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

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.

References

  1. Karsenty, G. & Wagner, E.F. Reaching a genetic and molecular understanding of skeletal development. Dev. Cell 2, 389–406 (2002).

    CAS  Article  Google Scholar 

  2. Teitelbaum, S.L. & Ross, F.P. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638–649 (2003).

    CAS  Article  Google Scholar 

  3. Zaidi, M. Skeletal remodeling in health and disease. Nat. Med. 13, 791–801 (2007).

    CAS  Article  Google Scholar 

  4. Boyle, W.J., Simonet, W.S. & Lacey, D.L. Osteoclast differentiation and activation. Nature 423, 337–342 (2003).

    CAS  Article  Google Scholar 

  5. Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 7, 292–304 (2007).

    CAS  Article  Google Scholar 

  6. Sato, K. et al. Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat. Med. 12, 1410–1416 (2006).

    CAS  Article  Google Scholar 

  7. Brown, D. & Breton, S. Mitochondria-rich, proton-secreting epithelial cells. J. Exp. Biol. 199, 2345–2358 (1996).

    CAS  PubMed  Google Scholar 

  8. Lin, J., Puigserver, P., Donovan, J., Tarr, P. & Spiegelman, B.M. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β), a novel PGC-1-related transcription coactivator associated with host cell factor. J. Biol. Chem. 277, 1645–1648 (2002).

    CAS  Article  Google Scholar 

  9. Lin, J., Handschin, C. & Spiegelman, B.M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005).

    Article  Google Scholar 

  10. St-Pierre, J. et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127, 397–408 (2006).

    CAS  Article  Google Scholar 

  11. Ahn, S. et al. A dominant-negative inhibitor of CREB reveals that it is a general mediator of stimulus-dependent transcription of c-fos. Mol. Cell. Biol. 18, 967–977 (1998).

    CAS  Article  Google Scholar 

  12. Lelliott, C.J. et al. Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol. 4, e369 (2006).

    Article  Google Scholar 

  13. Dunn, L.L., Rahmanto, Y.S. & Richardson, D.R. Iron uptake and metabolism in the new millennium. Trends Cell Biol. 17, 93–100 (2007).

    CAS  Article  Google Scholar 

  14. Andrews, N.C. Iron homeostasis: insights from genetics and animal models. Nat. Rev. Genet. 1, 208–217 (2000).

    CAS  Article  Google Scholar 

  15. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).

    CAS  Article  Google Scholar 

  16. Vianna, C.R. et al. Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance. Cell Metab. 4, 453–464 (2006).

    CAS  Article  Google Scholar 

  17. Sonoda, J., Mehl, I.R., Chong, L.W., Nofsinger, R.R. & Evans, R.M. PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc. Natl. Acad. Sci. USA 104, 5223–5228 (2007).

    CAS  Article  Google Scholar 

  18. Arany, Z. et al. The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metab. 5, 35–46 (2007).

    CAS  Article  Google Scholar 

  19. Lee, N.K. et al. A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 106, 852–859 (2005).

    CAS  Article  Google Scholar 

  20. Garrett, I.R. et al. Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J. Clin. Invest. 85, 632–639 (1990).

    CAS  Article  Google Scholar 

  21. Bax, B.E. et al. Stimulation of osteoclastic bone resorption by hydrogen peroxide. Biochem. Biophys. Res. Commun. 183, 1153–1158 (1992).

    CAS  Article  Google Scholar 

  22. Steinbeck, M.J., Appel, W.H. Jr., Verhoeven, A.J. &, Karnovsky M.J. NADPH-oxidase expression and in situ production of superoxide by osteoclasts actively resorbing bone. J. Cell Biol. 126, 765–772 (1994).

    CAS  Article  Google Scholar 

  23. Lean, J.M. et al. A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J. Clin. Invest. 112, 915–923 (2003).

    CAS  Article  Google Scholar 

  24. Wan, Y., Chong, L.W. & Evans, R.M. PPAR-γ regulates osteoclastogenesis in mice. Nat. Med. 13, 1496–1503 (2007).

    CAS  Article  Google Scholar 

  25. Koga, T. et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758–763 (2004).

    CAS  Article  Google Scholar 

  26. Novack, D.V. et al. The IκB function of NF-κB2 p100 controls stimulated osteoclastogenesis. J. Exp. Med. 198, 771–781 (2003).

    CAS  Article  Google Scholar 

  27. Borgna-Pignatti, C. Thalassemia. A few new tiles in a large mosaic. Haematologica 91, 1159–1161 (2006).

    PubMed  Google Scholar 

  28. Voskaridou, E. & Terpos, E. New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br. J. Haematol. 127, 127–139 (2004).

    CAS  Article  Google Scholar 

  29. Morabito, N. et al. Osteoprotegerin and RANKL in the pathogenesis of thalassemia-induced osteoporosis: new pieces of the puzzle. J. Bone Miner. Res. 19, 722–727 (2004).

    CAS  Article  Google Scholar 

  30. Manolagas, S.C. & Jilka, R.L. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N. Engl. J. Med. 332, 305–311 (1995).

    CAS  Article  Google Scholar 

  31. Takeshita, S. et al. SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts. Nat. Med. 8, 943–949 (2002).

    CAS  Article  Google Scholar 

  32. Ashizuka, M. et al. Novel translational control through an iron-responsive element by interaction of multifunctional protein YB-1 and IRP2. Mol. Cell. Biol. 22, 6375–6383 (2002).

    CAS  Article  Google Scholar 

  33. Tokumitsu, H. et al. Mechanism of the generation of autonomous activity of Ca2+/calmodulin-dependent protein kinase IV. J. Biol. Chem. 279, 40296–40302 (2004).

    CAS  Article  Google Scholar 

  34. Takahashi, N. et al. Osteoblastic cells are involved in osteoclast formation. Endocrinology 123, 2600–2602 (1988).

    CAS  Article  Google Scholar 

  35. Takeshita, S. et al. c-Fms tyrosine 559 is a major mediator of M-CSF-induced proliferation of primary macrophages. J. Biol. Chem. 282, 18980–18990 (2007).

    CAS  Article  Google Scholar 

  36. Allerson, C.R., Cazzola, M. & Rouault, T.A. Clinical severity and thermodynamic effects of iron-responsive element mutations in hereditary hyperferritinemia-cataract syndrome. J. Biol. Chem. 274, 26439–26447 (1999).

    CAS  Article  Google Scholar 

  37. Sassa, S. & Kappas, A. Induction of aminolevulinate synthase and porphyrins in cultured liver cells maintained in chemically defined medium. Permissive effects of hormones on induction process. J. Biol. Chem. 252, 2428–2436 (1977).

    CAS  PubMed  Google Scholar 

  38. Ito, M. et al. Multi-detector row CT imaging of vertebral microstructure for evaluation of fracture risk. J. Bone Miner. Res. 20, 1828–1836 (2005).

    Article  Google Scholar 

  39. Tatsumi, S. et al. Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. Cell Metab. 5, 464–475 (2007).

    CAS  Article  Google Scholar 

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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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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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