Phosphoglycerol dihydroceramide,a distinctive ceramide produced by Porphyromonas gingivalis,promotes RANKL-induced osteoclastogenesis by acting on non-muscle myosin II-A (Myh9), an osteoclast cell fusion regulatory factor |
| |
| Institution: | 1. The Forsyth Institute, Department of Immunology and Infectious Diseases, Cambridge, MA, USA;2. Tsurumi University, School of Dental Medicine, Department of Orthodontics, Kanagawa, Japan;3. Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia;4. Laboratory of Immunology and Molecular Biology, São Leopoldo Mandic Institute and Research Center, São Paulo, Brazil;5. Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA;6. LION Corporation, Research and Development Headquarters, Odawara, Kanagawa, Japan;7. The Forsyth Institute, Department of Microbiology, Cambridge, MA, USA;8. Harvard School of Dental Medicine, Department of Oral Medicine, Infection and Immunity, Boston, MA, USA;9. Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Farmington, CT, USA;10. NOVA Southeastern University College of Dental Medicine, Department of Periodontology, Fort Lauderdale, FL, USA;1. Department of Pharmacy, Sunchon National University, Suncheon 540-742, Republic of Korea;2. Research Institute of Basic Science, Sunchon National University, Suncheon 540-742, Republic of Korea;3. Laboratory of Translational Therapeutics, Pharmacology Research Center, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea;4. Department of Biology, Chungnam National University, Daejeon 305-510, Republic of Korea;5. College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea |
| |
| Abstract: | Among several virulence factors produced by the periodontal pathogen Porphyromonas gingivalis (Pg), a recently identified novel class of dihydroceramide lipids that contains a long acyl-chain has the potential to play a pathogenic role in periodontitis because of its higher level of tissue penetration compared to other lipid classes produced by Pg. However, the possible impact of Pg ceramides on osteoclastogenesis is largely unknown. In the present study, we report that the phosphoglycerol dihydroceramide (PGDHC) isolated from Pg enhanced osteoclastogenesis in vitro and in vivo. Using RAW264.7 cells, in vitro assays indicated that PGDHC can promote RANKL-induced osteoclastogenesis by generating remarkably larger TRAP + multinuclear osteoclasts compared to Pg LPS in a TLR2/4-independent manner. According to fluorescent confocal microscopy, co-localization of non-muscle myosin II-A (Myh9) and PGDHC was observed in the cytoplasm of osteoclasts, indicating the membrane-permeability of PGDHC. Loss- and gain-of-function assays using RNAi-based Myh9 gene silencing, as well as overexpression of the Myh9 gene, in RAW264.7 cells showed that interaction of PGDHC with Myh9 enhances RANKL-induced osteoclastogenesis. It was also demonstrated that PGDHC can upregulate the expression of dendritic cell-specific transmembrane protein (DC-STAMP), an important osteoclast fusogen, through signaling that involves Rac1, suggesting that interaction of PGDHC with Myh9 can elicit the cell signal that promotes osteoclast cell fusion. Taken together, our data indicated that PGDHC is a Pg-derived, cell-permeable ceramide that possesses a unique property of promoting osteoclastogenesis via interaction with Myh9 which, in turn, activates a Rac1/DC-STAMP pathway for upregulation of osteoclast cell fusion. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
