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Pasteurella multocida toxin- induced osteoclastogenesis requires mTOR activation

Kloos, Bianca ; Chakraborty, Sushmita ; Lindner, Sonja G. ; Noack, Katrin ; Harre, Ulrike ; Schett, Georg ; Krämer, Oliver H. ; Kubatzky, Katharina F.

In: Cell communication and signaling, 13 (2015), Nr. 40. S. 1-13. ISSN 1478-811X

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Abstract

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.

Dokumententyp: Artikel
Titel der Zeitschrift: Cell communication and signaling
Band: 13
Nummer: 40
Verlag: Biomed Central
Ort der Veröffentlichung: London
Erstellungsdatum: 30 Nov. 2015 14:12
Erscheinungsjahr: 2015
ISSN: 1478-811X
Seitenbereich: S. 1-13
Institute/Einrichtungen: Medizinische Fakultät Heidelberg und Uniklinikum > Department für Infektiologie
DDC-Sachgruppe: 570 Biowissenschaften, Biologie
610 Medizin
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