Bone density and hyperlipidemia: the T-lymphocyte connection.
Osteoporosis, which contributes to morbidity and mortality, often coexists with cardiovascular disease, especially atherosclerosis. We have reported recently that in vitro exposure of human T-lymphocytes to oxidized lipids induced expression of a key osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL). Our previous studies have shown that mice fed an atherogenic high-fat diet developed osteopenia and that bone marrow preosteoclasts from these hyperlipidemic mice have increased osteoclastic potential. To investigate the role of T-lymphocytes in the diet-induced bone loss, C57BL/6 mice were fed either chow or a high-fat diet, and bone parameters and T-lymphocyte activation were assessed at 6 and 11 months. Consistent with our previous findings, peripheral quantitative computed tomographic (pQCT) analysis showed that mice in the high-fat group had lower bone mineral content than mice in the chow group. Furthermore, histomorphometric analysis showed decreased structural parameters in the high-fat group. Coculture studies showed that bone marrow cells isolated from the high-fat group, which contained increased levels of activated memory T-lymphocytes compared with bone marrow cells from the chow mice, supported osteoclastic differentiation of RAW 264.7 cells. Additionally, RANKL expression was upregulated significantly in the T-lymphocytes isolated from the bone marrow of the high-fat group. Splenic T-lymphocytes isolated from the high-fat group also had increased expression of transcripts for the receptor for oxidized lipids (LOX-1) as well as for inflammatory and osteoclastogenic cytokines, including RANKL, interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), IL-1β, and interferon γ (IFN-γ). Together these findings suggest that T-lymphocytes play a key role in the osteoclastogenesis induced by a high-fat diet and may contribute to the bone loss associated with diet-induced osteopenia.
Department of Pathology and Laboratory Medicine and David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095-1732, USA.
Lucia S
LS
Graham
Yin
Y
Tintut
Farhad
F
Parhami
Christina M R
CM
Kitchen
Yevgeniv
Y
Ivanov
Sotirios
S
Tetradis
Rita B
RB
Effros
D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006949:Hyperlipidemias / Q000276:immunology* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects; D014057:Tomography, X-Ray Computed
D016207:Cytokines; D004041:Dietary Fats; D018836:Inflammation Mediators; D008055:Lipids; C495138:Olr1 protein, mouse; D051127:Scavenger Receptors, Class E