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Metabolic regulation of osteoclast differentiation and function
Author(s) -
Indo Yoriko,
Takeshita Sunao,
Ishii KiyoAki,
Hoshii Takayuki,
Aburatani Hiroyuki,
Hirao Atsushi,
Ikeda Kyoji
Publication year - 2013
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.1976
Subject(s) - osteoclast , ampk , glutamine , glucose transporter , glut1 , glutaminase , chemistry , glucose uptake , gene knockdown , pi3k/akt/mtor pathway , microbiology and biotechnology , protein kinase a , biology , endocrinology , biochemistry , kinase , signal transduction , gene , amino acid , receptor , insulin
The osteoclast is a giant cell that resorbs calcified matrix by secreting acids and collagenolytic enzymes. The molecular mechanisms underlying metabolic adaptation to the increased biomass and energetic demands of osteoclastic bone resorption remain elusive. Here we show that during osteoclastogenesis the expression of both glucose transporter 1 (Glut1) and glycolytic genes is increased, whereas the knockdown of hypoxia‐inducible factor 1‐alpha (Hif1α), as well as glucose deprivation, inhibits the bone‐resorbing function of osteoclasts, along with a suppression of Glut1 and glycolytic gene expression. Furthermore, the expression of the glutamine transporter solute carrier family 1 (neutral amino acid transporter), member 5 (Slc1a5) and glutaminase 1 was increased early in differentiation, and a depletion of L‐glutamine or pharmacological inhibition of the Slc1a5 transporter suppressed osteoclast differentiation and function. Inhibition of c‐Myc function abrogated osteoclast differentiation and function, along with a suppression of Slc1a5 and glutaminase 1 gene expression. Genetic and pharmacological inhibition of mammalian target of rapamycin (mTOR), as well as the activation of adenosine monophosphate (AMP)‐activated protein kinase (AMPK), inhibited osteoclastogenesis. Thus, the uptake of glucose and glutamine and utilization of the carbon sources derived from them, coordinated by HIF1α and c‐Myc, are essential for osteoclast development and bone‐resorbing activity through a balanced regulation of the nutrient and energy sensors, mTOR and AMPK. © 2013 American Society for Bone and Mineral Research