36 results on '"Esbrit, Pedro"'
Search Results
2. Papel de la proteína relacionada con la parathormona (PTHrP) en el metabolismo óseo: de la investigación básica a la clínica.
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Esbrit, Pedro
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- 2023
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3. Oxidative stress, autophagy, epigenetic changes and regulation by miRNAs as potential therapeutic targets in osteoarthritis.
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Portal-Núñez, Sergio, Esbrit, Pedro, Alcaraz, María José, and Largo, Raquel
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OXIDATIVE stress , *AUTOPHAGY , *EPIGENETICS , *MICRORNA , *OSTEOARTHRITIS treatment - Abstract
Aging is a natural process characterized by the declining ability of the different organs and tissues to respond to stress, increasing homeostatic imbalance and risk of disease. Osteoarthritis (OA) is a multifactorial disease in which cartilage degradation is a central feature. Aging is the main risk factor for OA. In OA cartilage, a decrease in the number of chondrocytes and in their ability to regenerate the extracellular matrix and adequately respond to stress has been described. OA chondrocytes show a senescence secretory phenotype (SSP) consisting on the overproduction of cytokines (interleukins 1 and 6), growth factors ( e.g ., epidermal growth factor) and matrix metalloproteinases (MMP) ( e.g ., MMP-3, MMP-13). Reactive Oxygen Species (ROS) play a major role in the induction of the SSP. In chondrocytes, an increase in ROS production leads to hyper-peroxidation, protein carbonylation and DNA damage which alter chondrocyte function. ROS overproduction also induces changes in metabolic pathways such as PI3K-Akt and ERK. Autophagy is a key mechanism for maintaining cell homeostasis by adjusting cell metabolism to nutrient supply and removing damaged organelles. In cartilage, aging-related loss of autophagy leads to cell death and OA, while stimulation of autophagy exerts protective effects on cartilage deterioration. Aging also interferes with epigenetic mechanisms such as activity of histone acetylases that control the pattern of DNA methylation, and induces up- or down-regulation of microRNAs expression. A deeper knowledge of the mechanisms involved in chondrocyte aging could identify potential targets for the treatment of OA, a prevalent and therapeutic-orphan disease. [ABSTRACT FROM AUTHOR]
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- 2016
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4. Parathyroid Hormone-Related Protein Analogs as Osteoporosis Therapies.
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Esbrit, Pedro, Herrera, Sabina, Portal-Núñez, Sergio, Nogués, Xavier, Díez-Pérez, Adolfo, Portal-Núñez, Sergio, Nogués, Xavier, and Díez-Pérez, Adolfo
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OSTEOPOROSIS treatment , *PARATHYROID hormone-related protein , *BONE metabolism , *OSTEOBLASTS , *BONE growth , *AMINO acids , *ANIMALS , *DIPHOSPHONATES , *OSTEOPOROSIS , *PEPTIDE hormones , *PHARMACODYNAMICS - Abstract
The only bone anabolic agent currently available for osteoporosis treatment is parathyroid hormone (PTH)-either its N-terminal 1-34 fragment or the whole molecule of 1-84 aminoacids-whose intermittent administration stimulates new bone formation by targeting osteoblastogenesis and osteoblast survival. PTH-related protein (PTHrP) is an abundant factor in bone which shows N-terminal homology with PTH and thus exhibits high affinity for the same PTH type 1 receptor in osteoblasts. Therefore, it is not surprising that intermittently administered N-terminal PTHrP peptides induce bone anabolism in animals and humans. Furthermore, the C-terminal region of PTHrP also elicits osteogenic features in vitro in osteoblastic cells and in various animal models of osteoporosis. In this review, we discuss the current concepts about the cellular and molecular mechanisms whereby PTHrP may induce anabolic actions in bone. Pre-clinical studies and clinical data using N-terminal PTHrP analogs are also summarized, pointing to PTHrP as a promising alternative to current bone anabolic therapies. [ABSTRACT FROM AUTHOR]
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- 2016
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5. Mesoporous Bioglasses Enriched with Bioactive Agents for Bone Repair, with a Special Highlight of María Vallet-Regí's Contribution.
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Salinas, Antonio J. and Esbrit, Pedro
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BIOACTIVE glasses , *PORE size distribution , *MESOPOROUS materials , *MESOPOROUS silica , *TISSUE engineering , *BIOCERAMICS - Abstract
Throughout her impressive scientific career, Prof. María Vallet-Regí opened various research lines aimed at designing new bioceramics, including mesoporous bioactive glasses for bone tissue engineering applications. These bioactive glasses can be considered a spin-off of silica mesoporous materials because they are designed with a similar technical approach. Mesoporous glasses in addition to SiO2 contain significant amounts of other oxides, particularly CaO and P2O5 and therefore, they exhibit quite different properties and clinical applications than mesoporous silica compounds. Both materials exhibit ordered mesoporous structures with a very narrow pore size distribution that are achieved by using surfactants during their synthesis. The characteristics of mesoporous glasses made them suitable to be enriched with various osteogenic agents, namely inorganic ions and biopeptides as well as mesenchymal cells. In the present review, we summarize the evolution of mesoporous bioactive glasses research for bone repair, with a special highlight on the impact of Prof. María Vallet-Regí´s contribution to the field. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Current perspectives on parathyroid hormone (PTH) and PTH-related protein (PTHrP) as bone anabolic therapies.
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Esbrit, Pedro and Alcaraz, María José
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PARATHYROID hormone , *PARATHYROID hormone-related protein , *OSTEOPOROSIS , *BONE density , *RISK factors of fractures , *ANABOLIC steroids , *BONE growth , *BONE resorption - Abstract
Abstract: Osteoporosis is characterized by low bone mineral density and/or poor bone microarchitecture leading to an increased risk of fractures. The skeletal alterations in osteoporosis are a consequence of a relative deficit of bone formation compared to bone resorption. Osteoporosis therapies have mostly relied on antiresorptive drugs. An alternative therapeutic approach for osteoporosis is currently available, based on the intermittent administration of parathyroid hormone (PTH). Bone anabolism caused by PTH therapy is mainly accounted for by the ability of PTH to increase osteoblastogenesis and osteoblast survival. PTH and PTH-related protein (PTHrP)–an abundant local factor in bone- interact with the common PTH type 1 receptor with similar affinities in osteoblasts. Studies mainly in osteoporosis rodent models and limited data in postmenopausal women suggest that N-terminal PTHrP peptides might be considered a promising bone anabolic therapy. In addition, putative osteogenic actions of PTHrP might be ascribed not only to its N-terminal domain but also to its PTH-unrelated C-terminal region. In this review, we discuss the underlying cellular and molecular mechanisms of the anabolic actions of PTH and the similar potential of PTH-related protein (PTHrP) to increase bone mass and improve bone regeneration. [Copyright &y& Elsevier]
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- 2013
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7. Unexpected Bone Formation Produced by RANKL Blockade.
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Portal-Núñez, Sergio, Mediero, Aranzazu, Esbrit, Pedro, Sánchez-Pernaute, Olga, Largo, Raquel, and Herrero-Beaumont, Gabriel
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BONE growth , *TRANCE protein , *BONE density , *MONOCLONAL antibodies , *OSTEOPOROSIS - Abstract
Denosumab (Dmab) is a humanized monoclonal antibody that blocks RANKL (receptor activator for nuclear factor κB ligand), thereby exerting a potent bone antiresorptive action. Dmab treatment leads to a dramatic and sustained increase in bone mass through mechanisms that are currently under debate. It is also a matter of controversy whether this potent action of Dmab could lead to intrabone dystrophic mineralization. Recent research has uncovered a possible anabolic role of Dmab involving RANKL-dependent reverse signaling in osteoblasts, and that bone marrow adipocytes can modulate osteoclastogenesis through the production of RANKL. We comment here on potential pathways which might account for the anabolic action of Dmab. The impact of this proposed mechanism needs to be addressed in further research. [ABSTRACT FROM AUTHOR]
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- 2017
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8. Oxidation inhibits PTH receptor signaling and trafficking.
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Ardura, Juan A., Alonso, Verónica, Esbrit, Pedro, and Friedman, Peter A.
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PARATHYROID hormone , *CELLULAR signal transduction , *OSTEOPOROSIS , *OXIDATIVE stress , *INTRACELLULAR calcium , *CELL imaging , *FLUORESCENCE resonance energy transfer - Abstract
Reactive Oxygen Species (ROS) increase during aging, potentially affecting many tissues including brain, heart, and bone. ROS alter signaling pathways and constitute potential therapeutic targets to limit oxidative damaging effects in aging-associated diseases. Parathyroid hormone receptors (PTHR) are widely expressed and PTH is the only anabolic therapy for osteoporosis. The effects of oxidative stress on PTHR signaling and trafficking have not been elucidated. Here, we used Fluorescence Resonance Energy Transfer (FRET)-based cAMP, ERK, and calcium fluorescent biosensors to analyze the effects of ROS on PTHR signaling and trafficking by live-cell imaging. PTHR internalization and recycling were measured in HEK-293 cells stably transfected with HA-PTHR. PTH increased cAMP production, ERK phosphorylation, and elevated intracellular calcium. Pre-incubation with H 2 O 2 reduced all PTH-dependent signaling pathways. These inhibitory effects were not a result of PTH oxidation since PTH incubated with H 2 O 2 triggered similar responses. PTH promoted internalization and recycling of the PTHR. Both events were significantly reduced by H 2 O 2 pre-incubation. These findings highlight the role of oxidation on PTHR signaling and trafficking, and suggest the relevance of ROS as a putative target in diseases associated with oxidative stress such as age-related osteoporosis. [ABSTRACT FROM AUTHOR]
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- 2017
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9. Effect of GLP-1 treatment on bone turnover in normal, type 2 diabetic, and insulin-resistant states.
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Nuche-Berenguer, Bernardo, Moreno, Paola, Esbrit, Pedro, Dapía, Sonia, Caeiro, José, Cancelas, Jesús, Haro-Mora, Juan, Villanueva-Peñacarrillo, María, Dapía, Sonia, Caeiro, José R, Cancelas, Jesús, Haro-Mora, Juan J, and Villanueva-Peñacarrillo, María L
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PEOPLE with diabetes , *BONE diseases , *OSTEOPOROSIS , *DIABETES , *BLOOD plasma , *ANTINEOPLASTIC antibiotics - Abstract
It has been suggested that hormones released after nutrient absorption, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 2 (GLP-2), could be responsible for changes in bone resorption. However, information about the role of GLP-1 in this regard is scanty. Diabetes-related bone loss occurs as a consequence of poor control of glucose homeostasis, but the relationship between osteoporosis and type 2 diabetes remains unclear. Since GLP-1 is decreased in the latter condition, we evaluated some bone characteristics in streptozotocin-induced type 2 diabetic (T2D) and fructose-induced insulin-resistant (IR) rat models compared to normal (N) and the effect of GLP-1 or saline (control) treatment (3 days by osmotic pump). Blood was taken before and after treatment for plasma measurements; tibiae and femora were collected for gene expression of bone markers (RT-PCR) and structure (microCT) analysis. Compared to N, plasma glucose and insulin were, respectively, higher and lower in T2D; osteocalcin (OC) and tartrate-resistant alkaline phosphatase 5b were lower; phosphate in IR showed a tendency to be higher; PTH was not different in T2D and IR; all parameters were unchanged after GLP-1 infusion. Bone OC, osteoprotegerin (OPG) and RANKL mRNA were lower in T2D and IR; GLP-1 increased OC and OPG in all groups and RANKL in T2D. Compared to N, trabecular bone parameters showed an increased degree of anisotropy in T2D and IR, which was reduced after GLP-1. These findings show an insulin-independent anabolic effect of GLP-1 and suggest that GLP-1 could be a useful therapeutic agent for improving the deficient bone formation and bone structure associated with glucose intolerance. [ABSTRACT FROM AUTHOR]
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- 2009
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10. Urinary excretion of parathyroid hormone-related protein correlates with renal function in control rats and rats with cisplatin nephrotoxicity.
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Ortega, Arantxa, Olea-Herrero, Nuria, Arenas, M. Isabel, Vélez-Vélez, Esperanza, Moreno-Gómez-Toledano, Rafael, Muñoz-Moreno, Carmen, Lázaro, Alberto, Esbrit, Pedro, Tejedor, Alberto, and Bosch, Ricardo J.
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PARATHYROID hormone-related protein , *RAT control , *EXCRETION , *WESTERN immunoblotting , *NEPHROTOXICOLOGY - Abstract
Parathyroid hormone-related protein (PTHrP) and its receptor are abundantly expressed throughout the renal parenchyma, where PTHrP exerts a modulatory action on renal function. PTHrP upregulation is a common event associated with the mechanism of renal injury and repair. However, no study has yet explored the putative excretion of PTHrP in urine, including its potential relationship with renal function. In the present study, we tested this hypothesis by studying the well-known rat model of acute renal injury induced by the chemotherapeutic agent cisplatin. Using Western blot analysis, we could detect a single protein band, corresponding to intact PTHrP, in the urine of both control and cisplatin-injected rats, whose levels were significantly higher in the latter group. PTHrP was detected in rat urine by dot blot, and its quantification with two specific ELISA kits showed that, compared with control rats, those treated with cisplatin displayed a significant increase in urinary PTHrP (expressed as the PTHrP-to-creatinine ratio or 24-h excretion). In addition, a positive correlation between urinary PTHrP excretion and serum creatinine was found in these animals. In conclusion, our data demonstrate that PTHrP is excreted in rat urine and that this excretion is higher with the decrease of renal function. This suggests that urinary PTHrP levels might be a renal function marker. [ABSTRACT FROM AUTHOR]
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- 2019
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11. Osteogenic Effect of ZnO-Mesoporous Glasses Loaded with Osteostatin.
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Pérez, Rebeca, Sanchez-Salcedo, Sandra, Lozano, Daniel, Heras, Clara, Esbrit, Pedro, Vallet-Regí, María, and Salinas, Antonio J.
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OSTEOINDUCTION , *BIOACTIVE glasses , *C-terminal residues - Abstract
Mesoporous Bioactive Glasses (MBGs) are a family of bioceramics widely investigated for their putative clinical use as scaffolds for bone regeneration. Their outstanding textural properties allow for high bioactivity when compared with other bioactive materials. Moreover, their great pore volumes allow these glasses to be loaded with a wide range of biomolecules to stimulate new bone formation. In this study, an MBG with a composition, in mol%, of 80% SiO2-15% CaO-5% P2O5 (Blank, BL) was compared with two analogous glasses containing 4% and 5% of ZnO (4ZN and 5ZN) before and after impregnationwith osteostatin, a C-terminal peptide froma parathyroid hormone-related protein (PTHrP107-111). Zn2+> ions were included in the glass for their bone growth stimulator properties, whereas osteostatin was added for its osteogenic properties. Glasses were characterized, and their cytocompatibility investigated, in pre-osteoblastic MC3T3-E1 cell cultures. The simultaneous additions of osteostatin and Zn2+> ions provoked enhanced MC3T3-E1 cell viability and a higher differentiation capacity, compared with either raw BL or MBGs supplemented only with osteostatin or Zn2+>. These in vitro results show that osteostatin enhances the osteogenic effect of Zn2+>-enriched glasses, suggesting the potential of this combined approach in bone tissue engineering applications. [ABSTRACT FROM AUTHOR]
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- 2018
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12. High glucose alters the secretome of mechanically stimulated osteocyte-like cells affecting osteoclast precursor recruitment and differentiation.
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Maycas, Marta, Portolés, María Teresa, Matesanz, María Concepción, Buendía, Irene, Linares, Javier, Feito, María José, Arcos, Daniel, Vallet-Regí, María, Plotkin, Lilian I., Esbrit, Pedro, and Gortázar, Arancha R.
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DIABETES , *DIABETES complications , *OSTEOCYTES , *VASCULAR endothelial growth factor receptors , *CCL5 (Chemokine) - Abstract
Diabetes mellitus (DM) induces bone deterioration, while mechanical stimulation promotes osteocyte-driven bone formation. We aimed to evaluate the interaction of acute exposure (24 h) to high glucose (HG) with both the pro-survival effect conferred to osteocytic MLO-Y4 cells and osteoblastic MC3T3-E1 cells by mechanical stimulation and the interaction of these cells with osteoclast precursor RAW264.7 cells. We found that 24 h of HG (25 mM) pre-exposure prevented both cell survival and ERK and β-catenin nuclear translocation upon mechanical stimulation by fluid flow (FF) (10 min) in both MLO-Y4 and MC3T3-E1 cells. However, migration of RAW 264.7 cells was inhibited by MLO-Y4 cell-conditioned medium (CM), but not by MC3T3-E1 cell-CM, with HG or FF. This inhibitory effect was associated with consistent changes in VEGF, RANTES, MIP-1α, MIP-1β MCP-1, and GM-CSF in MLO-Y4 cell-CM. RAW264.7 proliferation was inhibited by MLO-Y4 CM under static or HG conditions, but it increased by FF-CM with or without HG. In addition, both FF and HG abrogated the capacity of RAW 264.7 cells to differentiate into osteoclasts, but in a different manner. Thus, HG-CM in static condition allowed formation of osteoclast-like cells, which were unable to resorb hydroxyapatite. In contrast, FF-CM prevented osteoclastogenesis even in HG condition. Moreover, HG did not affect basal RANKL or IL-6 secretion or their inhibition induced by FF in MLO-Y4 cells. In conclusion, this in vitro study demonstrates that HG exerts disparate effects on osteocyte mechanotransduction, and provides a novel mechanism by which DM disturbs skeletal metabolism through altered osteocyte-osteoclast communication. [ABSTRACT FROM AUTHOR]
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- 2017
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13. Anti-senescence and Anti-inflammatory Effects of the C-terminal Moiety of PTHrP Peptides in OA Osteoblasts.
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Platas, Julia, Guillén, Maria Isabel, Gomar, Francisco, Castejón, Miguel Angel, Esbrit, Pedro, and Alcaraz, Maria José
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OSTEOARTHRITIS , *ANTI-inflammatory agents , *PARATHYROID hormone-related protein , *PEOPLE with disabilities , *CELL metabolism , *CELL culture , *CELLULAR aging , *FLUORESCENT antibody technique , *INFLAMMATORY mediators , *INTERLEUKIN-1 , *INTERLEUKINS , *PEPTIDE hormones , *PEPTIDES , *POLYMERASE chain reaction , *TUMOR necrosis factors , *OSTEOBLASTS , *DINOPROSTONE , *PHARMACODYNAMICS , *PREVENTION - Abstract
Osteoarthritis (OA) is characterized by degenerative changes in the whole joint leading to physical disability in the elderly population. This condition is associated with altered bone metabolism in subchondral areas suggesting that therapeutic strategies aimed at modifying bone cell metabolism may be of interest. We have investigated the effects of several parathyroid hormone-related protein (PTHrP)-derived peptides (1-37): (N-terminal), (107-111) and (107-139) (C-terminal) on senescence features induced by inflammatory stress in human OA osteoblasts. Incubation of these primary cells with interleukin(IL)-1β led to an increased expression of senescence markers senescence-associated-β-galactosidase activity, γH2AX foci, p16, p21, p53, and caveolin-1. PTHrP (107-111) and PTHrP (107-139) significantly reduced all these parameters. Both peptides decreased the production of IL-6 and prostaglandin E2 which was the consequence of cyclo-oxygenase-2 downregulation. PTHrP (107-139) also reduced tumor necrosis factor-α release. These anti-inflammatory effects would be related to the reduction of nuclear factor-κB activation by both peptides and activator protein-1 by PTHrP (107-139). The three PTHrP peptides favored osteoblastic function although the C-terminal domain of PTHrP was more efficient than its N-terminal domain. Our data support an anti-senescence and anti-inflammatory role for the C-terminal moiety of PTHrP with potential applications in chronic inflammatory conditions such as OA. [ABSTRACT FROM AUTHOR]
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- 2017
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14. Parathyroid Hormone-Related Protein Protects Osteoblastic Cells From Oxidative Stress by Activation of MKP1 Phosphatase.
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Ardura, Juan A., Portal‐Núñez, Sergio, Castelbón‐Calvo, Irantzu, Martínez de Toda, Irene, De la Fuente, Mónica, and Esbrit, Pedro
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PARATHYROID hormone , *OSTEOBLASTS , *OXIDATIVE stress , *PHOSPHATASES , *ENZYME activation - Abstract
Oxidative damage is an important contributor to the morphological and functional changes in osteoporotic bone. Aging increases the levels of reactive oxygen species (ROS) that cause oxidative stress and induce osteoblast apoptosis. ROS modify several signaling responses, including mitogen-activated protein kinase (MAPK) activation, related to cell survival. Both parathyroid hormone (PTH) and its bone counterpart, PTH-related protein (PTHrP), can regulate MAPK activation by modulating MAPK phosphatase-1 (MKP1). Thus, we hypothesized that PTHrP might protect osteoblasts from ROS-induced apoptosis by targeting MKP1. In osteoblastic MC3T3-E1 and MG-63 cells, H2O2 triggered p38, JNK, ERK and p66Shc phosphorylation, and cell apoptosis. Meanwhile, PTHrP (1-37) rapidly but transiently increased ERK and Akt phosphorylation without affecting p38, JNK, or p66Shc activation. H2O2-induced p38 and ERK phosphorylation and apoptosis were both decreased by pre-treatment with specific kinase inhibitors or PTHrP (1-37) in both osteoblastic cell types. These dephosphorylating and prosurvival actions of PTHrP (1-37) were prevented by a phosphatase inhibitor cocktail, the phosphatase MKP1 inhibitor sanguinarine or a MKP1 siRNA. PTHrP (1-37) promptly enhanced MKP1 protein and gene expression and MKP1-dependent catalase activity in osteoblastic cells. Furthermore, exposure to PTHrP (1-37) adsorbed in an implanted hydroxyapatite-based ceramic into a tibial defect in aging rats increased MKP1 and catalase gene expression in the healing bone area. Our findings demonstrate that PTHrP counteracts the pro-apoptotic actions of ROS by a mechanism dependent on MKP1-induced dephosphorylation of MAPKs in osteoblasts. J. Cell. Physiol. 232: 785-796, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2017
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15. Colon cancer modulation by a diabetic environment: A single institutional experience.
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Prieto, Isabel, del Puerto-Nevado, Laura, Gonzalez, Nieves, Portal-Nuñez, Sergio, Zazo, Sandra, Corton, Marta, Minguez, Pablo, Gomez-Guerrero, Carmen, Arce, Jose Miguel, Sanz, Ana Belen, Mas, Sebastian, Aguilera, Oscar, Alvarez-Llamas, Gloria, Esbrit, Pedro, Ortiz, Alberto, Ayuso, Carmen, Egido, Jesus, Rojo, Federico, Garcia-Foncillas, Jesus, and null, null
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COLON cancer , *PEOPLE with diabetes , *MEDICAL records , *METFORMIN , *ADJUVANT treatment of cancer - Abstract
Background: Multiple observational studies suggest an increased risk of colon cancer in patients with diabetes mellitus (DM). This can theoretically be the result of an influence of the diabetic environment on carcinogenesis or the tumor biologic behavior. Aim: To gain insight into the influence of a diabetic environment on colon cancer characteristics and outcomes. Material and methods: Retrospective analysis of clinical records in an academic tertiary care hospital with detailed analysis of 81 diabetic patients diagnosed of colon cancer matched with 79 non-diabetic colon cancer patients. The impact of streptozotocin-induced diabetes on the growth of colon cancer xenografts was studied in mice. Results: The incidence of DM in 1,137 patients with colorectal cancer was 16%. The diabetic colon cancer cases and non-diabetic colon cancer controls were well matched for demographic and clinical variables. The ECOG Scale Performance Status was higher (worse) in diabetics (ECOG ≥1, 29.1% of controls vs 46.9% of diabetics, p = 0.02), but no significant differences were observed in tumor grade, adjuvant therapy, tumor site, lymphovascular invasion, stage, recurrence, death or cancer-related death. Moreover, no differences in tumor variables were observed between patients treated or not with metformin. In the xenograft model, tumor growth and histopathological characteristics did not differ between diabetic and nondiabetic animals. Conclusion: Our findings point towards a mild or negligible effect of the diabetes environment on colon cancer behavior, once cancer has already developed. [ABSTRACT FROM AUTHOR]
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- 2017
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16. Adverse Effects of Diabetes Mellitus on the Skeleton of Aging Mice.
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Portal-Núñez, Sergio, Antonio Ardura, Juan, Lozano, Daniel, Hernández Bolívar, Oskarina, López-Herradón, Ana, Gutiérrez-Rojas, Irene, Proctor, Alexander, van der Eerden, Bram, Schreuders-Koedam, Marijke, van Leeuwen, Johannes, José Alcaraz, María, Mulero, Francisca, de la Fuente, Mónica, Esbrit, Pedro, Ardura, Juan Antonio, Bolívar, Oskarina Hernández, and Alcaraz, María José
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DIABETES , *AGE factors in disease , *STREPTOZOTOCIN , *VASCULAR endothelial growth factor receptors , *PEROXISOME proliferator-activated receptors , *LABORATORY mice , *DIABETES complications , *OSTEOPOROSIS diagnosis , *BONE remodeling , *AGING , *ANIMAL experimentation , *BONE growth , *COMPUTED tomography , *LUMBAR vertebrae , *MICE , *OSTEOPOROSIS , *BONE density - Abstract
In the present study, the possibility that a diabetic (DM) status might worsen age-related bone deterioration was explored in mice. Male CD-1 mice aged 2 (young control group) or 16 months, nondiabetic or made diabetic by streptozotocin injections, were used. DM induced a decrease in bone volume, trabecular number, and eroded surface, and in mineral apposition and bone formation rates, but an increased trabecular separation, in L1-L3 vertebrae of aged mice. Three-point bending and reference point indentation tests showed slight changes pointing to increased frailty and brittleness in the mouse tibia of diabetic old mice. DM was related to a decreased expression of both vascular endothelial growth factor and its receptor 2, which paralleled that of femoral vasculature, and increased expression of the pro-adipogenic gene peroxisome proliferator-activated receptor γ and adipocyte number, without affecting β-catenin pathway in old mouse bone. Concomitant DM in old mice failed to affect total glutathione levels or activity of main anti-oxidative stress enzymes, although xanthine oxidase was slightly increased, in the bone marrow, but increased the senescence marker caveolin-1 gene. In conclusion, DM worsens bone alterations of aged mice, related to decreased bone turnover and bone vasculature and increased senescence, independently of the anti-oxidative stress machinery. [ABSTRACT FROM AUTHOR]
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- 2016
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17. Effects of bleaching on osteoclast activity and their modulation by osteostatin and fibroblast growth factor 2.
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Torres-Rodríguez, Carolina, Portolés, M. Teresa, Matesanz, M. Concepción, Linares, Javier, Feito, M. José, Izquierdo-Barba, Isabel, Esbrit, Pedro, and Vallet-Regí, María
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OSTEOCLASTS , *TOOTH whitening , *INCISORS , *FIBROBLAST growth factor 2 , *HUMAN growth hormone - Abstract
Hypothesis Dental bleaching with H 2 O 2 is a common daily practice in dentistry to correct discoloration of anterior teeth. The aim of this study has been to determine whether this treatment of human teeth affects growth, differentiation and activity of osteoclast-like cells, as well as the putative modulatory action of osteostatin and fibroblast growth factor 2 (FGF-2). Experiments Previously to the in vitro assays, structural, physical–chemical and morphological features of teeth after bleaching were studied. Osteoclast-like cells were cultured on human dentin disks, pre-treated or not with 38% H 2 O 2 bleaching gel, in the presence or absence of osteostatin (100 nM) or FGF-2 (1 ng/ml). Cell proliferation and viability, intracellular content of reactive oxygen species (ROS), pro-inflammatory cytokine (IL-6 and TNFα) secretion and resorption activity were evaluated. Findings Bleaching treatment failed to affect either the structural or the chemical features of both enamel and dentin, except for slight morphological changes, increased porosity in the most superficial parts (enamel), and a moderate increase in the wettability degree. In this scenario, bleaching produced an increased osteoclast-like cell proliferation but decreased cell viability and cytokine secretion, while it augmented resorption activity on dentin. The presence of either osteostatin or FGF-2 reduced the osteoclast-like cell proliferation induced by bleaching. FGF-2 enhanced ROS content, whereas osteostatin decreased ROS but increased TNFα secretion. The bleaching effect on resorption activity was increased by osteostatin, but this effect was less evident with FGF-2. Conclusions These findings further confirm the deleterious effects of tooth bleaching by affecting osteoclast growth and function as well as different modulatory actions of osteostatin and FGF-2. [ABSTRACT FROM AUTHOR]
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- 2016
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18. VEGF Receptor 2 (VEGFR2) Activation Is Essential for Osteocyte Survival Induced by Mechanotransduction.
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de Castro, Luis F., Maycas, Marta, Bravo, Beatriz, Esbrit, Pedro, and Gortazar, Arancha
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VASCULAR endothelial growth factor receptors , *OSTEOCYTES , *MECHANOTRANSDUCTION (Cytology) , *BONE growth , *APOPTOSIS , *CATENINS , *CELL survival - Abstract
Mechanical loading plays a key role in bone formation and maintenance. While unloading induces osteocyte apoptosis and bone loss in vivo, mechanical stimuli prevents osteocyte death through a mechanism involving β-catenin accumulation and ERK nuclear translocation. Vascular endothelial growth factor (VEGF) has a crucial role in bone formation, but its interaction with osteocytes is not completely understood. Of interest, VEGF receptor 2 (VEGFR2) has recently been shown to mediate the mechanical response of endothelial cells. The present study aimed to evaluate the putative role of the VEGF system in osteocyte mechanosensing. We show that either short (10 min) mechanical stimulus by pulsatile fluid flow (FF) (10 dyn/cm2, 8 Hz) or exogenous VEGF165 (6 ng/ml) similarly stimulated cell viability, ERK phosphorylation, and β-catenin membrane translocation. A VEGFR2 antagonist (SU5416) or transfection with specific VEGFR2 siRNAs (siVEGFR2) decreased these events. FF for 10 min increased VEGFR2 phosphorylation at both Tyr-1059 and Tyr-1175; an effect that was mimicked by VEGF165 but was unaffected by a VEGF neutralizing antibody. Subsequently (at 6 h), this mechanical stimulus induced VEGF gene overexpression, which was prevented by siVEGFR2 transfection. Depletion of the structural protein caveolin-1 by using siRNA technology impaired FF-induced VEGFR2 phosphorylation. In conclusion, these in vitro findings point to caveolin-1-dependent VEGFR2 activation as an important mechanism whereby mechanical stimuli promote osteocyte viability. J. Cell. Physiol. 230: 278-285, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2015
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19. Treatment with N- and C-Terminal Peptides of Parathyroid Hormone-Related Protein Partly Compensate the Skeletal Abnormalities in IGF-I Deficient Mice.
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Rodríguez-de la Rosa, Lourdes, López-Herradón, Ana, Portal-Núñez, Sergio, Murillo-Cuesta, Silvia, Lozano, Daniel, Cediel, Rafael, Varela-Nieto, Isabel, and Esbrit, Pedro
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N-terminal residues , *C-terminal residues , *PEPTIDES , *PARATHYROID hormone , *SKELETAL muscle , *SOMATOMEDIN C , *PROTEIN deficiency , *LABORATORY mice - Abstract
Insulin-like growth factor-I (IGF-I) deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH). PTH-related protein (PTHrP) is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1–36) and PTHrP (107–111) (osteostatin) to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype) or saline vehicle (3 males and 3 females for each genotype). We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a,cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1–36) and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1–36) and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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20. Autophagy impairment aggravates the inhibitory effects of high glucose on osteoblast viability and function.
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BARTOLOMÉ, Alberto, LÓPEZ-HERRADÓN, Ana, PORTAL-NÚÑEZ, Sergio, GARC'IA-AGUILAR, Ana, ESBRIT, Pedro, BENITO, Manuel, and GUILLÉN, Carlos
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AUTOPHAGY , *GLUCOSE , *OSTEOBLASTS , *OXIDATIVE stress , *BIOENERGETICS , *REACTIVE oxygen species - Abstract
Autophagy is a highly regulated homoeostatic process involved in the lysosomal degradation of damaged cell organelles and proteins. This process is considered an important pro-survival mechanism under diverse stress conditions. A diabetic milieu is known to hamper osteoblast viability and function. In the present study, we explored the putative protective role of autophagy in osteoblastic cells exposed to an HG (high glucose) medium. HG was found to increase protein oxidation and triggered autophagy by a mechanism dependent on reactive oxygen species overproduction in osteoblastic MC3T3-E1 cells. MC3T3-E1 cell survival was impaired by HG and worsened by chemical or genetic inhibition of autophagy. These findings were mimicked by H2O2-induced oxidative stress in these cells. Autophagy impairment led to both defective mitochondrial morphology and decreased bioenergetic machinery and inhibited further osteoblast differentiation in MC3T3-E1 cells upon exposure to HG. These novel findings indicate that autophagy is an essential mechanism to maintain osteoblast viability and function in an HG environment. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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21. Recombinant Proteins-Based Strategies in Bone Tissue Engineering.
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Paulini, Marina, Camal Ruggieri, Iván Nadir, Ramallo, Melina, Alonso, Matilde, Rodriguez-Cabello, José Carlos, Esbrit, Pedro, Mardegan Issa, João Paulo, and Feldman, Sara
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RECOMBINANT proteins , *REGENERATIVE medicine , *TISSUE scaffolds , *TISSUE engineering - Abstract
The increase in fracture rates and/or problems associated with missing bones due to accidents or various pathologies generates socio-health problems with a very high impact. Tissue engineering aims to offer some kind of strategy to promote the repair of damaged tissue or its restoration as close as possible to the original tissue. Among the alternatives proposed by this specialty, the development of scaffolds obtained from recombinant proteins is of special importance. Furthermore, science and technology have advanced to obtain recombinant chimera's proteins. This review aims to offer a synthetic description of the latest and most outstanding advances made with these types of scaffolds, particularly emphasizing the main recombinant proteins that can be used to construct scaffolds in their own right, i.e., not only to impregnate them, but also to make scaffolds from their complex structure, with the purpose of being considered in bone regenerative medicine in the near future. [ABSTRACT FROM AUTHOR]
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- 2022
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22. Parathyroid hormone-related protein protects renal tubuloepithelial cells from apoptosis by activating transcription factor Runx2.
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Ardura, Juan A, Sanz, Ana B, Ortiz, Alberto, and Esbrit, Pedro
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PARATHYROID hormone-related protein , *APOPTOSIS , *RUNX proteins , *OSTEOBLASTS , *PARATHYROID hormone - Abstract
Runx2 is a key transcription factor in bone development regulating several processes, including osteoblast apoptosis. The antiapoptotic effects of parathyroid hormone (PTH) in osteoblasts depend on Runx2-mediated transcription of prosurvival genes. In the kidney, PTH-related protein (PTHrP) promotes tubulointerstitial cell survival by activating the PTH/PTHrP type 1 receptor. We found that Runx2 is expressed in renal tubuloepithelial MCT and HK2 cell lines in vitro and in the mouse kidney tubuloepithelium in vivo. The 1-36 amino-acid fragment of PTHrP was found to increase the expression and nuclear translocation of Runx2 in both cell lines in a dose- and time-dependent manner. PTHrP(1-36) protected renal tubuloepithelial cells from folic acid toxicity and serum deprivation, an effect inhibited by a dominant-negative Runx2 construct or a Runx2 siRNA. Furthermore, PTHrP(1-36) upregulated the antiapoptotic proteins Bcl-2 and osteopontin, and these effects were abolished by Runx2 siRNA. Runx2, osteopontin, and Bcl-2 were increased in tubuloepithelial cells from transgenic mice with PTHrP overexpression and in wild-type mice with acute or chronic renal failure. Thus, PTHrP regulates renal tubuloepithelial cell survival via Runx2 in the mammalian kidney. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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23. Characterization of skeletal alterations in a model of prematurely aging mice.
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Portal-Núñez, Sergio, Manassra, Rashed, Lozano, Daniel, Acitores, Alicia, Mulero, Francisca, Villanueva-Peñacarrillo, María, Fuente, Mónica, and Esbrit, Pedro
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BONE density , *DISEASE risk factors , *OSTEOPOROSIS , *GENE expression , *OSTEOCLASTS , *OXIDATIVE stress , *LABORATORY mice - Abstract
An age-related bone loss occurs, apparently associated with the concomitant increase in an oxidative stress situation. However, the underlying mechanisms of age-related osteopenia are ill defined since these studies are time consuming and require the use of many animals (mainly rodents). Here, we aimed to characterize for the first time the bone status of prematurely aging mice (PAM), which exhibit an increased oxidative stress. Tibiae from adult (6 months) PAM show an increase in bone mineral density (BMD) and bone mineral content (assessed by bone densitometry) versus those in their normal counterparts (non-prematurely aging mice, NPAM) and similarly decreased in both kinds of mouse with age. However, at this bone site, trabecular BMD (determined by μ-computerized tomography) was similar in both adult PAM and old (18 months) NPAM. Femurs from these groups of mice present an increase in oxidative stress, inflammation, osteoclastogenic, and adipogenic markers, but a decrease in the gene expression of osteoblastic differentiation markers and of the Wnt/β-catenin pathway. Our findings show that adult PAM recapitulate various age-related bone features, and thus are a suitable model for premature bone senescence studies. [ABSTRACT FROM AUTHOR]
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- 2013
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24. Novel Role of Parathyroid Hormone-Related Protein in the Pathophysiology of the Diabetic Kidney: Evidence from Experimental and Human Diabetic Nephropathy.
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Romero, Montserrat, Ortega, Arantxa, Olea, Nuria, Arenas, María Isabel, Izquierdo, Adriana, Bover, Jordi, Esbrit, Pedro, and Bosch, Ricardo J.
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DIABETIC nephropathies , *PARATHYROID hormone-related protein , *PATHOLOGICAL physiology , *EXPERIMENTAL biology , *KIDNEY function tests , *KIDNEY hypertrophy , *TRANSFORMING growth factors-beta , *ANGIOTENSIN II - Abstract
Parathyroid hormone-related protein (PTHrP) and its receptor type 1 (PTH1R) are extensively expressed in the kidney, where they are able tomodulate renal function. Renal PTHrP is known to be overexpressed in acute renal injury. Recently, we hypothesized that PTHrP involvement in the mechanisms of renal injury might not be limited to conditions with predominant damage of the renal tubulointerstitium and might be extended to glomerular diseases, such as diabetic nephropathy (DN). In experimental DN, the overexpression of both PTHrP and the PTH1R contributes to the development of renal hypertrophy as well as proteinuria. More recent data have shown, for the first time, that PTHrP is upregulated in the kidney from patients with DN. Collectively, animal and human studies have shown that PTHrP acts as an important mediator of diabetic renal cell hypertrophy by amechanism which involves the modulation of cell cycle regulatory proteins and TGF-β1. Furthermore, angiotensin II (Ang II), a critical factor in the progression of renal injury, appears to be responsible for PTHrP upregulation in these conditions. These findings provide novel insights into the well-known protective effects of Ang II antagonists in renal diseases, paving the way for new therapeutic approaches. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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25. Parathyroid hormone-related protein is a hypertrophy factor for human mesangial cells: Implications for diabetic nephropathy.
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Ortega, Arantxa, Romero, Montserrat, Izquierdo, Adriana, Troyano, Nuria, Arce, Yolanda, Ardura, Juan Antonio, Arenas, María Isabel, Bover, Jordi, Esbrit, Pedro, and Bosch, Ricardo J.
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PARATHYROID hormone , *HYPERTROPHY , *DIABETIC nephropathies , *KIDNEY hypertrophy , *GENE expression , *BLOOD sugar , *LABORATORY mice - Abstract
Hypertrophy of human mesangial cells (HMC) is among the earliest characteristics in patients with diabetic nephropathy (DN). Recently, we observed the upregulation of parathyroid hormone (PTH)-related protein (PTHrP) in experimental DN, associated with renal hypertrophy. Herein, we first examined whether PTHrP was overexpressed in human DN, and next assessed the putative role of this protein on high glucose (HG)-induced HMC hypertrophy. As previously found in mice, kidneys from diabetic patients showed an increased tubular and glomerular immunostaining for PTHrP. In HMC, HG medium increased PTHrP protein expression associated with the development of hypertrophy as assessed by cell protein content. This effect was also induced by PTHrP(1-36). HG and PTHrP(1-36)-induced hypertrophy were associated with an increase in cyclin D1 and p27Kip1 protein expression, a decreased cyclin E expression, and the prevention of cyclin E/cdk2 complex activation. Both PTHrP neutralizing antiserum (α-PTHrP) and the PTH/PTHrP receptor antagonist (JB4250) were able to abolish HG induction of hypertrophy, the aforementioned changes in cell cycle proteins, and also TGF-β1 up-regulation. Moreover, the capability of both HG and PTHrP(1-36) to induce HMC hypertrophy was abolished by α-TGFβ1. These data show for the first time that PTHrP is upregulated in the kidney of patients with DN. Our findings also demonstrate that PTHrP acts as an important mediator of HG-induced HMC hypertrophy by modulating cell cycle regulatory proteins and TGF-β1. J. Cell. Physiol. 227: 1980-1987, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2012
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26. Comparison of the skeletal effects induced by daily administration of PTHrP (1-36) and PTHrP (107-139) to ovariectomized mice.
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de Castro, Luis Fernández, Lozano, Daniel, Portal-Núñez, Sergio, Maycas, Marta, De la Fuente, Mónica, Caeiro, José R., and Esbrit, Pedro
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DRUG administration , *INJECTIONS , *BONE remodeling , *BONE marrow cells , *OXIDATIVE stress , *CELL differentiation , *COMPARATIVE studies , *LABORATORY mice - Abstract
We here compared the changes induced by subcutaneous injection of PTHrP (1-36) or PTHrP (107-139) (80 µg/kg/day, 5 days/week for 4 or 8 weeks) in bone histology and bone remodeling factors, and in bone marrow cells (BMCs) ex vivo, in ovariectomized (OVX) mice. We also examined the osteogenic effects of these peptides in mouse mesenchymal C3H10T1/2 cells under oxidative stress condition in vitro, which recapitulates the effects of OVX. We confirmed that PTHrP (1-36) exerts bone anabolic actions, as assessed by bone histology and osteoblast differentiation markers in the long bones and plasma from OVX mice. PTHrP (107-139) was also efficient in stimulating several bone formation parameters, and it dramatically decreased bone resorption markers. Moreover, both PTHrP peptides modulate DKK-1 and Sost/sclerostin in osteoblast-like UMR-106 cells highly expressing these Wnt pathway inhibitors, related to their osteogenic action in this in vivo scenario. Administration of either PTHrP peptide improved osteogenic differentiation in BMCs from OVX mice ex vivo and in mouse mesenchymal C3H10T1/2 cells under oxidative stress condition in vitro. These data demonstrate that PTHrP (1-36) and PTHrP (107-139) can exert similar osteogenic effects in the appendicular skeleton of OVX mice. Our results suggest that these effects might occur in part by modulating the Wnt pathway. These findings lend credence to the notion that the osteogenic action of PTHrP (107-139) is likely a consequence of its anti-resorptive and anabolic features, and further support the usefulness of PTHrP (1-36) as a bone anabolic peptide in the setting of estrogen-depletion. J. Cell. Physiol. 227: 1752-1760, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2012
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27. A Transgenic Mouse Model for Studying the Role of the Parathyroid Hormone-Related Protein System in Renal Injury.
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Bosch, Ricardo J., Ortega, Arantxa, Izquierdo, Adriana, Arribas, Ignacio, Bover, Jordi, and Esbrit, Pedro
- Abstract
Parathyroid hormone- (PTH-) related protein (PTHrP) and its receptor, the PTH1 receptor (PTH1R), are widely expressed in the kidney, where PTHrP exerts a modulatory action on renal function. PTHrP is known to be upregulated in several experimental nephropathies such as acute renal failure (ARF), obstructive nephropathy (ON) as well as diabetic nephropathy (DN). In this paper, we will discuss the functional consequences of chronic PTHrP overexpression in the damaged kidney using a transgenic mouse strain overexpressing PTHrP in the renal proximal tubule. In both ARF and ON, PTHrP displays proinflammatory and profibrogenic actions including the induction of epithelia to mesenquima transition. Moreover, PTHrP participates in the mechanisms of renal hypertrophy as well as proteinuria in experimental DN. Angiotensin II (Ang II), a critical factor in the progression of renal injury, appears to be, at least in part, responsible for endogenous PTHrP upregulation in these pathophysiological settings. These findings provide novel insights into the well-known protective effects of Ang II antagonists in renal diseases, paving the way for new therapeutic approaches. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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28. The osteoinductive properties of mesoporous silicate coated with osteostatin in a rabbit femur cavity defect model
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Trejo, Cynthia G., Lozano, Daniel, Manzano, Miguel, Doadrio, Juan C., Salinas, Antonio J., Dapía, Sonia, Gómez-Barrena, Enrique, Vallet-Regí, María, García-Honduvilla, Natalio, Buján, Julia, and Esbrit, Pedro
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MESOPOROUS materials , *PARATHYROID hormone-related protein , *SILICATES , *BONE regeneration , *LABORATORY rabbits , *BONE growth , *TISSUE engineering ,FEMUR abnormalities - Abstract
Abstract: Parathyroid hormone-related protein (PTHrP) is an important regulator of bone formation and remodeling. Our recent findings demonstrate that PTHrP (107–111) (osteostatin) loaded onto silica-based ordered mesoporous SBA15 materials exhibit osteogenic features in osteoblastic cell cultures. We aimed here to elucidate whether these peptide-coated materials might be suitable for promoting bone repair following a cavitary defect in the rabbit femur. Histological examination revealed the absence of significant inflammation or bone resorption within the time of study (4 and 8 weeks) after implantation. At 8 weeks, the peptide-unloaded materials were still separated from the bone marrow by a fibrous cap, which was greatly diminished by the presence of the PTHrP peptide. By using μCT analysis, new bone formation was evident at different distances from the implants, mainly for the latter peptide-loaded biomaterials. This was confirmed by performing immunostaining for different osteoblast markers. Our findings demonstrate that these PTHrP (107–111)-loaded bioceramics significantly improve local bone induction, as compared to that observed with the unloaded material. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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29. Presence of a functional receptor for GLP-1 in osteoblastic cells, independent of the cAMP-linked GLP-1 receptor.
- Author
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NUCHE-BERENGUER, BERNARDO, PORTAL-NÚÑEZ, SERGIO, MORENO, PAOLA, GONZÁLEZ, NIEVES, ACITORES, ALICIA, LÓPEZ-HERRADÓN, ANA, ESBRIT, PEDRO, VALVERDE, ISABEL, and VILLANUEVA-PEÑACARRILLO, MARÍA
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GLUCAGON-like peptide 1 , *GLUCOSE , *CYCLIC adenylic acid , *TYPE 2 diabetes , *INSULIN , *MITOGEN-activated protein kinases - Abstract
Glucagon-like peptide 1 (GLP-1) controls glucose metabolism in extrapancreatic tissues through receptors other than the pancreatic cAMP-linked GLP-1 receptor; also, GLP-1 induces an insulin- and PTH-independent bone anabolic action in insulin-resistant and type-2 diabetic rats. Here we searched for the presence and characteristics of GLP-1 receptors in osteoblastic MC3T3-E1 cells. [125I]-GLP-1 specific binding to MC3T3-E1 cells was time- and temperature-dependent, reaching maximal value at 30 min at 25°C; in these conditions, [125I]-GLP-1 binding was dissociable, and displaced by GLP-1, partially by GLP-2, but not by exendin-4 (Ex-4), exendin-9 (Ex-9), glucagon or insulin; Scatchard analysis of the unlabeled GLP-1 data showed high and low affinity binding sites; cross-linking of GLP-1 binding revealed an estimated 70 kDa band, almost undetectable in the presence of 10-6 M GLP-1. GLP-1, Ex-9, insulin or glucagon failed to modify cellular cAMP content, while GLP-2 and Ex-4 increased it. However, GLP-1 induced an immediate hydrolysis of glycosylphosphatidylinositols (GPIs) generating short-lived inositolphosphoglycans (IPGs), and an increase in phosphatidylinositol-3 kinase (PI3K) and mitogen activated protein kinase (MAPK) activities; Ex-4 also affected GPIs, but its action was delayed with respect to that of GLP-1. This incretin was found to decrease Runx2 but increased osteocalcin gene expression, without affecting that of osteoprotegerin or the canonical Wnt pathway activity in MC3T3-E1 cells which do not express the pancreatic GLP-1 receptor. Our data demonstrate for the first time that GLP-1 can directly and functionally interact with osteoblastic cells, possibly through a GPI/IPG-coupled receptor. J. Cell. Physiol. 225: 585–592, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
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- 2010
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30. Exendin-4 exerts osteogenic actions in insulin-resistant and type 2 diabetic states
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Nuche-Berenguer, Bernardo, Moreno, Paola, Portal-Nuñez, Sergio, Dapía, Sonia, Esbrit, Pedro, and Villanueva-Peñacarrillo, María L.
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BONE growth , *INSULIN resistance , *TYPE 2 diabetes , *GLUCOSE , *HOMEOSTASIS , *HYPOGLYCEMIC agents , *STREPTOZOTOCIN , *GLUCAGON-like peptide 1 - Abstract
Abstract: Poor control of glucose homeostasis accounts for diabetes-related bone loss. Incretins – GLP-1 and GIP – have been proposed to affect bone turnover. GLP-1, apart from its anti-diabetic and other actions, has shown to exert a bone anabolic effect in streptozotocin-induced type 2 diabetic (T2D) and fructose-induced insulin-resistant (IR) rats. Exendin-4 (Ex-4), a peptide of non-mammalian nature, is sharing with GLP-1 part of its structural sequence, and also several glucoregulatory effects in mammals in an even more efficient manner. We have explored the effect of continuous administration (3 days by osmotic pump) of Ex-4 or saline (control) on bone turnover factors and bone structure in T2D and IR rats, compared to N, and the possible interaction of Ex-4 with the Wnt signalling pathway. Blood was taken before and after treatment for plasma measurements; tibiae and femurs were collected for gene expression of bone markers (RT-PCR) and structure (µCT) analysis; we also measured the mRNA levels of LRP5 – an activator of the Wnt pathway – and those of DKK1 and sclerostin (SOST) — both blockers of LRP5 activity. Compared to N-control, plasma glucose and insulin were respectively higher and lower in T2D; osteocalcin (OC) and tartrate-resistant alkaline phosphatase 5b (TRAP5b) were lower; after Ex-4, these turnover markers were further reduced in T2D and IR, while TRAP5b increased in N. Bone OC, osteoprogeterin (OPG) and receptor activator of NF-kB ligand (RANKL) mRNA were lower in T2D and IR; Ex-4 increased OC in all groups and OPG in N and IR, reduced RANKL in N and T2D but increased it in IR; the LRP5/DKK1 and LRP5/SOST mRNA ratios were similarly decreased in T2D, but in IR, the latter ratio was reduced while the former was increased; after Ex-4, both ratios augmented in N, and that of LRP5/DKK1 tended to normalize in T2D and IR. In conclusion, Ex-4 exerts osteogenis effects in T2D and IR models, and interacts with the Wnt pathway to promote bone formation. [Copyright &y& Elsevier]
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- 2010
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31. Parathyroid hormone-related protein (107–139) increases human osteoblastic cell survival by activation of vascular endothelial growth factor receptor-2.
- Author
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Alonso, Verónica, De Gortázar, Arancha R., Ardura, Juan A., Andrade-Zapata, Irene, Alvarez-Arroyo, M. Victoria, and Esbrit, Pedro
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PARATHYROID hormone-related protein , *VASCULAR endothelial growth factors , *GROWTH factors , *CELLS , *PEPTIDE hormones - Abstract
Parathyroid hormone-related protein (PTHrP) (107–139), in contrast to the N-terminal fragment PTHrP (1–36), has been shown to interact with the vascular endothelial growth factor (VEGF) system to modulate human osteoblast differentiation. In this study, we evaluated whether this interaction might affect human osteoblastic cell survival. Pre-incubation with PTHrP (107–139) for 1–24 h dose-dependently (0.1–100 nM) inhibited dexamethasone- or etoposide-induced cell death in human osteoblastic MG-63 cells and human osteoblast-like cells from trabecular bone. This effect, but not that elicited by PTHrP (1–36), was abolished by the VEGF receptor (VEGFR)-2 inhibitors SU5614 and SU1498 or VEGFR-2 siRNA transfection in these cells. PTHrP (107–139), but not PTHrP (1–36), at 100 nM, rapidly (within 2 min) increased VEGFR-2 tyrosine-phosphorylation in MG-63 cells; an effect unaffected by several inhibitors of metalloproteinases, neutralizing VEGF165 or VEGFR-2 antibodies, or the VEGF binding inhibitor CBO-PP1. The latter two antagonists also failed to affect 125I-[Tyr116] PTHrP (107–115) binding to these cells. Consistent with its effect on VEGFR-2 activation, PTHrP (107–139) rapidly induced extracellular signal-regulated kinase (ERK) 1/2 and Akt activaton, and both ERK and phosphatidylinsositol-3 kinase (PI3K) inhibitors abolished its pro-survival effect in human osteoblastic cells. In addition, SU5614 and the latter two types of inhibitors abrogated Runx2 activation by this peptide in MG-63 cells. Transfection with a dominant-negative Runx2 construct abolished the pro-survival effect of PTHrP (107–139), associated with a decrease in Bcl-2/Bax protein ratio. Our findings demonstrate that PTHrP (107–139) interacts with VEGFR-2 to promote human osteoblastic cell survival by a mechanism involving Runx2 activation. J. Cell. Physiol. 217: 717–727, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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32. Parathyroid hormone-related protein interacts with vascular endothelial growth factor to promote fibrogenesis in the obstructed mouse kidney.
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Ardura, Juan A., Berruguete, Raúl, Rámila, David, Alvarez-Arroyo, M. Victoria, and Esbrit, Pedro
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MESSENGER RNA , *IMMUNOSUPPRESSIVE agents , *APOPTOSIS , *CYTOKINES , *CYCLOSPORINE , *GROWTH factors - Abstract
Parathyroid hormone-related protein (PTHrP) interacts with vascular endothelial growth factor (VEGF) in osteoblasts. Since both PTHrP and VEGF have both proinflammatory and profibrogenic features, we assessed here whether these factors might act in concert to promote fibrogenesis in the obstructed kidney. VEGF receptor (VEGFR)-1 was upregulated, while VEGFR-2 was downregulated (at both mRNA and protein levels) in the mouse kidney within 2-6 days after ureteral obstruction. VEGF protein levels also increased in the obstructed kidney at the latter time. Moreover, this VEGF and VEGFR-1 upregulation was higher in mice overexpressing PTHrP in the proximal tubule than in control littermates. These changes were associated with higher fibronectin mRNA expression and α-smooth muscle actin (α-SMA) and integrin- linked kinase (ILK) immunostaining and lower apoptotic tubulointersti- tial cells in the mouse obstructed kidney than in control littermates. Pretreatment with a neutralizing anti-VEGF antibody reversed these responses in the obstructed kidney of both types of mice. In vitro, PTHrP-(1-36) increased (maximal 2-fold vs. basal, at 100 nM) α-SMA and ILK protein expression and decreased E-cadherin protein levels in renal tubuloepithelial mouse cortical tubule and normal rat kidney (NRK) 52E cells. PTHrP-(1-36) also decreased cyclosporine A-and/or osmotic stress-induced apoptosis in these cells and in renal fibroblastic NRK 49F cells. These effects elicited by PTHrP-(1-36) were associated with both VEGF and VEGFR-1 upregulation, and abolished by the anti-VEGF antibody. Collectively, these findings strongly suggest that VEGF acts as an important mediator of PTHrP to promote fibrogenesis in the obstructed kidney. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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33. LDL induces parathyroid hormone-related protein expression in vascular smooth muscle cells: Modulation by simvastatin
- Author
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Martin-Ventura, Jose Luis, Blanco-Colio, Luis Miguel, Aparicio, Cesar, Ortega, Luis, Esbrit, Pedro, and Egido, Jesús
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SMOOTH muscle , *MUSCLES , *STATINS (Cardiovascular agents) , *VASCULAR smooth muscle - Abstract
Abstract: Background: Parathyroid hormone-related protein (PTHrP) is overexpressed in atherosclerotic plaques by unknown mechanisms. We have examined here the putative mechanism(s) responsible for this overexpression in the atherosclerotic lesion and its potential modulation by simvastatin, both in vitro and in vivo. Methods and results: Atherosclerosis was induced in rabbits by femoral endothelial dessication and atherogenic diet. After 2 weeks, animals were randomized to receive either 5mg/(kgd) simvastatin (n =7) or no treatment (n =6) during 4 additional weeks. An increase in PTHrP immunostaining was observed in atherosclerotic lesions of hyperlipidemic rabbits, which was significantly reduced by simvastatin. However, PTH/PTHrP type 1 receptor staining was similar in both groups. In cultured vascular smooth muscle cells (VSMCs), atherogenic concentrations of native LDL (0.125–0.5mg/mL) increased PTHrP expression. This effect was prevented by preincubation with simvastatin (1μmol/L) and was reversed by mevalonate, geranylgeranylpyrophosphate and, to a lesser extent, by farnesylpyrophosphate. Moreover, in transfection studies, we showed that RhoA appears to participate in the mechanism whereby LDL induces PTHrP in VSMC. Finally, native LDL-induced VSMC growth and this mitogenic effect was blocked by PTHrP silencing. Conclusions: LDL might be responsible for PTHrP overexpression in atherosclerotic plaques of hyperlipidemic rabbits. The inhibition of this effect by simvastatin provides further insights into the mechanisms of action of statins. [Copyright &y& Elsevier]
- Published
- 2008
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34. Immunohistochemical analysis of low-grade and high-grade prostate carcinoma: relative changes of parathyroid hormone-related protein and its parathyroid hormone 1 receptor, osteoprotegerin and receptor activator of nuclear factor-kB hgand.
- Author
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Pérez-Martínez, Francisco C., Alonso, Verónica, Sarasa, José L., Syon-Ghyun Nam-Cha, Vela-Navarrete, Remigio, Manzarbeitia, Félix, Calahorra, Francisco J., and Esbrit, Pedro
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CYTOKINES , *PROSTATE cancer , *IMMUNOHISTOCHEMISTRY , *TRANSURETHRAL prostatectomy , *TUMORS - Abstract
Aim: To investigate multiple bone cytokines produced by prostate carcinoma (PCa) as a novel strategy to differentiate potential aggressiveness in localised PCa using immunohistochemical analysis. Methods: A total of 47 cases of PCa undergoing radical prostatectomy or transurethral prostatic resection at our institution (Fundación Jiménez Díaz (Grupo Capio), Madrid, Spain) between January 1991 and June 1998 were identified as low-grade (≤ 4; n = 22) or high-grade (≥7, excluding 7 (3+4) cases; n = 25) PCa according to Gleason grade. PCa specimens were immunostained for: parathyroid hormone (PTH)-related protein (PTHrP), the PTH1 receptor, osteoprotegerin and receptor activator of nuclear factor-κ B ligand (RANKL), as well as Ki67 (a proliferation marker) and CD34 (an angiogenesis marker). Results: PCa samples showed an increased immunostaining far both osteaprotegerin and RANKL, associated with tumour grade and PTHrP positivity, in the tumoral epithelium. Using a score value of 4-corresponding to moderate staining-as cut-off, the best sensitivity value was for PTHrP (with C-terminal antiserum C6; 100 %); wheras the best specificity value was far RANKL (95 %). Conclusions: All the evaluated factors are overexpressed mainly in the high-grade tumours. Our Findings indicate that, in most patients with PCa (with Ki67 values between 1% and 9%), sequential determination of Published Online First C-terminal PTHrP and RANKL immunoreactivities is a useful approach to discriminate low-grade and high-grade tumours. [ABSTRACT FROM AUTHOR]
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- 2007
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35. Up-regulation of parathyroid hormone-related protein in folic acid-induced acute renal failure.
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Santos, Soledad, Bosch, Ricardo J., Ortega, Arantxa, Largo, Raquel, Fernández-Agulló, Teresa, Gazapo, Rosa, Egido, Jesús, and Esbrit, Pedro
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PARATHYROID hormone-related protein , *ACUTE kidney failure , *LABORATORY rats - Abstract
Up-regulation of parathyroid hormone-related protein in folic acid-induced acute renal failure. Background. Parathyroid hormone (PTH)-related protein (PTHrP) is present in many normal tissues, including the kidney. Current evidence supports that PTHrP is involved in renal pathophysiology, although its role on the mechanisms of renal damage and/or repair is unclear. Our present study examined the changes in PTHrP and the PTH/PTHrP receptor (type 1) in folic acid-induced acute renal failure in rats. The possible role of PTHrP on the process of renal regeneration following folic acid administration, and potential interaction between angiotensin II (Ang II) and endothelin-1, and PTHrP, were examined in this animal model. Methods. PTHrP, PTH/PTHrP receptor, ACE, and preproendothelin-1 (preproET-1) mRNA levels in the rat kidney were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and/or RNase protection assay. Immunohistochemistry also was performed for PTHrP, the PTH/PTHrP receptor, and Ang II in the renal tissue of folic acid-injected rats. The role of PTHrP on tubular cell proliferation following folic acid injury was investigated in vitro in rat renal epithelial cells (NRK 52E). PTHrP secretion in the medium conditioned by these cells was measured by an immunoradiometric assay specific for the 1-36 sequence. Results. Using RT-PCR, PTHrP mRNA was rapidly (1 hour) and maximally increased (3-fold) in the rat kidney after folic acid, decreasing after six hours. At 72 hours, renal function was maximally decreased in these rats, associated with an increased PTHrP immunostaining in both renal tubules and glomeruli. In contrast, the PTH/PTHrP receptor mRNA (RNase protection assay) decreased shortly after folic acid administration. Moreover, PTH/PTHrP receptor immunostaining dramatically decreased in renal tubular cell membranes after folic acid. A single subcutaneous administration of PTHrP (1-36), 3 or 50 μg/kg body weight, shortly after folic... [ABSTRACT FROM AUTHOR]
- Published
- 2001
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36. Renal expression of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP receptor in a rat model of tubulointerstitial damage.
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LARGO, RAQUEL, GÓMEZ-GARRE, DULCENOMBRE, SANTOS, SOLEDAD, PEÑARANDA, CARLOS, BLANCO, JULIA, ESBRIT, PEDRO, and EGIDO, JESÚS
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PARATHYROID hormone-related protein , *KIDNEY diseases - Abstract
Renal expression of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP receptor in a rat model of tubulointerstitial damage. Background. PTHrP, which appears to act as a growth/differentiation factor in a variety of tissues, is present in the kidney; however, its role is unclear. Methods. The expression of PTHrP and the PTH/PTHrP receptor were investigated by reverse transcription-polymerase chain reaction (RT–PCR) and immunohistochemistry in the remnant kidney of uninephrectomized (UNX) rats after protein overloading [1 g/day of bovine serum albumin (BSA)]. Results. Compared with UNX-control rats, proteinuria in BSA-overloaded animals was detected within the first 24 hours and increased during the entire study period (28 days). Kidney examination by light microscopy showed no significant renal lesions at day 1 of BSA treatment, whereas at days 8 and 28, tubular lesions, infiltration of mononuclear cells, and mesangial expansion were observed. PTHrP mRNA expression in the renal cortex was already increased at day 1 (fourfold) and plateaued between days 8 and 28 (12- and 15-fold, respectively) in BSA-overloaded animals compared with UNX-control rats. At day 8, immunohistochemical analysis with two different anti-PTHrP antibodies showed a dramatic increase of PTHrP staining in the damaged proximal and distal tubules from BSA-overloaded rats with respect to UNX-control rats. Moreover, intense PTHrP immunostaining was also observed in glomerular mesangial and endothelial cells in BSA-overloaded rats, but not in the UNX-control rats. A reciprocal decrease of PTH/PTHrP receptor mRNA and immunostaining, without significant changes in the cellular localization (proximal and distal tubule, and glomerular mesangial and epithelial cells) of the PTH/PTHrP receptor positivity was found to occur in the renal cortex of BSA-overloaded rats. At day 8, coinciding with the up-regulation of PTHrP, an increase in the angiotensin converting enzyme and preproendothelin-1... [ABSTRACT FROM AUTHOR]
- Published
- 1999
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