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

被引:332
作者
Ishii, Kiyo-aki [1 ]
Fumoto, Toshio [1 ]
Iwai, Kazuhiro [2 ,3 ,4 ,5 ]
Takeshita, Sunao [1 ]
Ito, Masako [6 ]
Shimohata, Nobuyuki [4 ]
Aburatani, Hiroyuki [7 ]
Taketani, Shigeru [8 ]
Lelliott, Christopher J. [9 ]
Vidal-Puig, Antonio [10 ]
Ikeda, Kyoji [1 ]
机构
[1] NCGG, Dept Bone & Joint Dis, Aichi 4748522, Japan
[2] Osaka Univ, Dept Biochem & Biophys, Grad Sch Med, Suita, Osaka 5650871, Japan
[3] Osaka Univ, Cell Biol & Metab Grp, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan
[4] Osaka City Univ, Dept Mol Cell Biol, Grad Sch Med, Abeno Ku, Osaka 5458585, Japan
[5] Japan Sci Technol Corp, CREST, Kawaguchi, Saitama 3320012, Japan
[6] Nagasaki Univ, Sch Med, Dept Radiol, Nagasaki 8528501, Japan
[7] Univ Tokyo, RCAST, Genomesci Div, Meguro Ku, Tokyo 1538904, Japan
[8] Kyoto Inst Technol, Dept Biotechnol, Sakyo Ku, Kyoto 6068585, Japan
[9] AstraZeneca R&D, Dept Biosci, SE-43183 Molndal, Sweden
[10] Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 0QQ, England
基金
英国医学研究理事会;
关键词
RESPONSIVE ELEMENT; BONE-RESORPTION; CRUCIAL ROLE; TRANSCRIPTION; OSTEOPOROSIS; COACTIVATOR; INSIGHTS; RANKL; PATHOPHYSIOLOGY; DIFFERENTIATION;
D O I
10.1038/nm.1910
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 1 beta (PGC-1 beta), 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 beta-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 beta, coupled with iron uptake through TfR1 and iron supply to mitochondrial respiratory proteins, as a fundamental pathway linked to osteoclast activation and bone metabolism.
引用
收藏
页码:259 / 266
页数:8
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