Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation.
Osteoclasts are acid-secreting polykaryons that have high energy demands and contain abundant mitochondria. How mitochondrial biogenesis is integrated with osteoclast differentiation is unknown. We found that the transcription of Ppargc1b, which encodes peroxisome proliferator-activated receptor-gamma coactivator 1beta (PGC-1beta), was induced during osteoclast differentiation by cAMP response element-binding protein (CREB) as a result of reactive oxygen species. Knockdown of Ppargc1b in vitro inhibited osteoclast differentiation and mitochondria biogenesis, whereas deletion of the Ppargc1b gene in mice resulted in increased bone mass due to impaired osteoclast function. We also observed defects in PGC-1beta-deficient osteoblasts. Owing to the heightened iron demand in osteoclast development, transferrin receptor 1 (TfR1) expression was induced post-transcriptionally via iron regulatory protein 2. TfR1-mediated iron uptake promoted osteoclast differentiation and bone-resorbing activity, associated with the induction of mitochondrial respiration, production of reactive oxygen species and accelerated Ppargc1b transcription. Iron chelation inhibited osteoclastic bone resorption and protected against bone loss following estrogen deficiency resulting from ovariectomy. These data establish mitochondrial biogenesis orchestrated by PGC-1beta, coupled with iron uptake through TfR1 and iron supply to mitochondrial respiratory proteins, as a fundamental pathway linked to osteoclast activation and bone metabolism.
Ishii
Kiyo-aki
KA
Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology (NCGG), 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan.
Fumoto
Toshio
T
Iwai
Kazuhiro
K
Takeshita
Sunao
S
Ito
Masako
M
Shimohata
Nobuyuki
N
Aburatani
Hiroyuki
H
Taketani
Shigeru
S
Lelliott
Christopher J
CJ
Vidal-Puig
Antonio
A
Ikeda
Kyoji
K
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017931:DNA Primers; D005260:Female; D055785:Gene Knockdown Techniques; D007501:Iron / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D011990:Receptors, Transferrin / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D017931:DNA Primers; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D007501:Iron