Metabolic regulation of osteoclast differentiation and function. (18th October 2013)

• Record Type: Journal Article
• Authors: Indo, Yoriko; Takeshita, Sunao; Ishii, Kiyo‐Aki; Hoshii, Takayuki; Aburatani, Hiroyuki; Hirao, Atsushi; Ikeda, Kyoji
• Is Part Of: Journal of bone and mineral research. Volume 28:Number 11(2013:Nov.)
• Page Start: 2392
• Page End: 2399
• Publication Date: 2013-10-18
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.1976
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr1976-sec-0001" sec-type="section"> <p>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</p> </sec> </abstract>