Oxidized low density lipoprotein decreases Rankl-induced differentiation of osteoclasts by inhibition of Rankl signaling.
The role of OxLDL in the generation and progression of atherosclerosis is well admitted. In addition, it is well known that atherosclerosis is often accompanied by perturbations in bone remodeling, resulting in osteoporosis. In the current studies, the effect of Cu(2+)-oxidized LDL (OxLDL) on RANKL-induced RAW264.7 mouse monocytes-macrophages differentiation to osteoclasts and on RANKL signaling pathway was investigated. OxLDL, within the range of 10-50 microg protein/ml, prevented RANKL-induced generation of multinucleated osteoclast-like cells and RANKL-induced tartrate resistant acid phosphatase (TRAP) activity. OxLDL also prevented the RANKL-induced phosphorylation of ERK, p38 and JNK kinases, together with the RANKL-induced DNA binding activities of NFkappaB and NFAT transcription factors. Concomitantly, OxLDL enhanced RANKL-induced generation of reactive oxygen species in a dose-dependent manner. The antioxidant glutathione (GSH) prevented whereas the prooxidant compound buthionine-sulfoximine (BSO) enhanced the effect of OxLDL on RANKL-induced oxidative stress and RANKL-induced differentiation. Finally, OxLDL also prevented RANKL-induced TRAP activity and RANKL-induced bone resorbing activity of human peripheral blood mononuclear cells. These results demonstrate that OxLDL, by generation of an intracellular oxidative stress, prevents the differentiation of osteoclasts by inhibition of RANKL signaling pathway. This might be related to the fact that atherosclerosis is accompanied by perturbations in bone and vascular remodeling, leading to osteoporosis and vascular calcification.
Mazière
Cécile
C
INSERM ERI-12, Amiens, France. maziere.cecile@chu-amiens.fr
Louvet
Loïc
L
Gomila
Cathy
C
Kamel
Said
S
Massy
Ziad
Z
Mazière
Jean-Claude
JC
D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000473:pathology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000071681:Tartrate-Resistant Acid Phosphatase; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007527:Isoenzymes; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D017382:Reactive Oxygen Species; C505688:TNFSF11 protein, human; C505689:Tnfsf11 protein, mouse; C099252:oxidized low density lipoprotein; D019328:Buthionine Sulfoximine; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D005978:Glutathione