title: Accelerated Lactate Dehydrogenase Activity Potentiates Osteoclastogenesis via NFATc1 Signaling.
abstract: Osteoclasts seem to be metabolic active during their differentiation and bone-resorptive activation. However, the functional role of lactate dehydrogenase (LDH), a tetrameric enzyme consisting of an A and/or B subunit that catalyzes interconversion of pyruvate to lactate, in RANKL-induced osteoclast differentiation is not known. In this study, RANKL treatment induced gradual gene expression and activation of the LDH A2B2 isotype during osteoclast differentiation as well as the LDH A1B3 and B4 isotypes during osteoclast maturation after pre-osteoclast formation. Glucose consumption and lactate production in growth media were accelerated during osteoclast differentiation, together with enhanced expression of H+-lactate co-transporter and increased extracellular acidification, demonstrating that glycolytic metabolism was stimulated during differentiation. Further, oxygen consumption via mitochondria was stimulated during osteoclast differentiation. On the contrary, depletion of LDH-A or LDH-B subunit suppressed both glycolytic and mitochondrial metabolism, resulting in reduced mature osteoclast formation via decreased osteoclast precursor fusion and down-regulation of the osteoclastogenic critical transcription factor NFATc1 and its target genes. Collectively, our findings suggest that RANKL-induced LDH activation stimulates glycolytic and mitochondrial respiratory metabolism, facilitating mature osteoclast formation via osteoclast precursor fusion and NFATc1 signaling.
authors.affiliation: Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, Korea.
authors.forename: Heejin
authors.initials: H
authors.lastname: Ahn
authors.affiliation: Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, Korea.
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, Korea.
authors.forename: Jin Man
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, Korea.
authors.forename: So Hyun
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Department of Oral Microbiology and Immunology, College of Dentistry, Wonkwang University, Iksan, Korea.
authors.forename: Seoung Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Life Science and Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, Korea.
authors.forename: Daewon
authors.initials: D
authors.lastname: Jeong
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D015151:Immunoblotting; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000235:genetics; D053245:RANK Ligand / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D007527:Isoenzymes; D007773:Lactates; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D016173:Macrophage Colony-Stimulating Factor; D007770:L-Lactate Dehydrogenase; D005947:Glucose