直近一年間の累計
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ID 118999
タイトル別表記
Cx43/miR21/HMGB1/RANKL pathway in osteocytes
著者
Davis, Hannah M. Indiana University
Pacheco-Costa, Rafael Indiana University
Atkinson, Emily G. Indiana University
Brun, Lucas R. Indiana University
Gortazar, Arancha R. Universidad San Pablo-CEU
Harris, Julia Indiana University
Bolarinwa, Surajudeen A. Indiana University
Yoneda, Toshiyuki Indiana University
Ivan, Mircea Indiana University
Bruzzaniti, Angela Indiana University
Bellido, Teresita Indiana University|Roudebush Veterans Administration Medical Center
Plotkin, Lilian I. Indiana University|Roudebush Veterans Administration Medical Center
キーワード
aging
apoptosis
connexin43
HMGB1
miR21
osteocyte
資料タイプ
学術雑誌論文
抄録
Skeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43-silenced MLO-Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase-3 activation and exhibit increased levels of apoptosis-related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro-survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43-expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis-related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high-mobility group box-1 (HMGB1)], and caspase-3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1-RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.
掲載誌名
Aging Cell
ISSN
14749726
14749718
cat書誌ID
AA1168790X
出版者
John Wiley & Sons|The Anatomical Society
16
3
開始ページ
551
終了ページ
563
発行日
2017-03-19
権利情報
This is an open access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
出版社版
部局
歯学系