title: Oxidized lipids enhance RANKL production by T lymphocytes: implications for lipid-induced bone loss.
abstract: Osteoporosis is a systemic disease that is associated with increased morbidity, mortality and health care costs. Whereas osteoclasts and osteoblasts are the main regulators of bone homeostasis, recent studies underscore a key role for the immune system, particularly via activation-induced T lymphocyte production of receptor activator of NFkappaB ligand (RANKL). Well-documented as a mediator of T lymphocyte/dendritic cell interactions, RANKL also stimulates the maturation and activation of bone-resorbing osteoclasts. Given that lipid oxidation products mediate inflammatory and metabolic disorders such as osteoporosis and atherosclerosis, and since oxidized lipids affect several T lymphocyte functions, we hypothesized that RANKL production might also be subject to modulation by oxidized lipids. Here, we show that short term exposure of both unstimulated and activated human T lymphocytes to minimally oxidized low density lipoprotein (LDL), but not native LDL, significantly enhances RANKL production and promotes expression of the lectin-like oxidized LDL receptor-1 (LOX-1). The effect, which is also observed with 8-iso-Prostaglandin E2, an inflammatory isoprostane produced by lipid peroxidation, is mediated via the NFkappaB pathway, and involves increased RANKL mRNA expression. The link between oxidized lipids and T lymphocytes is further reinforced by analysis of hyperlipidemic mice, in which bone loss is associated with increased RANKL mRNA in T lymphocytes and elevated RANKL serum levels. Our results suggest a novel pathway by which T lymphocytes contribute to bone changes, namely, via oxidized lipid enhancement of RANKL production. These findings may help elucidate clinical associations between cardiovascular disease and decreased bone mass, and may also lead to new immune-based approaches to osteoporosis.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA.
authors.forename: Lucia S
authors.initials: LS
authors.lastname: Graham
authors.forename: Farhad
authors.initials: F
authors.lastname: Parhami
authors.forename: Yin
authors.initials: Y
authors.lastname: Tintut
authors.forename: Christina M R
authors.initials: CM
authors.lastname: Kitchen
authors.forename: Linda L
authors.initials: LL
authors.lastname: Demer
authors.forename: Rita B
authors.initials: RB
authors.lastname: Effros
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000139:chemically induced* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D028421:Isoprostanes / Q000494:pharmacology; D008055:Lipids / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D053244:Osteoprotegerin / Q000235:genetics; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000494:pharmacology; D053245:RANK Ligand / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D028421:Isoprostanes; D008055:Lipids; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C495137:OLR1 protein, human; D053244:Osteoprotegerin; D010713:Phosphatidylcholines; D053245:RANK Ligand; D051127:Scavenger Receptors, Class E; C505688:TNFSF11 protein, human; D051996:Transcription Factor RelA; C099252:oxidized low density lipoprotein; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D015232:Dinoprostone; C011987:8-isoprostaglandin E2
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