Human apolipoprotein e isoforms differentially affect bone mass and turnover in vivo

Marco Dieckmann, F. Timo Beil, Brigitte Mueller, Alexander Bartelt, Robert P. Marshall, Till Koehne, Michael Amling, Wolfgang Ruether, Jackie A. Cooper, Steve E. Humphries, Joachim Herz, Andreas Niemeier

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)236-245
Number of pages10
JournalJournal of Bone and Mineral Research
Volume28
Issue number2
DOIs
StatePublished - Feb 2013

Fingerprint

Apolipoprotein E2
Apolipoproteins
Bone Remodeling
Apolipoproteins E
Protein Isoforms
Apolipoprotein E3
Apolipoprotein E4
Osteoprotegerin
Bone and Bones
Lumbar Vertebrae
Bone Resorption
Thigh
Osteogenesis
Lipoproteins
Alleles
Tomography
Ligands
Phenotype
Serum
Genes

Keywords

  • Apolipoprotein E
  • bone mass
  • genetic risk factor
  • OPG
  • RANKL

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Dieckmann, M., Timo Beil, F., Mueller, B., Bartelt, A., Marshall, R. P., Koehne, T., ... Niemeier, A. (2013). Human apolipoprotein e isoforms differentially affect bone mass and turnover in vivo. Journal of Bone and Mineral Research, 28(2), 236-245. https://doi.org/10.1002/jbmr.1757

Human apolipoprotein e isoforms differentially affect bone mass and turnover in vivo. / Dieckmann, Marco; Timo Beil, F.; Mueller, Brigitte; Bartelt, Alexander; Marshall, Robert P.; Koehne, Till; Amling, Michael; Ruether, Wolfgang; Cooper, Jackie A.; Humphries, Steve E.; Herz, Joachim; Niemeier, Andreas.

In: Journal of Bone and Mineral Research, Vol. 28, No. 2, 02.2013, p. 236-245.

Research output: Contribution to journalArticle

Dieckmann, M, Timo Beil, F, Mueller, B, Bartelt, A, Marshall, RP, Koehne, T, Amling, M, Ruether, W, Cooper, JA, Humphries, SE, Herz, J & Niemeier, A 2013, 'Human apolipoprotein e isoforms differentially affect bone mass and turnover in vivo', Journal of Bone and Mineral Research, vol. 28, no. 2, pp. 236-245. https://doi.org/10.1002/jbmr.1757
Dieckmann M, Timo Beil F, Mueller B, Bartelt A, Marshall RP, Koehne T et al. Human apolipoprotein e isoforms differentially affect bone mass and turnover in vivo. Journal of Bone and Mineral Research. 2013 Feb;28(2):236-245. https://doi.org/10.1002/jbmr.1757
Dieckmann, Marco ; Timo Beil, F. ; Mueller, Brigitte ; Bartelt, Alexander ; Marshall, Robert P. ; Koehne, Till ; Amling, Michael ; Ruether, Wolfgang ; Cooper, Jackie A. ; Humphries, Steve E. ; Herz, Joachim ; Niemeier, Andreas. / Human apolipoprotein e isoforms differentially affect bone mass and turnover in vivo. In: Journal of Bone and Mineral Research. 2013 ; Vol. 28, No. 2. pp. 236-245.
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