title: Metabolic regulation of osteoclast differentiation and function.
abstract: 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.
authors: Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
authors: Yoriko
authors: Y
authors: Indo
authors: Sunao
authors: S
authors: Takeshita
authors: Kiyo-Aki
authors: KA
authors: Ishii
authors: Takayuki
authors: T
authors: Hoshii
authors: Hiroyuki
authors: H
authors: Aburatani
authors: Atsushi
authors: A
authors: Hirao
authors: Kyoji
authors: K
authors: Ikeda
mesh_terms: D026962:Amino Acid Transport System ASC / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D026962:Amino Acid Transport System ASC; D051272:Glucose Transporter Type 1; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015778:Minor Histocompatibility Antigens; D016271:Proto-Oncogene Proteins c-myc; C498850:Slc1a5 protein, mouse; C495678:Slc2a1 protein, mouse; D005973:Glutamine; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: BIOENERGETICS; BIOSYNTHESIS; GLUTAMINOLYSIS; GLYCOLYSIS; OSTEOCLAST