Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1862, Issue 5, Pages 452-462Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2017.01.008
Keywords
RANKL-induced osteoclastogenesis; Non-muscle myosin II-A; Phosphoglycerol dihydroceramide; Racl small GTPase; DC-STAMP; Porphyromonas gingivalis
Funding
- NIH grants [T32 DE 007327-12]
- Forsyth Pilot from the National Institute of Dental and Craniofacial Research [DE-003420, DE-018310, DE-019917, DE-018499, DE-021055]
- Japan Society for the Promotion of Science [23689081, 25670841, 15 K11376]
- King Abdulaziz University (KAU)
- Grants-in-Aid for Scientific Research [25670841] Funding Source: KAKEN
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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 RANKLinduced 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 Racl, 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 Racl/DC-STAMP pathway for upregulation of osteoclast cell fusion. (C) 2017 Published by Elsevier B.V.
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