Inorganic phosphate regulates multiple genes during osteoblast differentiation, including Nrf2

Beck, George R.; Morán, Elizabeth; Knecht, Nicole

doi:10.1016/s0014-4827(03)00213-1

Cited by 178 publications

(176 citation statements)

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“…In our study, we have identified the involvement of specific MAPK signaling pathways responsible for Opn regulation by PP i . Recently, others have shown that P i itself can regulate osteoblast and cementoblast gene expression (31,35,38,39). However, whereas P i regulation of Opn is dependent on intracellular uptake via Na ϩ /P i cotransporters (39), most notably Pit-1 (47), we demonstrate here that PP i directly regulates Opn in a phosphate uptake-independent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Pyrophosphate Up-regulates Opn Expression-Recent data have shown that mineralizing cell culture systems (primarily osteoblasts and cementoblasts) are sensitive to local levels of P i and PP i (22,31,35,38). The role of anions such as PP i in skeletal and dental tissues appears not to be limited to their crystal binding properties.…”

Section: Pyrophosphate Inhibits Mineralization Of Mc3t3-e1 Osteoblastmentioning

confidence: 99%

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Pyrophosphate Inhibits Mineralization of Osteoblast Cultures by Binding to Mineral, Up-regulating Osteopontin, and Inhibiting Alkaline Phosphatase Activity

Addison

Azari

Sørensen

et al. 2007

Journal of Biological Chemistry

325

264

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Inorganic pyrophosphate (PP i ) produced by cells inhibits mineralization by binding to crystals. Its ubiquitous presence is thought to prevent "soft" tissues from mineralizing, whereas its degradation to P i in bones and teeth by tissue-nonspecific alkaline phosphatase (Tnap, Tnsalp, Alpl, Akp2) may facilitate crystal growth. Whereas the crystal binding properties of PP i are largely understood, less is known about its effects on osteoblast activity. We have used MC3T3-E1 osteoblast cultures to investigate the effect of PP i on osteoblast function and matrix mineralization. Mineralization in the cultures was dose-dependently inhibited by PP i . This inhibition could be reversed by Tnap, but not if PP i was bound to mineral. PP i also led to increased levels of osteopontin (Opn) induced via the Erk1/2 and p38 MAPK signaling pathways. Opn regulation by PP i was also insensitive to foscarnet (an inhibitor of phosphate uptake) and levamisole (an inhibitor of Tnap enzymatic activity), suggesting that increased Opn levels did not result from changes in phosphate. Exogenous OPN inhibited mineralization, but dephosphorylation by Tnap reversed this effect, suggesting that OPN inhibits mineralization via its negatively charged phosphate residues and that like PP i , hydrolysis by Tnap reduces its mineral inhibiting potency. Using enzyme kinetic studies, we have shown that PP i inhibits Tnap-mediated P i release from ␤-glycerophosphate (a commonly used source of organic phosphate for culture mineralization studies) through a mixed type of inhibition. In summary, PP i prevents mineralization in MC3T3-E1 osteoblast cultures by at least three different mechanisms that include direct binding to growing crystals, induction of Opn expression, and inhibition of Tnap activity.

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Section: Discussionmentioning

confidence: 99%

Section: Pyrophosphate Inhibits Mineralization Of Mc3t3-e1 Osteoblastmentioning

confidence: 99%

Pyrophosphate Inhibits Mineralization of Osteoblast Cultures by Binding to Mineral, Up-regulating Osteopontin, and Inhibiting Alkaline Phosphatase Activity

Addison

Azari

Sørensen

et al. 2007

Journal of Biological Chemistry

325

264

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“…56 On the other hand, in addition to being crucial for bone mineralization, Pi acts as a signaling molecule and affects bone cells' physiology and gene expression, including the expression of osteocalcin. 57,58 Thus, ENPP1, ANKH, and ALPL, the central local regulatory factors affecting bone mineralization and Pi levels, may represent one of the main nodes in the regulatory circuit connecting bone and adipose tissues by controlling osteocalcin-plasma levels via Pi concentration.…”

Section: Discussionmentioning

confidence: 99%

Morphological and biochemical features of obesity are associated with mineralization genes’ polymorphisms

et al. 2010

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Background: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was recently extensively studied as a candidate gene for obesity phenotypes. As the human homologue of the mouse progressive ankylosis (ANKH) and alkaline phosphatase (ALPL) are known functional partners of ENPP1 in bone mineralization, we hypothesized that these genes may also be jointly involved in determining obesity features. Aim: To examine the effects of the three genes, possible gene-sex and gene-gene interactions on variability of four obesity phenotypes: the body mass index (BMI), the waist-hip ratio (WHR), the epidermal growth factor receptor (EGFR), and leptin. Subjects and methods: In all, 962 healthy individuals from 230 families were genotyped for 45 single nucleotide polymorphisms (SNPs). The association analysis was performed using two family based association tests (family based association test and pedigree disequilibrium test). The combined P-values of the two tests were estimated by Monte-Carlo simulations. Relative magnitude of the genetic and familial effects, gene-sex and gene-gene interactions were assessed using variance component models. Results: Associations were observed between ENPP1 polymorphisms and BMI (P ¼ 0.0037) and leptin (P ¼ 0.0068). ALPL markers were associated with WHR (P ¼ 0.0026) and EGFR (P ¼ 0.0001). The ANKH gene was associated with all four studied obesity-related traits (Po0.0184), and its effects were modulated by sex. Gene-gene interactions were not detected. Conclusion: The observed pattern of association signals indicates that ANKH may have a generalized effect on adipose tissue physiology, whereas ENPP1 and ALPL affect distinct obesity features. The joint analysis of related genes and integration of the results obtained by different methods used in this research should benefit other studies of similar design.

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“…During this process, osteoblasts are exposed to high levels of inorganic phosphate. Using the MC3T3-E1 osteoblast differentiation model (1-3), we have recently described the significance of inorganic phosphate, which is generated during differentiation, as a signaling molecule capable of altering specific signal transduction pathways, gene expression, and ultimately mineralization (4,5). Furthermore, a number of studies have demonstrated the ability of inorganic phosphate to alter gene expression and or cell function in other cell types, including parathyroid (6), neurons (7), kidney (8), vascular smooth muscle (9), chondrocytes (10), and osteoclasts (11).…”

mentioning

confidence: 99%

A Combined Proteome and Microarray Investigation of Inorganic Phosphate-induced Pre-osteoblast Cells

Conrads

Simpson

et al. 2005

Molecular & Cellular Proteomics

118

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Inorganic phosphate, which is generated during osteoblast differentiation and mineralization, has recently been identified as an important signaling molecule capable of altering signal transduction pathways and gene expression. A large scale quantitative proteomic investigation of pre-osteoblasts stimulated with inorganic phosphate for 24 h resulted in the identification of 2501 proteins, of which 410 (16%) had an altered abundance ratio of greater than or equal to 1.75-fold, either up or down, revealing both novel and previously defined osteoblastregulated proteins. A pathway/function analysis of these proteins revealed an increase in cell cycle and proliferation that was subsequently verified by conventional biochemical means. To further analyze the mechanisms by which inorganic phosphate regulates cellular protein levels, we undertook a mRNA microarray analysis of preosteoblast cells at 18, 21, and 24 h after inorganic phosphate exposure. Comparison of the mRNA microarray data with the 24-hour quantitative proteomic data resulted in a generally weak overall correlation; the 21-hour RNA sample showed the highest correlation to the proteomic data. However, an analysis of osteoblast relevant proteins revealed a much higher correlation at all time points. A comparison of the microarray and proteomic datasets allowed for the identification of a number of candidate proteins that are post-transcriptionally regulated by elevated inorganic phosphate, including Fra-1, a member of the activator protein-1 family of transcription factors. The analysis of the data presented here not only sheds new light on the important roles of inorganic phosphate in osteoblast function but also begins to address the contribution of post-transcriptional and post-translational regulation to a cell's expressed proteome. The ability to accurately measure changes in both protein abundance and mRNA levels on a system-wide scale represents a novel means to extract data from previously

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Inorganic phosphate regulates multiple genes during osteoblast differentiation, including Nrf2

Cited by 178 publications

References 45 publications

Pyrophosphate Inhibits Mineralization of Osteoblast Cultures by Binding to Mineral, Up-regulating Osteopontin, and Inhibiting Alkaline Phosphatase Activity

Pyrophosphate Inhibits Mineralization of Osteoblast Cultures by Binding to Mineral, Up-regulating Osteopontin, and Inhibiting Alkaline Phosphatase Activity

Morphological and biochemical features of obesity are associated with mineralization genes’ polymorphisms

A Combined Proteome and Microarray Investigation of Inorganic Phosphate-induced Pre-osteoblast Cells

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