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

Ishii, Kiyo‐aki; Fumoto, Toshio; Iwaï, Kazuhiro; Takeshita, Satoshi; Ito, Masako; Shimohata, Nobuyuki; Aburatani, Hiroyuki; Taketani, Shigeru; Lelliott, Christopher J.; Vidal-Puig, António; Ikeda, Kyoji

doi:10.1038/nm.1910

Cited by 338 publications

(360 citation statements)

References 38 publications

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“…1A, Lower). Among the 13 genes selected were Nfatc1, Ppargc1b, and Fosl2, which are known to function as transcriptional activators in osteoclast differentiation (13,28,29). Blimp1 also has been classified with this group of transcription factors but is known to be a transcriptional repressor required for plasma cell function (24).…”

Section: Resultsmentioning

confidence: 99%

Blimp1-mediated repression of negative regulators is required for osteoclast differentiation

Nishikawa

Nakashima²,

Hayashi³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

157

154

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Regulation of irreversible cell lineage commitment depends on a delicate balance between positive and negative regulators, which comprise a sophisticated network of transcription factors. Receptor activator of NF-κB ligand (RANKL) stimulates the differentiation of bone-resorbing osteoclasts through the induction of nuclear factor of activated T cells c1 (NFATc1), the essential transcription factor for osteoclastogenesis. Osteoclast-specific robust induction of NFATc1 is achieved through an autoamplification mechanism, in which NFATc1 is constantly activated by calcium signaling while the negative regulators of NFATc1 are suppressed. However, it has been unclear how such negative regulators are repressed during osteoclastogenesis. Here we show that B lymphocyte-induced maturation protein-1 (Blimp1; encoded by Prdm1), which is induced by RANKL through NFATc1 during osteoclastogenesis, functions as a transcriptional repressor of antiosteoclastogenic genes such as Irf8 and Mafb. Overexpression of Blimp1 leads to an increase in osteoclast formation, and Prdm1-deficient osteoclast precursor cells do not undergo osteoclast differentiation efficiently. The importance of Blimp1 in bone homeostasis is underscored by the observation that mice with an osteoclast-specific deficiency in the Prdm1 gene exhibit a high bone mass phenotype caused by a decreased number of osteoclasts. Thus, NFATc1 choreographs the determination of cell fate in the osteoclast lineage by inducing the repression of negative regulators as well as through its effect on positive regulators.B lymphocyte induced maturation protein 1 | nuclear factor of activated T cells c1 | osteoclastogenesis | transcription | bone

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Section: Resultsmentioning

confidence: 99%

Blimp1-mediated repression of negative regulators is required for osteoclast differentiation

Nishikawa

Nakashima²,

Hayashi³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

157

154

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“…16 Iron chelation inhibits osteoclastic bone resorption in vitro. 8 In sickle cell disease, iron overload was reported to be associated with a lower bone mass index in one study. 25 However, current information is inconclusive for a possible correlation between bone mineral density and iron stores as reflected by serum ferritin concentration in patients with sickle cell disease.…”

Section: Beta (95% Ci) P Standardized Betamentioning

confidence: 97%

“…3 Both in vitro and animal experiments indicate that iron may play a role in bone formation and/or destruction. [6][7][8] An increased amount of iron has been associated with reduced in vitro osteoblast proliferation 9 and extracellular calcium deposition. 10 In a mouse model, iron dextran injection increased the osteoclast population in the bone structure and reduced the number and thickness of trabeculae.…”

Section: Introductionmentioning

confidence: 99%

Predictors of osteoclast activity in patients with sickle cell disease

Nouraie¹,

Cheng²,

Niu³

et al. 2011

Haematologica

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BackgroundBone changes are common in sickle cell disease, but the pathogenesis is not fully understood. Tartrate-resistant acid phosphatase (TRACP) type 5b is produced by bone-resorbing osteoclasts. In other forms of hemolytic anemia, increased iron stores are associated with osteoporosis. We hypothesized that transfusional iron overload would be associated with increased osteoclast activity in patients with sickle cell disease. Design and MethodsWe examined tartrate-resistant acid phosphatase 5b concentrations in patients with sickle cell disease and normal controls of similar age and sex distribution at steady state. Serum tartrateresistant acid phosphatase 5b concentration was measured using an immunocapture enzyme assay and plasma concentrations of other cytokines were assayed using the Bio-Plex suspension array system. Tricuspid regurgitation velocity, an indirect measure of systolic pulmonary artery pressure, was determined by echocardiography. ResultsTartrate-resistant acid phosphatase 5b concentrations were higher in 58 adults with sickle cell disease than in 22 controls (medians of 4.4 versus 2.4 U/L, respectively; P=0.0001). Among the patients with sickle cell disease, tartrate-resistant acid phosphatase 5b independently correlated with blood urea nitrogen (standardized beta=0.40, P=0.003), interleukin-8 (standardized beta=0.30, P=0.020), and chemokine C-C motif ligand 5 (standardized beta=-0.28, P=0.031) concentrations, but not with serum ferritin concentration. Frequent blood transfusions (>10 units in life time) were not associated with higher tartrate-resistant acid phosphatase 5b levels in multivariate analysis. There were strong correlations among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity (r>0.35, P<0.001). ConclusionsPatients with sickle cell disease have increased osteoclast activity as reflected by serum tartrateresistant acid phosphatase 5b concentrations. Our results may support a potential role of inflammation rather than increased iron stores in stimulating osteoclast activity in sickle cell disease. The positive relationships among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity raise the possibility of a common pathway in the pulmonary and bone complications of sickle cell disease.Key words: sickle cell disease, osteoclast activity, bone turnover, inflammation, TRACP 5b, pulmonary complications.Citation: Nouraie M, Cheng K, Niu X, Moore-King E, Fadojutimi-Akinsi MF, Minniti CP, Sable C, Rana S, Dham N, Campbell A, Ensing G, Kato GJ, Gladwin MT, Castro OL, and Gordeuk VR. Predictors of osteoclast activity in sickle cell disease patients. Haematologica 2011;96(8):1092-1098. doi:10.3324/haematol.2011 This is an open-access paper. Predictors of osteoclast activity in patients with sickle cell disease

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“…PGC-1 is further implicated in osteoclast activation and PRC has a nonredundant function in proliferative growth [136,137].…”

Section: Other Organ-specific Functions Of Pgc-1 Coactivatorsmentioning

confidence: 99%

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Eisele

Handschin

2013

Semin Immunopathol

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(150 -250 words) [165] Skeletal muscle is an organ involved in whole body movement and energy metabolism with the ability to dynamically adapt to different states of (dis-)use. At a molecular level, the peroxisome proliferatoractivated receptor  coactivators 1 (PGC-1) are important mediators of oxidative metabolism in skeletal muscle and in other organs. Musculoskeletal disorders as well as obesity and its sequelae are associated with PGC-1 dysregulation in muscle with a concomitant local or systemic inflammatory reaction. In this review, we outline the function of PGC-1 coactivators in physiological and pathological conditions as well as the complex interplay of metabolic dysregulation and inflammation in obesity with special focus on skeletal muscle. We further put forward the hypothesis that in this tissue, oxidative metabolism and inflammatory processes mutually antagonize each other. The nuclear factor κB (NF-B) pathway thereby plays a key role in linking metabolic and inflammatory programs in muscle cells. We conclude this review with a perspective about the consequences of such a negative crosstalk on the immune system and the possibilities this opens for clinical applications.

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

Cited by 338 publications

References 38 publications

Blimp1-mediated repression of negative regulators is required for osteoclast differentiation

Blimp1-mediated repression of negative regulators is required for osteoclast differentiation

Predictors of osteoclast activity in patients with sickle cell disease

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

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