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Biochem Biophys Res Commun. 2018 Sep 5;503(2):644-650. doi: 10.1016/j.bbrc.2018.06.055. Epub 2018 Jun 15.

Apolipoprotein E plays crucial roles in maintaining bone mass by promoting osteoblast differentiation via ERK1/2 pathway and by suppressing osteoclast differentiation via c-Fos, NFATc1, and NF-κB pathway.

Author information

1
Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Department of Orthopaedic Surgery, Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka, 586-8521, Japan.
2
Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. Electronic address: k-ebina@umin.ac.jp.
3
Department of Orthopaedic Surgery, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
4
Department of Orthopaedics, University of Maryland School of Medicine, MD, 21201, USA.
5
Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA.
6
Department of Cardiovascular Medicine, Sousei Hospital, 596 Oaza-Yokochi, Kadoma, Osaka, 571-0023, Japan.
7
Department of Cardiovascular Medicine, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Department of Dental Anesthesiology, Osaka University, Graduate School of Medicine, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.
8
Department of Cardiovascular Medicine, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Department of Community Medicine, Osaka University, Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Rinku General Medical Center, 2-23 Ohrai-kita, Rinku, Izumisano, Osaka, 598-8577, Japan.

Abstract

Apolipoprotein E (ApoE) plays crucial roles not only in lipid metabolism but also in bone metabolism. Specifically ApoE4, one of major ApoE isoforms, has been demonstrated to be associated with increased risk of developing osteoporosis compared to another major isoform ApoE3. However, the detailed mechanism of how the different ApoE isoforms affect bone metabolism remains unclear. Micro-CT analyses of distal femora demonstrated severely decreased bone mass in 48-week-old female homozygous ApoE-knockout (ApoE-KO) mice compared to age- and gender-matched wild type C57BL/6 J (WT) mice. Physiological levels of either ApoE3 or ApoE4 protein (1-20 μg/ml) significantly increased the expression of osteoblast-related genes and alkaline phosphatase (ALP) activity of primary calvarial osteoblasts by inhibiting extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in a dose-dependent manner, and ApoE3 showed greater osteoblastic induction compared to ApoE4. Furthermore, both ApoE3 and ApoE4 protein inhibited osteoclastogenesis and the expression of osteoclast-related genes of mouse bone marrow derived macrophages (BMDM) via down regulation of c-Fos, nuclear factor of activated T-cells 1 (NFATc1) and nuclear factor-kappa B (NF-κB) pathway. Moreover, ApoE3 showed greater inhibition of c-Fos, dendritic cell-specific transmembrane protein (DC-STAMP), and Cathepsin K gene expression compared to ApoE4. Collectively, ApoE plays crucial roles in preserving bone mass, suggesting that targeting ApoE and its isoforms as a promising treatment candidate of both osteoporosis and hyperlipidemia.

KEYWORDS:

Apolipoprotein E; Hyperlipidemia; Osteoblast; Osteoclast; Osteoporosis

PMID:
29906458
DOI:
10.1016/j.bbrc.2018.06.055
[Indexed for MEDLINE]

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