Human apolipoprotein E isoforms differentially affect bone mass and turnover in vivo.
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Human apolipoprotein E isoforms differentially affect bone mass and turnover in vivo. / Dieckmann, Marco; Beil, Frank Timo; Müller, Brigitte; Bartelt, Alexander; Marshall, Robert Percy; Köhne, Till; Amling, Michael; Ruether, Wolfgang; Cooper, Jackie A; Humphries, Steve E; Herz, Joachim; Niemeier, Andreas.
in: J BONE MINER RES, Jahrgang 28, Nr. 2, 2, 2013, S. 236-245.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Human apolipoprotein E isoforms differentially affect bone mass and turnover in vivo.
AU - Dieckmann, Marco
AU - Beil, Frank Timo
AU - Müller, Brigitte
AU - Bartelt, Alexander
AU - Marshall, Robert Percy
AU - Köhne, Till
AU - Amling, Michael
AU - Ruether, Wolfgang
AU - Cooper, Jackie A
AU - Humphries, Steve E
AU - Herz, Joachim
AU - Niemeier, Andreas
N1 - Copyright © 2013 American Society for Bone and Mineral Research.
PY - 2013
Y1 - 2013
N2 - The primary role of apolipoprotein E (apoE) is to mediate the cellular uptake of lipoproteins. However, a new role for apoE as a regulator of bone metabolism in mice has recently been established. In contrast to mice, the human APOE gene is characterized by three common isoforms APOE ε2, ε3, and ε4 that result in different metabolic properties of the apoE isoforms, but it remains controversial whether the APOE polymorphism influences bone traits in humans. To clarify this, we investigated bone phenotypes of apoE knock-in (k.i.) mice, which express one human isoform each (apoE2 k.i., apoE3 k.i., apoE4 k.i.) in place of the mouse apoE. Analysis of 12-week-old female k.i. mice revealed increased levels of biochemical bone formation and resorption markers in apoE2 k.i. animals as compared to apoE3 k.i. and apoE4 k.i., with a reduced osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio in apoE2 k.i., indicating increased turnover with prevailing resorption in apoE2 k.i. Accordingly, histomorphometric and micro-computed tomography (µCT) analyses demonstrated significantly lower trabecular bone mass in apoE2 than in apoE3 and apoE4 k.i. animals, which was reflected by a significant reduction of lumbar vertebrae maximum force resistance. Unlike trabecular bone, femoral cortical thickness, and stability was not differentially affected by the apoE isoforms. To extend these observations to the human situation, plasma from middle-aged healthy men homozygous for ε2/ε2, ε3/ε3, and ε4/ε4 (n = 21, n = 80, n = 55, respectively) was analyzed with regard to bone turnover markers. In analogy to apoE2 k.i. mice, a lower OPG/RANKL ratio was observed in the serum of ε2/ε2 carriers as compared to ε3/ε3 and ε4/ε4 individuals (p = 0.02 for ε2/ε2 versus ε4/ε4). In conclusion, the current data strongly underline the general importance of apoE as a regulator of bone metabolism and identifies the APOE ε2 allele as a potential genetic risk factor for low trabecular bone mass and vertebral fractures in humans.
AB - The primary role of apolipoprotein E (apoE) is to mediate the cellular uptake of lipoproteins. However, a new role for apoE as a regulator of bone metabolism in mice has recently been established. In contrast to mice, the human APOE gene is characterized by three common isoforms APOE ε2, ε3, and ε4 that result in different metabolic properties of the apoE isoforms, but it remains controversial whether the APOE polymorphism influences bone traits in humans. To clarify this, we investigated bone phenotypes of apoE knock-in (k.i.) mice, which express one human isoform each (apoE2 k.i., apoE3 k.i., apoE4 k.i.) in place of the mouse apoE. Analysis of 12-week-old female k.i. mice revealed increased levels of biochemical bone formation and resorption markers in apoE2 k.i. animals as compared to apoE3 k.i. and apoE4 k.i., with a reduced osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio in apoE2 k.i., indicating increased turnover with prevailing resorption in apoE2 k.i. Accordingly, histomorphometric and micro-computed tomography (µCT) analyses demonstrated significantly lower trabecular bone mass in apoE2 than in apoE3 and apoE4 k.i. animals, which was reflected by a significant reduction of lumbar vertebrae maximum force resistance. Unlike trabecular bone, femoral cortical thickness, and stability was not differentially affected by the apoE isoforms. To extend these observations to the human situation, plasma from middle-aged healthy men homozygous for ε2/ε2, ε3/ε3, and ε4/ε4 (n = 21, n = 80, n = 55, respectively) was analyzed with regard to bone turnover markers. In analogy to apoE2 k.i. mice, a lower OPG/RANKL ratio was observed in the serum of ε2/ε2 carriers as compared to ε3/ε3 and ε4/ε4 individuals (p = 0.02 for ε2/ε2 versus ε4/ε4). In conclusion, the current data strongly underline the general importance of apoE as a regulator of bone metabolism and identifies the APOE ε2 allele as a potential genetic risk factor for low trabecular bone mass and vertebral fractures in humans.
KW - Animals
KW - Humans
KW - Male
KW - Female
KW - Middle Aged
KW - Mice
KW - Mice, Inbred C57BL
KW - Homozygote
KW - Mice, Transgenic
KW - Biomechanics
KW - Organ Size
KW - Gene Knock-In Techniques
KW - Bone Remodeling/physiology
KW - Biological Markers/metabolism
KW - Osteogenesis
KW - Bone Density/physiology
KW - Apolipoprotein E2/blood/genetics
KW - Apolipoprotein E3/genetics/metabolism
KW - Apolipoprotein E4/genetics/metabolism
KW - Apolipoproteins E/genetics/metabolism
KW - Bone and Bones/anatomy & histology/physiology
KW - Femur/physiology
KW - Lumbar Vertebrae/physiology
KW - Osteoprotegerin/blood/metabolism
KW - Protein Isoforms
KW - RANK Ligand/blood/metabolism
KW - Animals
KW - Humans
KW - Male
KW - Female
KW - Middle Aged
KW - Mice
KW - Mice, Inbred C57BL
KW - Homozygote
KW - Mice, Transgenic
KW - Biomechanics
KW - Organ Size
KW - Gene Knock-In Techniques
KW - Bone Remodeling/physiology
KW - Biological Markers/metabolism
KW - Osteogenesis
KW - Bone Density/physiology
KW - Apolipoprotein E2/blood/genetics
KW - Apolipoprotein E3/genetics/metabolism
KW - Apolipoprotein E4/genetics/metabolism
KW - Apolipoproteins E/genetics/metabolism
KW - Bone and Bones/anatomy & histology/physiology
KW - Femur/physiology
KW - Lumbar Vertebrae/physiology
KW - Osteoprotegerin/blood/metabolism
KW - Protein Isoforms
KW - RANK Ligand/blood/metabolism
U2 - 10.1002/jbmr.1757
DO - 10.1002/jbmr.1757
M3 - SCORING: Journal article
C2 - 22991192
VL - 28
SP - 236
EP - 245
JO - J BONE MINER RES
JF - J BONE MINER RES
SN - 0884-0431
IS - 2
M1 - 2
ER -