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Coordination of PGC-1β and iron uptake in mitochondrial biogenesis and osteoclast activation

Nature Medicine volume 15, pages 259–266 (2009)Cite this article

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-γ coactivator 1β (PGC-1β), 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-1β–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-1β, coupled with iron uptake through TfR1 and iron supply to mitochondrial respiratory proteins, as a fundamental pathway linked to osteoclast activation and bone metabolism.

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Figure 1: Transcriptional induction of Ppargc1b with osteoclastogenesisis by CREB through ROS.
Figure 2: Impaired bone resorption in PGC-1β knockout (Ppargc1b−/−) mice.
Figure 3: Induction of the transferrin (Tf) receptor with osteoclast differentiation and stimulation of osteoclastogenesis by iron-transferrin.
Figure 4: Transferrin (Tf) promotes and iron chelation inhibits bone resorption by mature osteoclasts.
Figure 5: Proposed model of the newly identified mitochondrial pathway in the regulation of osteoclast development and bone resorption.

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Acknowledgements

We thank H. Bito (University of Tokyo) and C. Vinson (US National Institutes of Health (NIH)) for permission to use the CREB and A-CREB cDNAs, respectively; H. Takayanagi (Tokyo Medical and Dental University) for retroviral vectors for the expression of CREB and A-CREB; T. Kitamura (University of Tokyo) for retroviral vectors; H. Zhao (Washington University) for instructions on the actin ring assay; N. Nozaki (Kanagawa Dental College) for the antibody to phospho-CaMKIV; A. Ito for providing photomicrographs of osteoclasts; M. Suzuki for technical assistance; and members of the National Center for Geriatrics and Gerontology (NCGG) for stimulating discussion. This study was supported in part by Grants-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (#19790655 to K. Ishii) and for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) of Japan (#06-31 to K. Ikeda and M.I.), by the Tokyo Biochemical Research Foundation (to K. Ikeda) and by the British Heart Foundation and the Medical Research Council Centre for Obesity and Related metabolic Diseases (MRC CORD (to A.V.-P.). Pacific Edit reviewed the manuscript before submission.

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Author notes

  1. Kiyo-aki Ishii & Nobuyuki Shimohata

    Present address: 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.).,

Authors and Affiliations

  1. Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology (NCGG), 36-3 Gengo, Morioka, Obu, Aichi, 474-8522, Japan

    Kiyo-aki Ishii, Toshio Fumoto, Sunao Takeshita & Kyoji Ikeda

  2. 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

    Kazuhiro Iwai

  3. Department of Molecular Cell Biology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Kazuhiro Iwai & Nobuyuki Shimohata

  4. CREST, Japan Science Technology Corporation, Kawaguchi, 332-0012, Saitama, Japan

    Kazuhiro Iwai

  5. Department of Radiology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    Masako Ito

  6. Genomescience Division, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan

    Hiroyuki Aburatani

  7. Department of Biotechnology, Kyoto Institute of Technology, Goshokaidoh-chou, Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan

    Shigeru Taketani

  8. Department of Biosciences, AstraZeneca R&D, Pepparedsleden 1, Mölndal, SE-43183, Sweden

    Christopher J Lelliott

  9. Metabolic Research Laboratories, Level 4, Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK

    Antonio Vidal-Puig

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Contributions

K. Ishii, T.F. and S.T. performed research and analyzed data on bone biology in vitro and in vivo; M.I. performed micro-CT scanning of bone and analyzed data; K. Iwai, N.S. and S.T. performed research and analyzed data on iron metabolism, and provided experimental advice; H.A. performed DNA chip analysis and provided data; C.J.L. and A.V.-P. developed PGC-1β knockout mice, contributed reagents and provided experimental advice; K. Ishii and K. Ikeda designed research; K. Ikeda wrote the paper; all authors reviewed the manuscript.

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Correspondence to Kyoji Ikeda.

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C.L. is an employee and stockholder of AstraZeneca.

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Ishii, Ka., Fumoto, T., Iwai, K. et al. Coordination of PGC-1β and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat Med 15, 259–266 (2009). https://doi.org/10.1038/nm.1910

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