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1.
J Bone Miner Metab ; 38(5): 631-638, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32350615

RESUMO

INTRODUCTION: Disuse-induced bone loss is caused by a suppression of osteoblastic bone formation and an increase in osteoclastic bone resorption. There are few data available for the effects of environmental conditions, i.e., atmospheric pressure and/or oxygen concentration, on osteoporosis. This study examined the effects of mild hyperbaric oxygen at 1317 hPa with 40% oxygen on unloading-induced osteoporosis. MATERIALS AND METHODS: Eighteen 8-week old male Wistar rats were randomly divided into three groups: the control for 21 days without unloading and mild hyperbaric oxygen (NOR, n = 6), the unloading for 21 days and recovery for 10 days without mild hyperbaric oxygen (HU + NOR, n = 6), and the unloading for 21 days and recovery for 10 days with mild hyperbaric oxygen (HU + MHO, n = 6). RESULTS: The cortical thickness and trabecular bone surface area were decreased in the HU + NOR group compared to the NOR group. There were no differences between the NOR and HU + MHO groups. Osteoclast surface area and Sclerostin (Sost) mRNA expression levels were decreased in the HU + MHO group compared to the HU + NOR group. These results suggested that the loss of the cortical and trabecular bone is inhibited by mild hyperbaric oxygen, because of an inhibition of osteoclasts and enhancement of bone formation with decreased Sost expression. CONCLUSIONS: We conclude that exposure to mild hyperbaric oxygen partially protects from the osteoporosis induced by hindlimb unloading.


Assuntos
Elevação dos Membros Posteriores/fisiologia , Oxigenação Hiperbárica , Osteoporose/fisiopatologia , Osteoporose/terapia , Animais , Peso Corporal , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Osso Esponjoso/patologia , Osso Esponjoso/fisiopatologia , Osso Cortical/patologia , Osso Cortical/fisiopatologia , Marcadores Genéticos/genética , Lâmina de Crescimento/patologia , Masculino , Osteocalcina/genética , Osteocalcina/metabolismo , Osteoclastos/patologia , Osteoporose/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar
2.
Med Sci Monit ; 26: e920943, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32248202

RESUMO

BACKGROUND Bone morphogenetic proteins (BMPs) are widely involved in cancer development. However, a wealth of conflicting data raises the question of whether BMPs serve as oncogenes or as cancer suppressors. MATERIAL AND METHODS By integrating multi-omics data across cancers, we comprehensively analyzed the genomic and pharmacogenomic landscape of BMP genes across cancers. RESULTS Surprisingly, our data indicate that BMPs are globally downregulated in cancers. Further genetics and epigenetics analyses show that this abnormal expression is driven by copy number variations, especially heterozygous amplification. We next assessed the BMP-associated pathways and demonstrated that they suppress cell cycle and estrogen hormone pathways. Bone morphogenetic protein interacts with 58 compounds, and their dysfunction can induce drug sensitivity. CONCLUSIONS Our results define the landscape of the BMP family at a systems level and open potential therapeutic opportunities for cancer patients.


Assuntos
Proteínas Morfogenéticas Ósseas , Neoplasias/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Morfogenéticas Ósseas/fisiologia , Variações do Número de Cópias de DNA , Humanos , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/fisiologia
3.
Cancer Sci ; 111(5): 1555-1566, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32128917

RESUMO

There is increasing evidence that bone morphogenetic proteins (BMP) are involved in the proliferation and drug tolerance of kidney cancer. However, the molecular mechanism of BMP8A in renal cell proliferation and drug tolerance is not clear. Here we showed that BMP8A was highly expressed in renal cell carcinoma, which suggests a poor prognosis of ccRCC. Promotion of cell proliferation and inhibition of apoptosis were detected by CCK-8 assay, Trypan Blue staining, flow cytometry and bioluminescence. BMP8A promoted resistance of As2 O3 by regulating Nrf2 and Wnt pathways in vitro and in vivo. Mechanistically, BMP8A enhanced phosphorylation of Nrf2, which, in turn, inhibited Keap1-mediated Nrf2 ubiquitination and, ultimately, promoted nuclear translocation and transcriptional activity of Nrf2. Nrf2 regulates the transcription of TRIM24 detected by ChIP-qPCR. BMP8A was highly expressed in ccRCC, which suggests a poor prognosis. BMP8A was expected to be an independent prognostic molecule for ccRCC. On the one hand, activated Nrf2 regulated reactive oxygen balance, and on the other hand, by regulating the transcription level of TRIM24, it was involved in the regulation of the Wnt pathway to promote the proliferation, invasion and metastasis of ccRCC and the resistance of As2 O3 . Taken together, our findings describe a regulatory axis where BMP8A promotes Nrf2 phosphorylation and activates TRIM24 to promote survival and drug resistance in ccRCC.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Carcinoma de Células Renais/patologia , Proteínas de Transporte/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Trióxido de Arsênio/farmacologia , Proteínas Morfogenéticas Ósseas/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Masculino , Camundongos , Camundongos Nus , Fator 2 Relacionado a NF-E2/genética , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Via de Sinalização Wnt
4.
Cancer Cell ; 37(3): 308-323.e12, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32142668

RESUMO

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.


Assuntos
Receptores de Ativinas Tipo I/química , Receptores de Ativinas Tipo I/genética , Neoplasias Encefálicas/patologia , Glioma/patologia , Mutação , Receptores de Ativinas Tipo I/antagonistas & inibidores , Receptores de Ativinas Tipo I/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Glioma/tratamento farmacológico , Glioma/genética , Histonas/genética , Histonas/metabolismo , Humanos , Lactonas/farmacologia , Masculino , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Oligodendroglia/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo
5.
Proc Natl Acad Sci U S A ; 117(9): 4910-4920, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071240

RESUMO

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor ß (TGF-ß) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality of Gdf11 null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show that Gdf11 null mice, despite significantly down-regulating Mstn expression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed in Mstn null mice that display enhanced bone mass. Mechanistically, Mstn deletion up-regulates Gdf11 expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlike Mstn null mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Osso e Ossos/metabolismo , Fatores de Diferenciação de Crescimento/metabolismo , Desenvolvimento Muscular/fisiologia , Miostatina/metabolismo , Osteogênese/fisiologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Osso e Ossos/patologia , Condrócitos/metabolismo , Regulação para Baixo , Folistatina , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Diferenciação de Crescimento/genética , Camundongos , Camundongos Knockout , Músculos/patologia , Osteoblastos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
6.
Am J Hematol ; 95(2): 188-197, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31737919

RESUMO

Dehydrated hereditary stomatocytosis (DHS), or xerocytosis, is an autosomal dominant hemolytic anemia. Most patients with DHS carry mutations in the PIEZO1 gene encoding a mechanosensitive cation channel. We here demonstrate that patients with DHS have low levels of hepcidin and only a slight increase of ERFE, the erythroid negative regulator of hepcidin. We demonstrated that at the physiological level, PIEZO1 activation induced Ca2+ influx and suppression of HAMP expression in primary hepatocytes. In two hepatic cellular models expressing PIEZO1 WT and two PIEZO1 gain-of-function mutants (R2456H and R2488Q), we highlight altered expression of a few genes/proteins involved in iron metabolism. Mutant cells showed increased intracellular Ca2+ compared to WT, which was correlated to increased phosphorylation of ERK1/2, inhibition of the BMP-SMADs pathway, and suppression of HAMP transcription. Moreover, the HuH7 cells, treated with PD0325901, a potent inhibitor of ERK1/2 phosphorylation, reduced the phosphorylation of ERK1/2 with the consequent increased phosphorylation of SMAD1/5/8, confirming the link between the two pathways. Another "proof of concept" for the mechanism that links PIEZO1 to HAMP regulation was obtained by mimicking PIEZO1 activation by cell Ca2+ overload, by the Ca2+ ionophore A23187. There was strong down-regulation of HAMP gene expression after this Ca2+ overload. Finally, the inhibition of PIEZO1 by GsMTx4 leads to phenotype rescue. This is the first demonstration of a direct link between PIEZO1 and iron metabolism, which defines the channel as a new hepatic iron metabolism regulator and as a possible therapeutic target of iron overload in DHS and other iron-loading anemias.


Assuntos
Anemia Hemolítica Congênita , Proteínas Morfogenéticas Ósseas/metabolismo , Mutação com Ganho de Função , Hepcidinas/biossíntese , Hidropisia Fetal , Canais Iônicos , Ferro/metabolismo , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Smad/metabolismo , Substituição de Aminoácidos , Anemia Hemolítica Congênita/genética , Anemia Hemolítica Congênita/metabolismo , Anemia Hemolítica Congênita/patologia , Benzamidas/farmacologia , Proteínas Morfogenéticas Ósseas/genética , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Regulação da Expressão Gênica , Células Hep G2 , Hepcidinas/genética , Humanos , Hidropisia Fetal/genética , Hidropisia Fetal/metabolismo , Hidropisia Fetal/patologia , Canais Iônicos/genética , Canais Iônicos/metabolismo , Fígado/patologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Smad/genética
7.
Am J Respir Crit Care Med ; 201(5): 575-585, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31661308

RESUMO

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Fator 2 de Diferenciação de Crescimento/genética , Hipertensão Arterial Pulmonar/genética , Adulto , Proteínas Morfogenéticas Ósseas/metabolismo , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , Feminino , Fator 2 de Diferenciação de Crescimento/metabolismo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Transporte Proteico , Hipertensão Arterial Pulmonar/metabolismo , Fatores Sexuais
8.
Gen Comp Endocrinol ; 285: 113249, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445010

RESUMO

The objective of this study was to document the expression and functional role of BMPs in the placental (caruncle; CAR, cotyledon; COT) during different stages of pregnancy in water buffalo. Samples collected from Early pregnancy 1 (EP1); Early pregnancy 2 (EP2), Mid pregnancy (MP), Late pregnancy (LP) while the third stage of oestrus cycle (NP) was taken as control. Also, the synergistic role of BMP4/BMP7 or combination on mRNA expression of vWF, PCNA, StAR, CYP11A1, 3ßHSD, and BAX were studied in trophoblast cells cultured (TCC) during an early stage. The qPCR and immunoblotting studies revealed that BMP2, BMPR1A, BMPR1B, and BMPR2 mRNA level was significantly (p < 0.05) upregulated during early pregnancy in COTs while in CARs it was significantly upregulated (p < 0.05) during all the stages of pregnancy.BMP4 mRNA level was significantly upregulated (p < 0.05) during early pregnancy in COTs as well as in CARs. BMP6 expression was significantly upregulated (p < 0.05) during early and late stages of pregnancy. BMP7 mRNA level was upregulated (p < 0.05) during the late stage of pregnancy in COTs. At 100 ng/ml, the BMP4 maximally stimulated the transcripts of StAR, CYP11A1, and 3ßHSD while BMP7 maximally stimulated the transcripts of 3ßHSD that paralleled with P4 accretion in the media (P < 0.05). BMP4 as well as BMP7 upregulated the transcripts of PCNA, vWF, and downregulated BAX in the TCC (P < 0.05). In conclusion, BMPs are expressed in a regulated manner with stage-specific differences in the placenta and promotes the angiogenesis, proliferation, cell survivability, and steroidogenesis thereby regulating placental function in an autocrine/paracrine manner in water buffalo.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Búfalos/genética , Regulação da Expressão Gênica no Desenvolvimento , Placenta/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Sobrevivência Celular , Feminino , Neovascularização Fisiológica/genética , Placenta/irrigação sanguínea , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Tempo , Trofoblastos/citologia
9.
Nat Commun ; 10(1): 5575, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31811118

RESUMO

Synapses are highly specialized for neurotransmitter signaling, yet activity-dependent growth factor release also plays critical roles at synapses. While efficient neurotransmitter signaling relies on precise apposition of release sites and neurotransmitter receptors, molecular mechanisms enabling high-fidelity growth factor signaling within the synaptic microenvironment remain obscure. Here we show that the auxiliary calcium channel subunit α2δ-3 promotes the function of an activity-dependent autocrine Bone Morphogenetic Protein (BMP) signaling pathway at the Drosophila neuromuscular junction (NMJ). α2δ proteins have conserved synaptogenic activity, although how they execute this function has remained elusive. We find that α2δ-3 provides an extracellular scaffold for an autocrine BMP signal, suggesting a mechanistic framework for understanding α2δ's conserved role in synapse organization. We further establish a transcriptional requirement for activity-dependent, autocrine BMP signaling in determining synapse density, structure, and function. We propose that activity-dependent, autocrine signals provide neurons with continuous feedback on their activity state for modulating both synapse structure and function.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Canais de Cálcio Tipo L/metabolismo , Drosophila melanogaster/metabolismo , Junção Neuromuscular/metabolismo , Transdução de Sinais/fisiologia , Sinapses/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Cálcio/metabolismo , Canais de Cálcio Tipo L/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Neurogênese/genética , Neurogênese/fisiologia , Junção Neuromuscular/citologia , Fenótipo , Sinapses/genética , Transmissão Sináptica/fisiologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
10.
Genes (Basel) ; 10(12)2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842416

RESUMO

Anti-Mullerian hormone (AMH) is an important reproductive marker of ovarian reserve produced by granulosa cells (GCs) of pre-antral and early-antral ovarian follicles in several species, including cattle. This hormone plays a vital role during the recruitment of primordial follicles and follicle stimulating hormone (FSH)-dependent follicular growth. However, the regulatory mechanism of AMH expression in follicles is still unclear. In this study, we compared the expression of AMH, AMHR-II, BMP2, BMP6, FSHR, and LHCGR genes during follicular development. In-vitro expression study was performed with and without FSH for AMH, AMHR-II, BMP2, and BMP6 genes in bovine GCs which were isolated from 3-8 mm follicles. Association among the mRNA expression and hormone level was estimated. GCs were collected from small (3-8 mm), medium (9-12 mm) and large size (13 to 24 mm) follicles before, during onset, and after deviation, respectively. Further, mRNA expression, hormones (AMH, FSH, and LH), apoptosis of GCs, and cell viability were detected by qRT-PCR, ELISA, flow cytometry, and spectrophotometry. AMH, AMHR-II, BMP2, and FSHR genes were highly expressed in small and medium follicles as compared to large ones. In addition, the highest level of AMH protein (84.14 ± 5.41 ng/mL) was found in medium-size follicles. Lower doses of FSH increased the viability of bovine GCs while higher doses repressed them. In-vitro cultured GCs treated with FSH significantly increased the AMH, AMHR-II, and BMP2 expression levels at lower doses, while expression levels decreased at higher doses. We found an optimum level of FSH (25 ng/mL) which can significantly enhance AMH and BMP2 abundance (p < 0.05). In summary, AMH, AMHR-II, and BMP2 genes showed a higher expression in follicles developed in the presence of FSH. However, lower doses of FSH demonstrated a stimulatory effect on AMH and BMP2 expression, while expression started to decline at the maximum dose. In this study, we have provided a better understanding of the mechanisms regulating AMH, AMHR II, and BMP2 signaling in GCs during folliculogenesis, which would improve the outcomes of conventional assisted reproductive technologies (ARTs), such as superovulation and oestrus synchronization in bovines.


Assuntos
Hormônio Antimülleriano/genética , Bovinos/genética , Células da Granulosa/metabolismo , Animais , Hormônio Antimülleriano/metabolismo , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Estradiol/metabolismo , Feminino , Hormônio Foliculoestimulante/genética , Líquido Folicular/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Folículo Ovariano/metabolismo , RNA Mensageiro/genética , Receptores do FSH/genética , Receptores do FSH/metabolismo , Receptores do LH/genética , Receptores do LH/metabolismo , Receptores de Peptídeos/genética , Receptores de Peptídeos/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo
11.
Int J Mol Sci ; 21(1)2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31861793

RESUMO

Hedgehog (Hh) signaling is an essential growth factor signaling pathway especially in the regulation of epithelial-mesenchymal interactions (EMI) during the development of the urogenital organs such as the bladder and the external genitalia (EXG). The Hh ligands are often expressed in the epithelia, affecting the surrounding mesenchyme, and thus constituting a form of paracrine signaling. The development of the urogenital organ, therefore, provides an intriguing opportunity to study EMI and its relationship with other pathways, such as hormonal signaling. Cellular interactions of prostate cancer (PCa) with its neighboring tissue is also noteworthy. The local microenvironment, including the bone metastatic site, can release cellular signals which can affect the malignant tumors, and vice versa. Thus, it is necessary to compare possible similarities and divergences in Hh signaling functions and its interaction with other local growth factors, such as BMP (bone morphogenetic protein) between organogenesis and tumorigenesis. Additionally, this review will discuss two pertinent research aspects of Hh signaling: (1) the potential signaling crosstalk between Hh and androgen signaling; and (2) the effect of signaling between the epithelia and the mesenchyme on the status of the basement membrane with extracellular matrix structures located on the epithelial-mesenchymal interface.


Assuntos
Transição Epitelial-Mesenquimal , Proteínas Hedgehog/metabolismo , Neoplasias da Próstata/metabolismo , Androgênios/genética , Androgênios/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Comunicação Celular , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Organogênese , Neoplasias da Próstata/genética , Mapas de Interação de Proteínas , Transdução de Sinais , Microambiente Tumoral
12.
Elife ; 82019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868592

RESUMO

Preventing terminal differentiation is important in the development and progression of many cancers including melanoma. Recent identification of the BMP ligand GDF6 as a novel melanoma oncogene showed GDF6-activated BMP signaling suppresses differentiation of melanoma cells. Previous studies have identified roles for GDF6 orthologs during early embryonic and neural crest development, but have not identified direct regulation of melanocyte development by GDF6. Here, we investigate the BMP ligand gdf6a, a zebrafish ortholog of human GDF6, during the development of melanocytes from the neural crest. We establish that the loss of gdf6a or inhibition of BMP signaling during neural crest development disrupts normal pigment cell development, leading to an increase in the number of melanocytes and a corresponding decrease in iridophores, another neural crest-derived pigment cell type in zebrafish. This shift occurs as pigment cells arise from the neural crest and depends on mitfa, an ortholog of MITF, a key regulator of melanocyte development that is also targeted by oncogenic BMP signaling. Together, these results indicate that the oncogenic role ligand-dependent BMP signaling plays in suppressing differentiation in melanoma is a reiteration of its physiological roles during melanocyte development.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Fator 6 de Diferenciação de Crescimento/genética , Melanócitos/metabolismo , Fator de Transcrição Associado à Microftalmia/genética , Proteínas de Peixe-Zebra/genética , Animais , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Diferenciação Celular/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Ligantes , Melanócitos/patologia , Neoplasias/genética , Neoplasias/patologia , Crista Neural/crescimento & desenvolvimento , Crista Neural/metabolismo , Pigmentação/genética , Transdução de Sinais/genética , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
13.
J Transl Med ; 17(1): 422, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847906

RESUMO

BACKGROUND: The growth differentiation factor 11 (GDF11) was shown to reverse age-related hypertrophy on cardiomyocytes and considered as anti-aging rejuvenation factor. The role of GDF11 in regulating metabolic homeostasis is unclear. In this study, we investigated the functions of GDF11 in regulating metabolic homeostasis and energy balance. METHODS: Using a hydrodynamic injection approach, plasmids carrying a mouse Gdf11 gene were delivered into mice and generated the sustained Gdf11 expression in the liver and its protein level in the blood. High fat diet (HFD)-induced obesity was employed to examine the impacts of Gdf11 gene transfer on HFD-induced adiposity, hyperglycemia, insulin resistance, and hepatic lipid accumulation. The impacts of GDF11 on metabolic homeostasis of obese and diabetic mice were examined using HFD-induced obese and STZ-induced diabetic models. RESULTS: Gdf11 gene transfer alleviates HFD-induced obesity, hyperglycemia, insulin resistance, and fatty liver development. In obese and STZ-induced diabetic mice, Gdf11 gene transfer restores glucose metabolism and improves insulin resistance. Mechanism study reveals that Gdf11 gene transfer increases the energy expenditure of mice, upregulates the expression of genes responsible for thermoregulation in brown adipose tissue, downregulates the expression of inflammatory genes in white adipose tissue and those involved in hepatic lipid and glucose metabolism. Overexpression of GDF11 also activates TGF-ß/Smad2, PI3K/AKT/FoxO1, and AMPK signaling pathways in white adipose tissue. CONCLUSIONS: These results demonstrate that GDF11 plays an important role in regulating metabolic homeostasis and energy balance and could be a target for pharmacological intervention to treat metabolic disease.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Terapia Genética , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/uso terapêutico , Homeostase , Obesidade/prevenção & controle , Obesidade/terapia , Tecido Adiposo/patologia , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Metabolismo Energético/genética , Fígado Gorduroso/complicações , Comportamento Alimentar , Regulação da Expressão Gênica , Intolerância à Glucose/complicações , Hiperinsulinismo/complicações , Hipertrofia , Inflamação/complicações , Inflamação/genética , Resistência à Insulina , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Masculino , Camundongos Obesos , Obesidade/complicações , Obesidade/genética , Consumo de Oxigênio/genética , Transdução de Sinais , Estreptozocina , Ganho de Peso
14.
Artif Cells Nanomed Biotechnol ; 47(1): 4159-4164, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31713441

RESUMO

Objective: To explore the regulation relationship between miR-181a-3p and BMP10, and their mechanism of osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (MSCs).Methods: After osteogenic induction of MSCs, the ALP activity was detected by ELISA. The expression of miRNA-181a-3p and BMP10 was detected by RT-qPCR, and the protein levels of BMP10 and osteogenic differentiation marker proteins ALK and RUNX2 were detected by Western blot. The TargetScan online website was used to predict the putative target of miR-181a-3p, and dual luciferase reporter assay was performed to validate the targeting relationship between miR-181a-3p and BMP10.Results: In osteogenic differentiation of MSCs, ALP activity, the level of ALK and RUNX2 was evidently increased (p < .05), and the expression of miR-181a-3p was significantly downregulated (p < .05). Moreover, overexpression of miR-181a-3p obviously decreased the expression of BMP10 (p < .05), miR-181a-3p knockdown increased the expression of BMP10 prominently (p < .05). The transfection of miR-181a-3p mimics resulted in significantly downregulation of ALP activity and RUNX2 protein expression in MSCs (p < .05). In addition, overexpression of BMP10 could reverse the inhibitory effect of miR-181a-3p on osteogenic differentiation (p < .05).Conclusions: In conclusion, we found that miR-181a-3p inhibited osteogenic differentiation of MCSs by targeting BMP10.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Diferenciação Celular/genética , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , Osteogênese/genética , Sequência de Bases , Regulação da Expressão Gênica/genética , Humanos
15.
Medicine (Baltimore) ; 98(42): e17594, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626133

RESUMO

RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by intense remodeling of small pulmonary arteries. Loss-of-function mutation of bone morphogenetic protein receptor II (BMPR2) gene and exaggerated activation of transforming growth factor (TGF)-ß signaling play a critical role in this process. PATIENT CONCERNS AND DIAGNOSIS: We report a novel frameshift mutation (c.117InsT, p.Y40fsX48) of the BMPR2 gene identified in a 19-year-old IPAH patient with syncope. Despite BMPR2 mutation, the phosphorylation of Smad2/3 and Samd1/5/8 was increased in the patient's peripheral blood mononuclear cells, and this event was accompanied by the upregulation of bone morphogenetic protein (BMP) signaling target genes, but not TGF-ß signaling target genes. Moreover, we observed an increased expression of other BMPRs, that is, anti-Mullerian hormone type-2 receptor and the activin receptor-like kinases (ALK) 1, ALK3, and ALK6. INTERVENTIONS AND OUTCOMES: The patient was prescribed a combination of macitentan, sildenafil, and nifedipine, which successfully controlled her symptom of syncope and normalized N-terminal pro-brain natriuretic peptide level after 3 months of medication. LESSONS: In light of these results, we propose a new pathogenetic mechanism for IPAH, based on enhanced BMP signaling via the functional replacement of mutated BMPR2 by other BMP receptors.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Proteínas Morfogenéticas Ósseas/genética , DNA/genética , Hipertensão Pulmonar Primária Familiar/genética , Mutação da Fase de Leitura , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Análise Mutacional de DNA , Hipertensão Pulmonar Primária Familiar/metabolismo , Feminino , Humanos , Transdução de Sinais , Adulto Jovem
16.
Biomed Res Int ; 2019: 9652649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31637260

RESUMO

Embryology of normal web space creation and the genetics of syndactyly in humans and experimental animals are well described in the literature. In this review, the author offers a 3-step pathway of pathogenesis for syndactyly. The first step is initiated either by the overactivation of the WNT canonical pathway or the suppression of the Bone Morphogenetic Protein (BMP) canonical pathway. This leads to an overexpression of Fibroblast Growth Factor 8 (FGF8). The final step is the suppression of retinoic acid in the interdigital mesenchyme leading to suppression of both apoptosis and extracellular matrix (ECM) degradation, resulting in syndactyly.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Fator 8 de Crescimento de Fibroblasto/genética , Sindactilia/genética , Animais , Apoptose/genética , Matriz Extracelular/genética , Humanos , Mesoderma/crescimento & desenvolvimento , Mesoderma/metabolismo , Modelos Animais , Sindactilia/fisiopatologia , Tretinoína/metabolismo , Via de Sinalização Wnt/genética
17.
PLoS Biol ; 17(10): e3000145, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31589603

RESUMO

Male reproductive glands like the mammalian prostate and the paired Drosophila melanogaster accessory glands secrete seminal fluid components that enhance fecundity. In humans, the prostate, stimulated by environmentally regulated endocrine and local androgens, grows throughout adult life. We previously showed that in fly accessory glands, secondary cells (SCs) and their nuclei also grow in adults, a process enhanced by mating and controlled by bone morphogenetic protein (BMP) signalling. Here, we demonstrate that BMP-mediated SC growth is dependent on the receptor for the developmental steroid ecdysone, whose concentration is reported to reflect sociosexual experience in adults. BMP signalling appears to regulate ecdysone receptor (EcR) levels via one or more mechanisms involving the EcR's N terminus or the RNA sequence that encodes it. Nuclear growth in virgin males is dependent on ecdysone, some of which is synthesised in SCs. However, mating induces additional BMP-mediated nuclear growth via a cell type-specific form of hormone-independent EcR signalling, which drives genome endoreplication in a subset of adult SCs. Switching to hormone-independent endoreplication after mating allows growth and secretion to be hyperactivated independently of ecdysone levels in SCs, permitting more rapid replenishment of the accessory gland luminal contents. Our data suggest mechanistic parallels between this physiological, behaviour-induced signalling switch and altered pathological signalling associated with prostate cancer progression.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Ecdisona/metabolismo , Genoma de Inseto , Proteínas de Insetos/genética , Receptores de Esteroides/genética , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Copulação/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/metabolismo , Masculino , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores de Esteroides/antagonistas & inibidores , Receptores de Esteroides/metabolismo , Transdução de Sinais
18.
Blood ; 134(20): 1712-1716, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31530563

RESUMO

Tightly regulated production of mature blood cells is essential for health and survival in vertebrates and dependent on discrete populations of blood-forming (hematopoietic) stem and progenitor cells. Prior studies suggested that inhibition of growth differentiation factor 11 (GDF11) through soluble activin receptor type II (ActRII) ligand traps or neutralizing antibodies promotes erythroid precursor cell maturation and red blood cell formation in contexts of homeostasis and anemia. As Gdf11 is expressed by mature hematopoietic cells, and erythroid precursor cell expression of Gdf11 has been implicated in regulating erythropoiesis, we hypothesized that genetic disruption of Gdf11 in blood cells might perturb normal hematopoiesis or recovery from hematopoietic insult. Contrary to these predictions, we found that deletion of Gdf11 in the hematopoietic lineage in mice does not alter erythropoiesis or erythroid precursor cell frequency under normal conditions or during hematopoietic recovery after irradiation and transplantation. In addition, although hematopoietic cell-derived Gdf11 may contribute to the pool of circulating GDF11 protein during adult homeostasis, loss of Gdf11 specifically in the blood system does not impair hematopoietic stem cell function or induce overt pathological consequences. Taken together, these results reveal that hematopoietic cell-derived Gdf11 is largely dispensable for native and transplant-induced blood formation.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Deleção de Genes , Fatores de Diferenciação de Crescimento/genética , Hematopoese , Animais , Células Cultivadas , Feminino , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos
19.
Oncogene ; 38(48): 7281-7293, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31417183

RESUMO

Bone morphogenetic protein 10 (BMP10), one member of the BMP family, is involved in various development events. Dysregulation of BMP10 has been observed in several diseases, including hypertensive cardiac hypertrophy, Hirschsprung disease and blood vessel formation. However, its role in liver cancer remains largely unknown. In this study, we reported that BMP10 was significantly downregulated in HCC at both mRNA and protein level. Decreased BMP10 was associated with bigger tumor size, worse TNM stage, earlier recurrence and poorer survival. BMP10 negatively regulated HCC cell proliferation in vitro and in vivo. Mechanism study revealed that BMP10 suppressed tumor cell growth by inhibiting STAT3 signaling. Interestingly, we found that cytoplasmic BMP10 interacted with both receptor protein tyrosine phosphatase sigma (PTPRS) and STAT3, which facilitated dephosphorylation of STAT3 by PTPRS. Altogether, our study has revealed the clinical significance of BMP10 in HCC, and suppression of HCC cell growth by BMP10 via PTPRS-STAT3 axis, providing a potential therapeutic strategy for targeting STAT3 signaling in HCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Fator de Transcrição STAT3/metabolismo , Adulto , Animais , Apoptose , Biomarcadores Tumorais/genética , Proteínas Morfogenéticas Ósseas/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Progressão da Doença , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica , Fosforilação , Prognóstico , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Braz Oral Res ; 33: e058, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31432925

RESUMO

Cementum is the mineralized tissue covering the tooth root that functions in tooth attachment and post-eruptive adjustment of tooth position. It has been reported to be highly similar to bone in several respects but remains poorly understood in terms of development and regeneration. Here, we investigate whether cementocytes, the residing cells in cellular cementum, have the potential to be protagonist in cementum homeostasis, responding to endocrine signals and directing local cementum metabolism. Cells from healthy erupted human teeth were isolated using sequential collagenase/EDTA digestions, and maintained in standard cell culture conditions. A cementocyte-like cell line was cloned (HCY-23, for human cementocyte clone 23), which presented a cementocyte compatible gene expression signature, including the expression of dentin matrix protein 1 ( DMP1 ), sclerostin ( SOST ), and E11/gp38/podoplanin ( E11 ). In contrast, these cells did not express the odontoblast/dentin marker dentin sialoprotein ( DSPP ). HCY-23 cells produced mineral-like nodules in vitro under differentiation conditions, and were highly responsive to inorganic phosphate (Pi). Within the limits of the present study, it can be concluded that cementocytes are phosphate-responsive cells, and have the potential do play a key role in periodontal homeostasis and regeneration.


Assuntos
Técnicas de Cultura de Células/métodos , Cemento Dentário/citologia , Adolescente , Adulto , Análise de Variância , Proteínas Morfogenéticas Ósseas/análise , Proteínas Morfogenéticas Ósseas/genética , Linhagem Celular , Cemento Dentário/metabolismo , Proteínas da Matriz Extracelular/análise , Proteínas da Matriz Extracelular/genética , Feminino , Imunofluorescência , Expressão Gênica , Marcadores Genéticos/genética , Humanos , Masculino , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/genética , Dente Molar/citologia , Fosfatos/farmacologia , Fosfoproteínas/análise , Fosfoproteínas/genética , Sialoglicoproteínas/análise , Sialoglicoproteínas/genética , Fatores de Tempo , Adulto Jovem
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