title: Skeletal inflammation and attenuation of Wnt signaling, Wnt ligand expression, and bone formation in atherosclerotic ApoE-null mice.
abstract: ApoE-null (ApoE-KO) mice fed a high-fat diet (HFD) develop atherosclerosis, due in part to activation of vascular inflammation by oxidized low-density lipoprotein. Since bone loss also occurs in these mice, we used them to investigate the impact of oxidized lipids on bone homeostasis and to search for underlying pathogenic pathways. Four-month-old female ApoE-KO mice fed a HFD for three months exhibited increased levels of oxidized lipids in bone, as well as decreased femoral and vertebral trabecular and cortical bone mass, compared with ApoE-KO mice on normal diet. Despite HFD-induced increase in expression of Alox15, a lipoxygenase that oxidizes LDL and promotes atherogenesis, global deletion of this gene failed to ameliorate the skeletal impact of HFD. Osteoblast number and function were dramatically reduced in trabecular and cortical bone of HFD-fed mice, whereas osteoclast number was modestly reduced only in trabecular bone, indicating that an imbalance in favor of osteoclasts was responsible for HFD-induced bone loss. These changes were associated with decreased osteoblast progenitors and increased monocyte/macrophages in the bone marrow as well as increased expression of IL-1β, IL-6, and TNF. HFD also attenuated Wnt signaling as evidenced by reduced expression of Wnt target genes, and it decreased expression of pro-osteoblastogenic Wnt ligands. These results suggest that oxidized lipids decrease bone mass by increasing anti-osteoblastogenic inflammatory cytokines and decreasing pro-osteoblastogenic Wnt ligands.
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Maria
authors.initials: M
authors.lastname: Almeida
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weinstein
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas rljilka@uams.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jilka
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001011:Aorta / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics*; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015153:Blotting, Western; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D000071538:Cortical Bone / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D018189:Immunomagnetic Separation; D007249:Inflammation; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D010006:Osteoblasts / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology; D010012:Osteogenesis; D016062:Porosity; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013131:Spine / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D051153:Wnt Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000276:immunology; D055114:X-Ray Microtomography
chemical_list: D001057:Apolipoproteins E; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D008077:Lipoproteins, LDL; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins; C577686:interleukin-6, mouse; C099252:oxidized low density lipoprotein; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
keywords: Wnt signaling; bone remodeling; inflammation; osteoblasts; osteoclasts; osteoporosis