Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia.
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Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. / Bozec, Aline; Bakiri, Latifa; Hoebertz, Astrid; Eferl, Robert; Schilling, Arndt; Komnenovic, Vukoslav; Scheuch, Harald; Priemel, Matthias; Stewart, Colin L; Amling, Michael; Wagner, Erwin F.
in: NATURE, Jahrgang 454, Nr. 7201, 7201, 2008, S. 221-225.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia.
AU - Bozec, Aline
AU - Bakiri, Latifa
AU - Hoebertz, Astrid
AU - Eferl, Robert
AU - Schilling, Arndt
AU - Komnenovic, Vukoslav
AU - Scheuch, Harald
AU - Priemel, Matthias
AU - Stewart, Colin L
AU - Amling, Michael
AU - Wagner, Erwin F
PY - 2008
Y1 - 2008
N2 - Osteoclasts are multinucleated haematopoietic cells that resorb bone. Increased osteoclast activity causes osteoporosis, a disorder resulting in a low bone mass and a high risk of fractures. Increased osteoclast size and numbers are also a hallmark of other disorders, such as Paget's disease and multiple myeloma. The protein c-Fos, a component of the AP-1 transcription factor complex, is essential for osteoclast differentiation. Here we show that the Fos-related protein Fra-2 controls osteoclast survival and size. The bones of Fra-2-deficient newborn mice have giant osteoclasts, and signalling through leukaemia inhibitory factor (LIF) and its receptor is impaired. Similarly, newborn animals lacking LIF have giant osteoclasts, and we show that LIF is a direct transcriptional target of Fra-2 and c-Jun. Moreover, bones deficient in Fra-2 and LIF are hypoxic and express increased levels of hypoxia-induced factor 1alpha (HIF1alpha) and Bcl-2. Overexpression of Bcl-2 is sufficient to induce giant osteoclasts in vivo, whereas Fra-2 and LIF affect HIF1alpha through transcriptional modulation of the HIF prolyl hydroxylase PHD2. This pathway is operative in the placenta, because specific inactivation of Fra-2 in the embryo alone does not cause hypoxia or the giant osteoclast phenotype. Thus placenta-induced hypoxia during embryogenesis leads to the formation of giant osteoclasts in young pups. These findings offer potential targets for the treatment of syndromes associated with increased osteoclastogenesis.
AB - Osteoclasts are multinucleated haematopoietic cells that resorb bone. Increased osteoclast activity causes osteoporosis, a disorder resulting in a low bone mass and a high risk of fractures. Increased osteoclast size and numbers are also a hallmark of other disorders, such as Paget's disease and multiple myeloma. The protein c-Fos, a component of the AP-1 transcription factor complex, is essential for osteoclast differentiation. Here we show that the Fos-related protein Fra-2 controls osteoclast survival and size. The bones of Fra-2-deficient newborn mice have giant osteoclasts, and signalling through leukaemia inhibitory factor (LIF) and its receptor is impaired. Similarly, newborn animals lacking LIF have giant osteoclasts, and we show that LIF is a direct transcriptional target of Fra-2 and c-Jun. Moreover, bones deficient in Fra-2 and LIF are hypoxic and express increased levels of hypoxia-induced factor 1alpha (HIF1alpha) and Bcl-2. Overexpression of Bcl-2 is sufficient to induce giant osteoclasts in vivo, whereas Fra-2 and LIF affect HIF1alpha through transcriptional modulation of the HIF prolyl hydroxylase PHD2. This pathway is operative in the placenta, because specific inactivation of Fra-2 in the embryo alone does not cause hypoxia or the giant osteoclast phenotype. Thus placenta-induced hypoxia during embryogenesis leads to the formation of giant osteoclasts in young pups. These findings offer potential targets for the treatment of syndromes associated with increased osteoclastogenesis.
M3 - SCORING: Zeitschriftenaufsatz
VL - 454
SP - 221
EP - 225
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 7201
M1 - 7201
ER -