Both aerobic glycolysis and mitochondrial respiration are required for osteoclast differentiation.
Animals
Bone Resorption
/ metabolism
Cell Differentiation
/ physiology
Cell Respiration
/ physiology
Energy Metabolism
/ physiology
Female
Glucose
/ metabolism
Glucose Transporter Type 1
/ metabolism
Glycolysis
/ physiology
Male
Mice
Mice, Inbred C57BL
Mitochondria
/ metabolism
Osteoclasts
/ metabolism
Osteogenesis
/ physiology
Oxidative Phosphorylation
Oxygen
/ metabolism
aerobic glycolysis
bone
metabolism
osteoclast
oxidative phosphorylation
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
08
04
2020
revised:
02
06
2020
accepted:
11
06
2020
pubmed:
7
7
2020
medline:
26
2
2021
entrez:
7
7
2020
Statut:
ppublish
Résumé
Excessive bone resorption over bone formation is the root cause for bone loss leading to osteoporotic fractures. Development of new antiresorptive therapies calls for a holistic understanding of osteoclast differentiation and function. Although much has been learned about the molecular regulation of osteoclast biology, little is known about the metabolic requirement and bioenergetics during osteoclastogenesis. Here, we report that glucose metabolism through oxidative phosphorylation (OXPHOS) is the predominant bioenergetic pathway to support osteoclast differentiation. Meanwhile, increased lactate production from glucose, known as aerobic glycolysis when oxygen is abundant, is also critical for osteoclastogenesis. Genetic deletion of Glut1 in osteoclast progenitors reduces aerobic glycolysis without compromising OXPHOS, but nonetheless diminishes osteoclast differentiation in vitro. Glut1 deficiency in the progenitors leads to osteopetrosis due to fewer osteoclasts specifically in the female mice. Thus, Glut1-mediated glucose metabolism through both lactate production and OXPHOS is necessary for normal osteoclastogenesis.
Identifiants
pubmed: 32627870
doi: 10.1096/fj.202000771R
doi:
Substances chimiques
Glucose Transporter Type 1
0
Glucose
IY9XDZ35W2
Oxygen
S88TT14065
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11058-11067Subventions
Organisme : NIH HHS
ID : P30 AR057235
Pays : United States
Organisme : NIH HHS
ID : R01 DK111212
Pays : United States
Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
Références
Sims NA, Martin TJ. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bonekey Rep. 2014;3:481.
Ramchand SK, Seeman E. Advances and unmet needs in the therapeutics of bone fragility. Front Endocrinol (Lausanne). 2018;9:505.
Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003;4:638-649.
Karner CM, Long F. Glucose metabolism in bone. Bone. 2018;115:2-7.
Arnett TR, Orriss IR. Metabolic properties of the osteoclast. Bone. 2018;115:25-30.
Miyazaki T, Iwasawa M, Nakashima T, et al. Intracellular and extracellular ATP coordinately regulate the inverse correlation between osteoclast survival and bone resorption. J Biol Chem. 2012;287:37808-37823.
Jin Z, Wei W, Yang M, Du Y, Wan Y. Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. Cell Metab. 2014;20:483-498.
Ishii KA, Fumoto T, Iwai K, et al. Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat Med. 2009;15:259-266.
Zeng R, Faccio R, Novack DV. Alternative NF-kappaB regulates RANKL-induced osteoclast differentiation and mitochondrial biogenesis via independent mechanisms. J Bone Miner Res. 2015;30:2287-2299.
Zhang Y, Rohatgi N, Veis DJ, Schilling J, Teitelbaum SL, Zou W. PGC1beta organizes the osteoclast cytoskeleton by mitochondrial biogenesis and activation. J Bone Miner Res. 2018;33:1114-1125.
Williams JP, Blair HC, McDonald JM, et al. Regulation of osteoclastic bone resorption by glucose. Biochem Biophys Res Commun. 1997;235:646-651.
Kim JM, Jeong D, Kang HK, Jung SY, Kang SS, Min BM. Osteoclast precursors display dynamic metabolic shifts toward accelerated glucose metabolism at an early stage of RANKL-stimulated osteoclast differentiation. Cell Physiol Biochem. 2007;20:935-946.
Indo Y, Takeshita S, Ishii KA, et al. Metabolic regulation of osteoclast differentiation and function. J Bone Miner Res. 2013;28:2392-2399.
Ahn H, Lee K, Kim JM, et al. Accelerated lactate dehydrogenase activity potentiates osteoclastogenesis via NFATc1 signaling. PLoS One. 2016;11:e0153886.
Clausen BE, Burkhardt C, Reith W, Renkawitz R, Forster I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 1999;8:265-277.
Young CD, Lewis AS, Rudolph MC, et al. Modulation of glucose transporter 1 (GLUT1) expression levels alters mouse mammary tumor cell growth in vitro and in vivo. PLoS One. 2011;6:e23205.
Novack DV, Yin L, Hagen-Stapleton A, et al. The IkappaB function of NF-kappaB2 p100 controls stimulated osteoclastogenesis. J Exp Med. 2003;198:771-781.
Takeshita S, Kaji K, Kudo A. Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts. J Bone Miner Res. 2000;15:1477-1488.
McHugh KP, Hodivala-Dilke K, Zheng M-H, et al. Mice lacking β3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Investig. 2000;105:433-440.
Almeida M, Laurent MR, Dubois V, et al. Estrogens and androgens in skeletal physiology and pathophysiology. Physiol Rev. 2017;97:135-187.
Spencer JA, Ferraro F, Roussakis E, et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature. 2014;508:269-273.