Document Detail


Sphingomyelinase mediates macrophage activation by titanium particles independent of phagocytosis: a role for free radicals, NFkappaB, and TNFalpha.
MedLine Citation:
PMID:  15949909     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The manner in which wear debris initiates intracellular signaling and macrophage activation remains poorly understood. While particle phagocytosis has been implicated in this process, recent studies have shown that phagocytosis is not required for macrophage activation. We examined the hypothesis that titanium particles stimulate macrophages through membrane associated signaling events involving free radicals, sphingomyelinase, NFkappaB, and TNFalpha. Titanium particles stimulated peroxidation of linoleic acid, producing malondialdehyde, while neither lipopolysaccharide nor PBS pre-incubated with particles did, suggesting that the increased peroxidation is related to the presence of the particles themselves. Furthermore, particles stimulated sphingomyelin metabolism in a neutral sphingomyelinase (NSmase) containing cell free system; this effect was inhibited by glutathione, indicating that NSmase activation was due to titanium induced free radicals. Titanium particles also stimulated NSmase activity in cultures of ANA-1 murine macrophages. Addition of purified NSmase to ANA-1 cell cultures stimulated NFkappaB binding, increased transcriptional activity in cells transfected with NFkappaB responsive promoters, and induced TNFalpha expression. These effects were also inhibited by addition of glutathione. Similarly, glutathione inhibited the ability of titanium particles to induce NFkappaB signaling and TNFalpha expression in ANA-1 cells. The findings demonstrate that titanium particles generate free radicals and induce plasma membrane peroxidation and NSmase activation. NSmase, in turn, hydrolyzes sphingomyelin, with activation of the NFkappaB signaling pathway and induction of responsive genes, including TNFalpha. This study demonstrates a mechanism for phagocytosis-independent macrophage activation and defines the sphingomyelin cycle as a potential therapeutic target for the prevention of wear debris induced osteolysis.
Authors:
Alexander Soloviev; Edward M Schwarz; Michael Darowish; Regis J O'Keefe
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2005-06-09
Journal Detail:
Title:  Journal of orthopaedic research : official publication of the Orthopaedic Research Society     Volume:  23     ISSN:  0736-0266     ISO Abbreviation:  J. Orthop. Res.     Publication Date:  2005 Nov 
Date Detail:
Created Date:  2005-10-17     Completed Date:  2005-12-09     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8404726     Medline TA:  J Orthop Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1258-65     Citation Subset:  IM    
Affiliation:
Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Free Radicals
Glutathione / pharmacology
Macrophage Activation*
Mice
NF-kappa B / physiology*
Osteolysis / etiology
Phagocytosis*
Sphingomyelin Phosphodiesterase / physiology*
Titanium / pharmacology*
Tumor Necrosis Factor-alpha / physiology*
Grant Support
ID/Acronym/Agency:
R01 AR46545/AR/NIAMS NIH HHS; R29 AR44220/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Free Radicals; 0/NF-kappa B; 0/Tumor Necrosis Factor-alpha; 70-18-8/Glutathione; 7440-32-6/Titanium; EC 3.1.4.12/Sphingomyelin Phosphodiesterase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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