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1.
Cell Rep ; 28(3): 759-772.e10, 2019 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-31315053

RESUMEN

Mechanisms coordinating pancreatic ß cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of ß cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial PEPCK (PEPCK-M) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xenotopic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and ß cell health.

2.
Artículo en Inglés | MEDLINE | ID: mdl-26284027

RESUMEN

CEACAM1 promotes insulin extraction, an event that occurs mainly in liver. Phenocopying global Ceacam1 null mice (Cc1(-/-) ), C57/BL6J mice fed a high-fat (HF) diet exhibited reduced hepatic CEACAM1 levels and impaired insulin clearance, followed by hyperinsulinemia, insulin resistance, and visceral obesity. Conversely, forced liver-specific expression of CEACAM1 protected insulin sensitivity and energy expenditure, and limited gain in total fat mass by HF diet in L-CC1 mice. Because CEACAM1 protein is barely detectable in white adipose tissue (WAT), we herein investigated whether hepatic CEACAM1-dependent insulin clearance pathways regulate adipose tissue biology in response to dietary fat. While HF diet caused a similar body weight gain in L-CC1, this effect was delayed and less intense relative to wild-type (WT) mice. Histological examination revealed less expansion of adipocytes in L-CC1 than WT by HF intake. Immunofluorescence analysis demonstrated a more limited recruitment of crown-like structures, and qRT-PCR analysis showed no significant rise in TNFα mRNA levels in response to HF intake in L-CC1 than WT mice. Unlike WT, HF diet did not activate TGF-ß in WAT of L-CC1 mice, as assessed by Western analysis of Smad2/3 phosphorylation. Consistently, HF diet caused relatively less collagen deposition in L-CC1 than WT mice, as shown by Trichrome staining. Coupled with reduced lipid redistribution from liver to visceral fat, lower inflammation and fibrosis could contribute to protected energy expenditure against HF diet in L-CC1 mice. The data underscore the important role of hepatic insulin clearance in the regulation of adipose tissue inflammation and fibrosis.

3.
Diabetes ; 64(8): 2780-90, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25972571

RESUMEN

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance. Liver-specific inactivation or global null-mutation of Ceacam1 impairs hepatic insulin extraction to cause chronic hyperinsulinemia, resulting in insulin resistance and visceral obesity. In this study we investigated whether diet-induced insulin resistance implicates changes in hepatic CEACAM1. We report that feeding C57/BL6J mice a high-fat diet reduced hepatic CEACAM1 levels by >50% beginning at 21 days, causing hyperinsulinemia, insulin resistance, and elevation in hepatic triacylglycerol content. Conversely, liver-specific inducible CEACAM1 expression prevented hyperinsulinemia and markedly limited insulin resistance and hepatic lipid accumulation that were induced by prolonged high-fat intake. This was partly mediated by increased hepatic ß-fatty acid oxidation and energy expenditure. The data demonstrate that the high-fat diet reduced hepatic CEACAM1 expression and that overexpressing CEACAM1 in liver curtailed diet-induced metabolic abnormalities by protecting hepatic insulin clearance.


Asunto(s)
Antígenos CD/metabolismo , Moléculas de Adhesión Celular/metabolismo , Dieta Alta en Grasa , Resistencia a la Insulina/genética , Hígado/metabolismo , Animales , Antígenos CD/genética , Moléculas de Adhesión Celular/genética , Metabolismo Energético/fisiología , Ácidos Grasos/metabolismo , Hiperinsulinismo/genética , Hiperinsulinismo/metabolismo , Insulina/sangre , Ratones , Ratones Transgénicos
4.
Proc Natl Acad Sci U S A ; 112(21): 6539-44, 2015 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-25964345

RESUMEN

The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.


Asunto(s)
Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Genes myc , Glutamina/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Animales , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inhibidores Enzimáticos/farmacología , Genes ras , Glutaminasa/antagonistas & inhibidores , Glutaminasa/metabolismo , Humanos , Neoplasias Renales/patología , Metabolismo de los Lípidos , Ratones , Ratones SCID , Ratones Transgénicos , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Sulfuros/farmacología , Tiadiazoles/farmacología , Regulación hacia Arriba
5.
Cell ; 156(5): 1045-59, 2014 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-24581500

RESUMEN

Mucus production by goblet cells of the large intestine serves as a crucial antimicrobial protective mechanism at the interface between the eukaryotic and prokaryotic cells of the mammalian intestinal ecosystem. However, the regulatory pathways involved in goblet cell-induced mucus secretion remain largely unknown. Here, we demonstrate that the NLRP6 inflammasome, a recently described regulator of colonic microbiota composition and biogeographical distribution, is a critical orchestrator of goblet cell mucin granule exocytosis. NLRP6 deficiency leads to defective autophagy in goblet cells and abrogated mucus secretion into the large intestinal lumen. Consequently, NLRP6 inflammasome-deficient mice are unable to clear enteric pathogens from the mucosal surface, rendering them highly susceptible to persistent infection. This study identifies an innate immune regulatory pathway governing goblet cell mucus secretion, linking nonhematopoietic inflammasome signaling to autophagy and highlighting the goblet cell as a critical innate immune player in the control of intestinal host-microbial mutualism. PAPERCLIP:


Asunto(s)
Colon/inmunología , Células Caliciformes/inmunología , Inflamasomas/inmunología , Mucosa Intestinal/inmunología , Receptores de Superficie Celular/inmunología , Animales , Autofagia , Colitis/inmunología , Colitis/microbiología , Colon/microbiología , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Células Caliciformes/citología , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Ratones , Moco/metabolismo
6.
Diabetes ; 58(11): 2525-35, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19690064

RESUMEN

OBJECTIVE: Insulin resistance is a major characteristic of type 2 diabetes and is causally associated with obesity. Inflammation plays an important role in obesity-associated insulin resistance, but the underlying mechanism remains unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine with lower circulating levels in obese subjects, and acute treatment with IL-10 prevents lipid-induced insulin resistance. We examined the role of IL-10 in glucose homeostasis using transgenic mice with muscle-specific overexpression of IL-10 (MCK-IL10). RESEARCH DESIGN AND METHODS: MCK-IL10 and wild-type mice were fed a high-fat diet (HFD) for 3 weeks, and insulin sensitivity was determined using hyperinsulinemic-euglycemic clamps in conscious mice. Biochemical and molecular analyses were performed in muscle to assess glucose metabolism, insulin signaling, and inflammatory responses. RESULTS: MCK-IL10 mice developed with no obvious anomaly and showed increased whole-body insulin sensitivity. After 3 weeks of HFD, MCK-IL10 mice developed comparable obesity to wild-type littermates but remained insulin sensitive in skeletal muscle. This was mostly due to significant increases in glucose metabolism, insulin receptor substrate-1, and Akt activity in muscle. HFD increased macrophage-specific CD68 and F4/80 levels in wild-type muscle that was associated with marked increases in tumor necrosis factor-alpha, IL-6, and C-C motif chemokine receptor-2 levels. In contrast, MCK-IL10 mice were protected from diet-induced inflammatory response in muscle. CONCLUSIONS: These results demonstrate that IL-10 increases insulin sensitivity and protects skeletal muscle from obesity-associated macrophage infiltration, increases in inflammatory cytokines, and their deleterious effects on insulin signaling and glucose metabolism. Our findings provide novel insights into the role of anti-inflammatory cytokine in the treatment of type 2 diabetes.


Asunto(s)
Citocinas/fisiología , Grasas de la Dieta/farmacología , Resistencia a la Insulina/fisiología , Interleucina-10/genética , Macrófagos/fisiología , Músculo Esquelético/fisiología , Animales , Creatina Quinasa/genética , Creatina Quinasa/metabolismo , Citocinas/antagonistas & inhibidores , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Modelos Animales de Enfermedad , Citometría de Flujo , Técnica de Clampeo de la Glucosa , Hiperinsulinismo , Inflamación/fisiopatología , Inflamación/prevención & control , Insulina/fisiología , Interleucina-10/metabolismo , Interleucina-10/farmacología , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología
7.
Bone ; 44(4): 528-36, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19095088

RESUMEN

Zfp521, a 30 C2H2 Kruppel-like zinc finger protein, is expressed at high levels at the periphery of early mesenchymal condensations prefiguring skeletal elements and in all developing bones in the perichondrium and periosteum, in osteoblast precursors and osteocytes, and in chondroblast precursors and growth plate prehypertrophic chondrocytes. Zfp521 expression in cultured mesenchymal cells is decreased by BMP-2 and increased by PTHrP, which promote and antagonize osteoblast differentiation, respectively. In vitro, Zfp521 overexpression reduces the expression of several downstream osteoblast marker genes and antagonizes osteoblast differentiation. Zfp521 binds Runx2 and represses its transcriptional activity, and Runx2 dose-dependently rescues Zfp521's inhibition of osteoblast differentiation. In contrast, osteocalcin promoter-targeted overexpression of Zfp521 in osteoblasts in vivo results in increased bone formation and bone mass. We propose that Zfp521 regulates the rate of osteoblast differentiation and bone formation during development and in the mature skeleton, in part by antagonizing Runx2.


Asunto(s)
Diferenciación Celular/fisiología , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Proteínas de Unión al ADN/metabolismo , Osteoblastos/citología , Osteogénesis/fisiología , Factores de Transcripción/metabolismo , Animales , Northern Blotting , Células Cultivadas , Proteínas de Unión al ADN/genética , Técnica del Anticuerpo Fluorescente , Hibridación in Situ , Técnicas In Vitro , Proteína del Locus del Complejo MDS1 y EV11 , Ratones , Ratones Transgénicos , Osteoblastos/metabolismo , Proto-Oncogenes/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/genética , Transfección
8.
J Bone Miner Res ; 23(5): 584-95, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18433296

RESUMEN

INTRODUCTION: Activator protein (AP)-1 family members play important roles in the development and maintenance of the adult skeleton. Transgenic mice that overexpress the naturally occurring DeltaFosB splice variant of FosB develop severe osteosclerosis. Translation of Deltafosb mRNA produces both DeltaFosB and a further truncated isoform (Delta2DeltaFosB) that lacks known transactivation domains but, like DeltaFosB, induces increased expression of osteoblast marker genes. MATERIALS AND METHODS: To test Delta2DeltaFosB's ability to induce bone formation in vivo, we generated transgenic mice that overexpress only Delta2DeltaFosB using the enolase 2 (ENO2) promoter-driven bitransgenic Tet-Off system. RESULTS: Despite Delta2DeltaFosB's failure to induce transcription of an AP-1 reporter gene, the transgenic mice exhibited both the bone and the fat phenotypes seen in the ENO2-DeltaFosB mice. Both DeltaFosB and Delta2DeltaFosB activated the BMP-responsive Xvent-luc reporter gene and increased Smad1 expression. Delta2DeltaFosB enhanced BMP-induced Smad1 phosphorylation and the translocation of phospho-Smad1 (pSmad1) to the nucleus more efficiently than DeltaFosB and showed a reduced induction of inhibitory Smad6 expression. CONCLUSIONS: DeltaFosB's AP-1 transactivating function is not needed to induce increased bone formation, and Delta2DeltaFosB may act, at least in part, by increasing Smad1 expression, phosphorylation, and translocation to the nucleus.


Asunto(s)
Osteoclastos/metabolismo , Osteosclerosis/genética , Isoformas de Proteínas/fisiología , Proteínas Proto-Oncogénicas c-fos/fisiología , Proteína Smad1/metabolismo , Factor de Transcripción AP-1/fisiología , Empalme Alternativo , Animales , Secuencia de Bases , Células Cultivadas , Cartilla de ADN , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosforilación , Isoformas de Proteínas/genética , Proteínas Proto-Oncogénicas c-fos/genética , ARN Mensajero/genética
9.
Diabetes ; 55(8): 2202-11, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16873682

RESUMEN

Humans with heterozygous loss-of-function mutations in the hepatocyte nuclear factor-1alpha (HNF1alpha) gene develop beta-cell-deficient diabetes (maturity-onset diabetes of the young type 3), indicating that HNF1alpha gene dosage is critical in beta-cells. However, whether increased HNF1alpha expression might be beneficial or deleterious for beta-cells is unknown. Furthermore, although it is clear that HNF1alpha is required for beta-cell function, it is not known whether this role is cell autonomous or whether there is a restricted developmental time frame for HNF1alpha to elicit gene activation in beta-cells. To address this, we generated a tetracycline-inducible mouse model that transcribes HNF1alpha selectively in beta-cells in either wild-type or Hnf1alpha-null backgrounds. Short-term induction of HNF1alpha in islets from adult Hnf1alpha(-/-) mice that did not express HNF1alpha throughout development resulted in the activation of target genes, indicating that HNF1alpha has beta-cell-autonomous functions that can be rescued postnatally. However, transgenic induction throughout development, which inevitably resulted in supraphysiological levels of HNF1alpha, strikingly caused a severe reduction of cellular proliferation, increased apoptosis, and consequently beta-cell depletion and diabetes. Thus, HNF1alpha is sensitive to both reduced and excessive concentrations in beta-cells. This finding illustrates the paramount importance of using the correct concentration of a beta-cell transcription factor in both gene therapy and artificial differentiation strategies.


Asunto(s)
Regulación de la Expresión Génica , Factor Nuclear 1-alfa del Hepatocito/deficiencia , Factor Nuclear 1-alfa del Hepatocito/genética , Islotes Pancreáticos/fisiología , Mutación , Animales , Apoptosis , División Celular , Células Cultivadas , Diabetes Mellitus/etiología , Diabetes Mellitus/patología , Técnica del Anticuerpo Fluorescente , Dosificación de Gen , Regulación de la Expresión Génica/efectos de los fármacos , Factor Nuclear 1-alfa del Hepatocito/fisiología , Islotes Pancreáticos/patología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tetraciclina/farmacología , Transcripción Genética , Activación Transcripcional
10.
J Invest Dermatol ; 126(9): 2127-34, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16675960

RESUMEN

In developing organs, parathyroid hormone (PTH)/parathyroid hormone-related protein (PTHrP) receptor (PPR) signaling inhibits proliferation and differentiation of mesenchyme-derived cell types resulting in control of morphogenic events. Previous studies using PPR agonists and antagonists as well as transgenic overexpression of the PPR ligand PTHrP have suggested that this ligand receptor combination might regulate the anagen to catagen transition of the hair cycle. To further understand the precise role of PTHrP and the PPR in the hair cycle, we have evaluated hair growth in the traditional K14-PTHrP (KrP) and an inducible bitransgenic PTHrP mice. High levels of PTHrP trangene expression limited to the adult hair cycle resulted in the production of shorter hair shafts. Morphometric analysis indicated that reduced proliferation in the matrix preceded the appearance of thinner hair follicles and shafts during late anagen. CD31 staining revealed that the late anagen hair follicles of the KrP mice were surrounded by reduced numbers of smaller diameter capillaries as compared to controls. Moreover, the fetal skins of the PTHrP and PPR knockouts (KOs) had reciprocal increases in the length, diameter, and density of capillaries. Finally, crossing the KrP transgene onto a thrombospondin-1 KO background reversed the vascular changes as well as the delayed catagen exhibited by these mice. Taken together, these findings suggest that PTHrP's influence on the hair cycle is mediated in part by its effects on angiogenesis.


Asunto(s)
Folículo Piloso/irrigación sanguínea , Folículo Piloso/embriología , Neovascularización Fisiológica/fisiología , Proteína Relacionada con la Hormona Paratiroidea/fisiología , Receptor de Hormona Paratiroídea Tipo 1/fisiología , Animales , Apoptosis/fisiología , Capilares/patología , Capilares/fisiología , División Celular/fisiología , Femenino , Regulación del Desarrollo de la Expresión Génica , Folículo Piloso/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteína Relacionada con la Hormona Paratiroidea/genética , Fenotipo , Embarazo , Receptor de Hormona Paratiroídea Tipo 1/genética , Transducción de Señal/fisiología , Trombospondina 1/genética
11.
J Bone Miner Res ; 21(1): 113-23, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16355280

RESUMEN

UNLABELLED: The PTHrP gene generates low-abundance mRNA and protein products that are not easily localized by in situ hybridization histochemistry or immunohistochemistry. We report here a PTHrP-lacZ knockin mouse in which beta-gal activity seems to provide a simple and sensitive read-out of PTHrP gene expression. INTRODUCTION: PTH-related protein (PTHrP) is widely expressed in fetal and adult tissues, typically as low-abundance mRNA and protein products that maybe difficult to localize by conventional methods. We created a PTHrP-lacZ knockin mouse as a means of surveying PTHrP gene expression in general and of identifying previously unrecognized sites of PTHrP expression. MATERIALS AND METHODS: We created a lacZ reporter construct under the control of endogenous PTHrP gene regulatory sequences. The AU-rich instability sequences in the PTHrP 3' untranslated region (UTR) were replaced with SV40 sequences, generating products with lacZ/beta gal kinetics rather than those of PTHrP. A nuclear localization sequence was not present in the construct. RESULTS: We characterized beta-galactosidase (beta-gal) activity in embryonic whole mounts and in the skeleton in young and adult animals. In embryos, we confirmed widespread PTHrP expression in many known sites and in several novel epidermal appendages (nail beds and footpads). In costal cartilage, beta-gal activity localized to the perichondrium but not the underlying chondrocytes. In the cartilaginous molds of forming long bones, beta-gal activity was first evident at the proximal and distal ends. Shortly after birth, the developing secondary ossification center formed in the center of this PTHrP-rich chondrocyte population. As the secondary ossification center developed, it segregated this population into two distinct PTHrP beta-gal+ subpopulations: a subarticular subpopulation immediately subjacent to articular chondrocytes and a proliferative chondrocyte subpopulation proximal to the chondrocyte columns in the growth plate. These discrete populations remained into adulthood. beta-gal activity was not identified in osteoblasts but was present in many periosteal sites. These included simple periosteum as well as fibrous tendon insertion sites of the so-called bony and periosteal types; the beta-gal-expressing cells in these sites were in the outer fibrous layer of the periosteum or its apparent equivalents at tendon insertion sites. Homozygous PTHrP-lacZ knockin mice had the expected chondrodysplastic phenotype and a much expanded region of proximal beta-gal activity in long bones, which appeared to reflect in large part the effects of feedback signaling by Indian hedgehog on proximal cell proliferation and PTHrP gene expression. CONCLUSIONS: The PTHrP-lacZ mouse seems to provide a sensitive reporter system that may prove useful as a means of studying PTHrP gene expression.


Asunto(s)
Desarrollo Óseo/fisiología , Regulación del Desarrollo de la Expresión Génica , Operón Lac , Proteína Relacionada con la Hormona Paratiroidea/biosíntesis , Animales , Huesos/citología , Huesos/embriología , Proliferación Celular , Condrocitos/citología , Condrocitos/metabolismo , Marcadores Genéticos/genética , Ratones , Ratones Transgénicos , Especificidad de Órganos , Osteoblastos/citología , Osteoblastos/metabolismo , Proteína Relacionada con la Hormona Paratiroidea/genética , Transgenes/genética
12.
J Clin Endocrinol Metab ; 90(2): 1012-20, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15562028

RESUMEN

Oncogenic osteomalacia (OO), a tumor-associated phosphate-wasting syndrome, provides an opportunity to identify regulators of renal phosphate homeostasis. We established cultures from OO-associated tumors. Conditioned medium from these cultures inhibited phosphate uptake in renal tubular epithelial cells. We then compared RNA from tumor-derived cultures expressing inhibitory activity with RNA from tumor-derived cultures in which inhibitory activity was not evident and identified candidate mRNAs specifically expressed by cultures inhibiting renal phosphate transport. Testing of identified candidates revealed that one protein, fibroblast growth factor 7 (FGF7), was a potent and direct inhibitor of phosphate uptake in vitro. A neutralizing monoclonal antibody to FGF7 reversed FGF7-dependent phosphate transport inhibition and inhibitory activity in conditioned medium from tumor cell cultures. Immunoassay revealed abundant FGF7 in inhibitory conditioned medium and minimal amounts in nonconditioned medium or conditioned medium with no phosphate transport inhibitory activity. Furthermore, only small amounts of FGF23 were present in inhibitory conditioned medium, comparable to concentrations found in conditioned medium with no phosphate transport inhibitory activity. Thus, FGF7 was specifically identified when selecting for in vitro phosphate transport inhibitory activity of tumor-derived cultures and was confirmed as a potent inhibitor of phosphate transport. Finally, FGF7 message was confirmed in PCR products of mRNA extracted from fragments of each tumor. Members of the FGF family (other than FGF23) are expressed by OO-associated tumors and may play a role in mediating this syndrome.


Asunto(s)
Neoplasias Óseas/fisiopatología , Factores de Crecimiento de Fibroblastos/fisiología , Osteomalacia/fisiopatología , Proteínas de Transporte de Fosfato/antagonistas & inhibidores , Adulto , Antígenos CD4/genética , Línea Celular Tumoral , Niño , Medios de Cultivo Condicionados , Factor 7 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Regulación de la Expresión Génica , Humanos , Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Cinética , Masculino , Persona de Mediana Edad
13.
Mol Cell Biol ; 24(7): 2820-30, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15024071

RESUMEN

Osteoblasts and adipocytes may develop from common bone marrow mesenchymal precursors. Transgenic mice overexpressing DeltaFosB, an AP-1 transcription factor, under the control of the neuron-specific enolase (NSE) promoter show both markedly increased bone formation and decreased adipogenesis. To determine whether the two phenotypes were linked, we targeted overexpression of DeltaFosB in mice to the osteoblast by using the osteocalcin (OG2) promoter. OG2-DeltaFosB mice demonstrated increased osteoblast numbers and an osteosclerotic phenotype but normal adipocyte differentiation. This result firmly establishes that the skeletal phenotype is cell autonomous to the osteoblast lineage and independent of adipocyte formation. It also strongly suggests that the decreased fat phenotype of NSE-DeltaFosB mice is independent of the changes in the osteoblast lineage. In vitro, overexpression of DeltaFosB in the preadipocytic 3T3-L1 cell line had little effect on adipocyte differentiation, whereas it prevented the induction of adipogenic transcription factors in the multipotential stromal cell line ST2. Also, DeltaFosB isoforms bound to and altered the DNA-binding capacity of C/EBPbeta. Thus, the inhibitory effect of DeltaFosB on adipocyte differentiation appears to occur at early stages of stem cell commitment, affecting C/EBPbeta functions. It is concluded that the changes in osteoblast and adipocyte differentiation in DeltaFosB transgenic mice result from independent cell-autonomous mechanisms.


Asunto(s)
Adipocitos/metabolismo , Tejido Adiposo/crecimiento & desarrollo , Diferenciación Celular/fisiología , Osteoblastos/metabolismo , Osteosclerosis/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Adipocitos/citología , Tejido Adiposo/citología , Animales , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Línea Celular , Linaje de la Célula , Femenino , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Transgénicos , Osteoblastos/citología , Osteocalcina/genética , Osteocalcina/metabolismo , Fenotipo , Regiones Promotoras Genéticas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Distribución Tisular , Factor de Transcripción CHOP , Factores de Transcripción/metabolismo
14.
Crit Rev Eukaryot Gene Expr ; 13(2-4): 181-93, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-14696966

RESUMEN

A "bone" is really a dynamic and highly interactive complex of many cell and tissue types. In particular, for the majority of skeletal elements to develop and grow, the process of endochondral ossification requires a constantly moving interface between cartilage, invading blood vessels, and bone. A great deal has been learned in recent years about the regulation of chondrocyte proliferation and differentiation by hormones, growth factors, and physiologic stimuli during skeletal development and growth. Likewise, the discovery that colony stimulating factor-1 (CSF-1, or M-CSF) and receptor activator of NF-kappaB ligand (RANKL, a tumor necrosis factor superfamily member also called TRANCE, ODF, OPGL, and TNFSF11) are pivotal in communicating from osteoblasts to osteoclasts has led to deeper insights into bone growth, turnover, and maintenance. Little is known, however, about how these two quite different systems communicate to solve the problem of providing integrated, continuous mechanical support during the dynamic invasion of cartilage by bone that characterizes endochondral bone growth. Evidence has accumulated in recent years that provides insight into the communication between growing bone and cartilage in the form of a subset of osteopetrotic mutations, which share a lack of osteoclasts and an accompanying chondrodysplasia of the growth plate. These mutations thus implicate some of the same gene products in regulating chondrocyte differentiation and bone resorption. We also consider expression studies of some known growth plate regulators, such as parathyroid hormone-related protein (PTHrP) and Indian hedgehog (Ihh), in light of this and propose a model in which the osteoclastogenic factors act also on chondrocytes, but downstream of PTRrP and Ihh in regulating proliferation and differentiation, and after early morphogenic patterns are established.


Asunto(s)
Condrocitos/citología , Placa de Crecimiento/citología , Animales , Proteínas Portadoras/metabolismo , Diferenciación Celular , División Celular , Condrocitos/metabolismo , Modelos Animales de Enfermedad , Proteínas Hedgehog , Humanos , Factor Estimulante de Colonias de Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Ratones , Modelos Biológicos , Mutación , FN-kappa B/metabolismo , Osteoclastos/metabolismo , Hormona Paratiroidea/metabolismo , Ligando RANK , Ratas , Receptor Activador del Factor Nuclear kappa-B , Transactivadores/metabolismo
15.
Brain Res ; 930(1-2): 58-66, 2002 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-11879796

RESUMEN

Parathyroid hormone-related protein (PTHrP) was discovered a dozen years ago as a product of malignant tumors. It is now known that PTHrP is a paracrine factor with multiple biological functions. One such function is to relax smooth muscle by inhibiting calcium influx into the cell. In the central nervous system, PTHrP and its receptor are widely expressed in neurons in the cerebral cortex, hippocampus and cerebellum. The function of PTHrP in the CNS is not known. Previous work has shown that expression of the PTHrP gene is depolarization-dependent in cultured cerebellar granule cells and depends specifically on L-type voltage sensitive calcium channel (L-VSCC) Ca(2+) influx. PTHrP has also been found to be capable of protecting these cells against kainic acid-induced excitotoxicity. Here, we tested the idea that mice with a PTHrP-null CNS might display hypersensitivity to kainic acid excitotoxicity. We found that these mice were six-fold more sensitive than control littermate mice to kainic-acid-induced seizures as well as hippocampal c-Fos expression. PTHrP-null embryonic mixed cerebral cortical cultures were more sensitive to kainic acid than control cultures, and PTHrP addition was found to be protective against kainate toxicity in both PTHrP-null and control cultures. By whole-cell techniques, PTHrP was found to reduce L-VSCC Ca(2+) influx in cultured mouse neuroblastoma cells. We conclude that PTHrP functions as a component of a neuroprotective feedback loop that is structured around the L-type calcium channel. This loop appears to be operative in vivo as well as in vitro.


Asunto(s)
Fármacos Neuroprotectores , Proteínas/fisiología , Animales , Neoplasias Encefálicas/metabolismo , Canales de Calcio/metabolismo , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Relación Dosis-Respuesta a Droga , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas de Aminoácidos Excitadores/toxicidad , Femenino , Inyecciones Intraperitoneales , Ácido Kaínico/farmacología , Ácido Kaínico/toxicidad , L-Lactato Deshidrogenasa/metabolismo , Ratones , Ratones Noqueados , Neuroblastoma/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proteína Relacionada con la Hormona Paratiroidea , Técnicas de Placa-Clamp , Embarazo , Proteínas/genética
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