title: Apolipoprotein E inhibits osteoclast differentiation via regulation of c-Fos, NFATc1 and NF-κB.
abstract: Apolipoprotein E (ApoE) plays a major role in the transport and metabolism of lipid. Other functions of ApoE include modulation of innate and adaptive immune responses. The expression of ApoE in osteoblasts and its relevance with bone formation have also been reported. However, the effect of ApoE on osteoclasts has not yet been examined. Here, we investigated the role of ApoE in osteoclast differentiation using bone marrow-derived macrophages (BMMs) and RAW264.7 cells. We found a down-regulation of ApoE gene expression during osteoclastic differentiation of those cells. Overexpression of ApoE in BMMs and RAW264.7 cells significantly blocked the induction of c-Fos and nuclear factor of activated T cell c1 (NFATc1), transcription factors critical for expression of osteoclast marker genes, by receptor activator of nuclear factor κB ligand (RANKL), the osteoclast differentiation factor. ApoE inhibited osteoclast differentiation, as measured by decreased number of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells (MNCs). In addition, ApoE reduced the expression of dendritic cell-specific transmembrane protein (DC-STAMP) and ATPase, H(+) transporting, lysosomal 38kDa, V0 subunit d2 (ATP6v0d2), genes involved in cell-cell fusion during osteoclastogenesis. Knock-down of ApoE using a specific siRNA promoted the RANKL-mediated induction of osteoclast differentiation. While ApoE did not affect the activation of ERK, JNK, and p38 MAPK signaling pathways by RANKL, the phosphorylation of p65 trans-activation domain on serine 536 and transcription activity of NF-κB were reduced by ApoE overexpression. These findings suggest that ApoE plays an inhibitory role in osteoclast differentiation via the suppression of RANKL-dependent activation of NF-κB and induction of c-Fos and NFATc1.
authors.affiliation: Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute, Seoul National University, 28 Yeongon-Dong, Chongno-Gu, Seoul 110-749, Republic of Korea.
authors.forename: Woo-Shin
authors.initials: WS
authors.lastname: Kim
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
authors.forename: Youngkyun
authors.initials: Y
authors.lastname: Lee
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D053245:RANK Ligand / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection
chemical_list: D001057:Apolipoproteins E; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D011994:Recombinant Proteins