title: Tetracyclines convert the osteoclastic-differentiation pathway of progenitor cells to produce dendritic cell-like cells.
abstract: Tetracyclines, such as doxycycline and minocycline, are used to suppress the growth of bacteria in patients with inflammatory diseases. Tetracyclines have been shown to prevent bone loss, but the mechanism involved is unknown. Osteoclasts and dendritic cells (DCs) are derived from common progenitors, such as bone marrow-derived macrophages (BMMs). In this article, we show that tetracyclines convert the differentiation pathway, resulting in DC-like cells not osteoclasts. Doxycycline and minocycline inhibited the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis of BMMs, but they had no effects on cell growth and phagocytic activity. They influenced neither the proliferation nor the differentiation of bone-forming osteoblasts. Surprisingly, doxycycline and minocycline induced the expression of DC markers, CD11c and CD86, in BMMs in the presence of RANKL. STAT5 is involved in DC differentiation induced by GM-CSF. Midostaurin, a STAT5-signaling inhibitor, and an anti-GM-CSF-neutralizing Ab suppressed the differentiation induced by GM-CSF but not by tetracyclines. In vivo, the injection of tetracyclines into RANKL-injected mice and RANKL-transgenic mice suppressed RANKL-induced osteoclastogenesis and promoted the concomitant appearance of CD11c(+) cells. These results suggested that tetracyclines prevent bone loss induced by local inflammation, including rheumatoid arthritis and periodontitis, through osteoclast-DC-like cell conversion.
authors.affiliation: Graduate School of Oral Medicine, Matsumoto Dental University, Nagano 399-0781, Japan.
authors.forename: Saya
authors.initials: S
authors.lastname: Kinugawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Koide
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Toshihide
authors.initials: T
authors.lastname: Mizoguchi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ninomiya
authors.forename: Akinori
authors.initials: A
authors.lastname: Muto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawahara
authors.forename: Midori
authors.initials: M
authors.lastname: Nakamura
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Udagawa
mesh_terms: D000818:Animals; D051940:B7-2 Antigen / Q000096:biosynthesis; D001862:Bone Resorption / Q000378:metabolism; D039521:CD11c Antigen / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology*; D004318:Doxycycline / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008911:Minocycline / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects; D016328:NF-kappa B; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000187:drug effects; D053245:RANK Ligand / Q000378:metabolism / Q000494:pharmacology; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*
chemical_list: D051940:B7-2 Antigen; D039521:CD11c Antigen; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D050799:STAT5 Transcription Factor; C505689:Tnfsf11 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; D008911:Minocycline; D019311:Staurosporine; C059539:midostaurin; D004318:Doxycycline