin, PMT was significantly less able to induce the formation of TRAP-positive osteoclasts. Accordingly, the resulting resorption of bone was strongly reduced. A major target of mTOR is the 70 kDa ribosomal protein S6 kinase 1 (p70 S6K1). Activated p70 S6K1 decreases the expression of programmed cell death protein 4 (PDCD4), a negative transcriptional regulator of osteoclastogenesis, at the protein and gene level. Ultimately this results in the activation of c-Jun, a component of the activator protein 1 (AP-1) complex, which is a major transcription factor for the induction of osteoclast-specific genes. We now demonstrate that c-Jun and its downstream target, the osteoclast-specific bone degrading protease cathepsin K, are upregulated upon PMT treatment in an mTOR-dependent manner. CONCLUSIONS: Activation of mTOR signalling plays a central role in the formation of osteoclasts through the bacterial toxin PMT. On the molecular level, PMT-induced activation of mTOR leads to down regulation of PDCD4, a known repressor of AP-1 complex, culminating in the activation of c-Jun, an essential transcription factor for triggering osteoclastogenesis. FAU - Kloos, Bianca AU - Kloos B AD - Zentrum fur Infektiologie, Medizinische Mikrobiologie und Hygiene, Universitatsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany. FAU - Chakraborty, Sushmita AU - Chakraborty S AD - Zentrum fur Infektiologie, Medizinische Mikrobiologie und Hygiene, Universitatsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany. FAU - Lindner, Sonja G AU - Lindner SG AD - Zentrum fur Infektiologie, Medizinische Mikrobiologie und Hygiene, Universitatsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany. FAU - Noack, Katrin AU - Noack K AD - Center for Molecular Biomedicine (CMB), Department of Biochemistry, University of Jena, Hans Knoll Str. 2, 07745, Jena, Germany. AD - Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Erlanger Allee 101, 07747, Jena, Germany. FAU - Harre, Ulrike AU - Harre U AD - Department of Internal Medicine 3 and Institute of Clinical Immunology, University of Erlangen-Nuremberg, 91054, Erlangen, Germany. FAU - Schett, Georg AU - Schett G AD - Department of Internal Medicine 3 and Institute of Clinical Immunology, University of Erlangen-Nuremberg, 91054, Erlangen, Germany. FAU - Kramer, Oliver H AU - Kramer OH AD - Institute of Toxicology, Medical Center of the University Mainz, Obere Zahlbacher Str. 67, 55131, Mainz, Germany. FAU - Kubatzky, Katharina F AU - Kubatzky KF AD - Zentrum fur Infektiologie, Medizinische Mikrobiologie und Hygiene, Universitatsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany. kubatzky@uni-heidelberg.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150914 PL - England TA - Cell Commun Signal JT - Cell communication and signaling : CCS JID - 101170464 RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Bacterial Proteins) RN - 0 (Bacterial Toxins) RN - 0 (Multiprotein Complexes) RN - 0 (Pasteurella multocida toxin) RN - 0 (Pdcd4 protein, mouse) RN - 0 (Proto-Oncogene Proteins c-jun) RN - 0 (RNA-Binding Proteins) RN - 0 (Transcription Factor AP-1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.22.38 (Cathepsin K) SB - IM MH - Animals MH - Apoptosis Regulatory Proteins/metabolism MH - Bacterial Proteins/*metabolism MH - Bacterial Toxins/*metabolism MH - Bone Resorption/metabolism/microbiology/pathology/*veterinary MH - Cathepsin K/metabolism MH - Cell Line MH - Macrophages/metabolism/*microbiology/pathology MH - Mechanistic Target of Rapamycin Complex 1 MH - Mice MH - Multiprotein Complexes/*metabolism MH - Osteoclasts/metabolism/*microbiology/pathology MH - Pasteurella Infections/complications/metabolism/pathology/*veterinary MH - Pasteurella multocida/*physiology MH - Proto-Oncogene Proteins c-jun/metabolism MH - RNA-Binding Proteins/metabolism MH - Signal Transduction MH - Swine MH - TOR Serine-Threonine Kinases/*metabolism MH - Transcription Factor AP-1/metabolism PMC - PMC4570759 EDAT- 2015/09/16 06:00 MHDA- 2016/03/10 06:00 PMCR- 2015/09/14 CRDT- 2015/09/16 06:00 PHST- 2015/06/11 00:00 [received] PHST- 2015/09/04 00:00 [accepted] PHST- 2015/09/16 06:00 [entrez] PHST- 2015/09/16 06:00 [pubmed] PHST- 2016/03/10 06:00 [medline] PHST- 2015/09/14 00:00 [pmc-release] AID - 10.1186/s12964-015-0117-7 [pii] AID - 117 [pii] AID - 10.1186/s12964-015-0117-7 [doi] PST - epublish SO - Cell Commun Signal. 2015 Sep 14;13:40. doi: 10.1186/s12964-015-0117-7.