title: A high-fat diet induces bone loss in mice lacking the Alox5 gene.
abstract: 5-Lipoxygenase catalyzes leukotriene generation from arachidonic acid. The gene that encodes 5-lipoxygenase, Alox5, has been identified in genome-wide association and mouse Quantitative Trait Locus studies as a candidate gene for obesity and low bone mass. Thus, we tested the hypothesis that Alox5(-/-) mice would exhibit metabolic and skeletal changes when challenged by a high-fat diet (HFD). On a regular diet, Alox5(-/-) mice did not differ in total body weight, percent fat mass, or bone mineral density compared with wild-type (WT) controls (P < 0.05). However, when placed on a HFD, Alox5(-/-) gained more fat mass and lost greater areal bone mass vs. WT (P < 0.05). Microarchitectural analyses revealed that on a HFD, WT showed increases in cortical area (P < 0.01) and trabecular thickness (P < 0.01), whereas Alox5(-/-) showed no change in cortical parameters but a decrease in trabecular number (P < 0.05) and bone volume fraction compared with WT controls (P < 0.05). By histomorphometry, a HFD did not change bone formation rates of either strain but produced an increase in osteoclast number per bone perimeter in Alox5(-/-) mice (P < 0.03). In vitro, osteoclastogenesis of marrow stromal cells was enhanced in mutant but not WT mice fed a HFD. Gene expression for Rankl, Pparg, and Cox-2 was greater in the femur of Alox5(-/-) than WT mice on a HFD (P < 0.01), but these increases were suppressed in the Alox5(-/-) mice after 8 wk of treatment with celecoxib, a cyclooxygenase-2 inhibitor. In sum, there is a strong gene by environmental interaction for bone mass when mice lacking the Alox5 gene are fed a HFD.
authors: Center for Clinical and Translational Research, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, Maine 04074-7205, USA.
authors: Phuong
authors: P
authors: Le
authors: Masanobu
authors: M
authors: Kawai
authors: Sheila
authors: S
authors: Bornstein
authors: Victoria E
authors: VE
authors: DeMambro
authors: Mark C
authors: MC
authors: Horowitz
authors: Clifford J
authors: CJ
authors: Rosen
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency* / Q000235:genetics; D015519:Bone Density; D001862:Bone Resorption / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications; D010010:Osteoclasts / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D047495:PPAR gamma; D011720:Pyrazoles; D013449:Sulfonamides; D001094:Arachidonate 5-Lipoxygenase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib