Article abstract
Nature Medicine 15, 259 - 266 (2009)
Published online: 1 March 2009 | doi:10.1038/nm.1910
Coordination of PGC-1
and iron uptake in mitochondrial biogenesis and osteoclast activation
Kiyo-aki Ishii1,10, Toshio Fumoto1, Kazuhiro Iwai2,3,4, Sunao Takeshita1, Masako Ito5, Nobuyuki Shimohata3,10, Hiroyuki Aburatani6, Shigeru Taketani7, Christopher J Lelliott8, Antonio Vidal-Puig9 & Kyoji Ikeda1
Abstract
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-
coactivator 1
(PGC-1), 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-1–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-1, coupled with iron uptake through TfR1 and iron supply to mitochondrial respiratory proteins, as a fundamental pathway linked to osteoclast activation and bone metabolism.
- Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology (NCGG), 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan.
- Department of Biophysics and Biochemistry, Graduate School of Medicine, and Cell Biology and Metabolism Group, Graduate School of Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
- Department of Molecular Cell Biology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
- CREST, Japan Science Technology Corporation, Kawaguchi, Saitama 332-0012, Japan.
- Department of Radiology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
- Genomescience Division, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
- Department of Biotechnology, Kyoto Institute of Technology, Goshokaidoh-chou, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
- Department of Biosciences, AstraZeneca R&D, Pepparedsleden 1, SE-43183, Mölndal, Sweden.
- Metabolic Research Laboratories, Level 4, Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
- Present addresses: Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan (K.Ishii); NEXT21, 3-38-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan (N.S.).
Correspondence to: Kyoji Ikeda1 e-mail: kikeda@nils.go.jp
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