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1.
Life Sci ; 235: 116820, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476308

RESUMO

AIMS: Osteoporosis (OP) is a systemic metabolic bone disease characterized by bone mass decrease and microstructural degradation, which may increase the risk of bone fracture and leading to high morbidity. Dipsaci Radix (DR), one typical traditional Chinese medicine (TCM), which has been applied in the treatment of OP with good therapeutic effects and few side effects. However, the underlying molecular mechanisms of DR to treat OP have not been fully elucidated. In this study, we aim to dissect the molecular mechanism of DR in the treatment of OP. MATERIALS AND METHODS: A systems pharmacology approach was employed to comprehensively dissect the action mechanisms of DR for the treatment of OP. KEY FINDINGS: 10 compounds were screened out as the potential active ingredients with excellent biological activity based on in silico ADME (absorption, distribution, metabolism and excretion) prediction model. Then, 36 key protein targets of 6 compounds were identified by systems drug targeting model (SysDT) and they were involved in several biological processes, such as osteoclast differentiation, osteoblast differentiation and anti-inflammation. The target-pathway network indicated that targets are mainly mapped in multiple signaling pathways, i.e., MAPK, Tumor necrosis factor α (TNF-α), NF-κb and Toll-like receptor pathways. The in vitro results indicated that the compounds ursolic acid and beta-sitosterol effectively inhibited the osteoclast differentiation. SIGNIFICANCE: These results systematically dissected that DR exhibits the therapeutic effects of OP by the regulation of immune system-related pathways, which provide novel perspective to drug development of OP.


Assuntos
Bases de Dados de Produtos Farmacêuticos , Dipsacaceae/química , Medicamentos de Ervas Chinesas/farmacologia , Redes Reguladoras de Genes , Redes e Vias Metabólicas , Osteoporose/tratamento farmacológico , Biologia de Sistemas/métodos , Células CACO-2 , Humanos , Osteoporose/genética , Osteoporose/metabolismo , Transdução de Sinais
2.
Environ Health Prev Med ; 24(1): 48, 2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31301734

RESUMO

AIMS: To investigate the association of four single-nucleotide polymorphisms (SNPs) of the IL-6 gene with osteoporosis (OST) susceptibility. METHODS: PCR restriction fragment length polymorphism (PCR-RFLP) was carried out for SNPs detection. Generalized multifactor dimensionality reduction (GMDR) model and logistic regression model were used to examine the interaction between SNP and obesity on OST. RESULTS: Logistic regression model revealed that G allele of rs1800796 and the T allele of rs2069849 were associated with increased OST risk, compared to those with wild genotype. However, no significant correlations were found when analyzing the association of rs1800795 and rs1554606 with OST risk. GMDR analysis suggested that the interaction model composed of the rs1800796 and obesity was the best model with statistical significance (P value from sign test [Psign] = 0.012), indicating a potential gene-environment interaction between rs1800796 and obesity. Overall, the two-locus models had a cross-validation consistency of 10/10 and had the testing accuracy of 0.641. We also conducted stratified analysis for rs1800796 genotype and obesity, and found that obese subjects with CG or GG genotype have the highest OST risk, compared to subjects with CC genotype, and normal BMI OR (95% CI) = 2.21 (1.52-3.49), after adjustment for age, smoke, and alcohol consumption status. CONCLUSIONS: Our results suggested that the C allele of rs1800796 and the C allele of rs2069849 of IL-6 gene interaction between rs1800796 and abdominal obesity were all associated with increased OST risk.


Assuntos
Interleucina-6/genética , Obesidade/genética , Osteoporose/epidemiologia , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/fisiologia , Idoso , Idoso de 80 Anos ou mais , China , Feminino , Interação Gene-Ambiente , Humanos , Interleucina-6/metabolismo , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/etiologia , Osteoporose/etiologia , Osteoporose/genética , Pós-Menopausa/genética , Fatores de Risco
3.
Adv Exp Med Biol ; 1211: 17-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309515

RESUMO

Osteoporosis is a disease with complex etiology where the genetic factors may account for as much as 50-85% of the risk of its development in postmenopausal women. The polymorphism of estrogen receptor genes (ESR1, ESR2) seems essential among the genetic factors. The goal of this study was to analyze polymorphisms of selected genes in a population of postmenopausal women treated for osteoporosis and to evaluate the influence of genetic and nongenetic factors on the estimated 10-year risk of fracture. The study group consisted of 214 women hospitalized for treatment of postmenopausal osteoporosis. We investigated the presence of ESR1, ESR2, LRP5, and WNT16 genetic polymorphisms and the risk of fracture in each woman. The main finding was that of significant differences in the polymorphisms of the WNT16 rs2908004 genetic variant, notably, the less frequent presence of TC allele in women with a greater risk of osteoporotic fractures. We conclude that the polymorphism of the WNT16 gene seems highly relevant in the pathogenesis of osteoporosis, which makes it a promising object for further research on the genetic background of fracture risk.


Assuntos
Fraturas Ósseas/genética , Predisposição Genética para Doença , Osteoporose/genética , Proteínas Wnt/genética , Densidade Óssea , Feminino , Genótipo , Humanos , Pós-Menopausa
4.
Cell Mol Life Sci ; 76(19): 3723-3744, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31147752

RESUMO

Starting from their role exerted on osteoblast and osteoclast differentiation and activity pathways, microRNAs (miRNAs) have been recently identified as regulators of different processes in bone homeostasis. For this purpose, in a recent review, we highlighted, as deregulated miRNAs could be involved in different bone diseases such as osteoporosis. In addition, recent studies supported the concept that osteoporosis-induced bone alterations might offer a receptive site for cancer cells to form bone metastases, However, to date, no data on specific-shared miRNAs between osteoporosis and bone metastases have been considered and described to clarify the evidence of this link. The main goal of this review is to underline as deregulated miRNAs in osteoporosis may have specific roles in the development of bone metastases. The review showed that several circulating osteoporotic miRNAs could facilitate tumor progression and bone-metastasis formation in several tumor types, i.e., breast cancer, prostate cancer, non-small-cell lung cancer, esophageal squamous cell carcinoma, and multiple myeloma. In detail, serum up-regulation of pro-osteoporotic miRNAs, as well as serum down-regulation of anti-osteoporotic miRNAs are common features of all these tumors and are able to promote bone metastasis. These results are of key importance and could help researcher and clinicians to establish new therapeutic strategies connected with deregulation of circulating miRNAs and able to interfere with pathogenic processes of osteoporosis, tumor progressions, and bone-metastasis formation.


Assuntos
Neoplasias Ósseas/secundário , MicroRNA Circulante/metabolismo , Osteoporose/genética , Animais , Neoplasias Ósseas/complicações , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/secundário , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , MicroRNAs/metabolismo , Mieloma Múltiplo/genética , Osteoporose/complicações , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
5.
Int J Mol Sci ; 20(9)2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31064048

RESUMO

Osteoporosis is a major concern all over the world. With aging, a gradual loss of bone mass results in osteopenia and osteoporosis. Heritable factors account for 60-80% of optimal bone mineralization. Modifiable factors, such as weight-bearing exercise, nutrition, body mass, and hormonal milieu, play an important role in the development of osteopenia and osteoporosis in adulthood. Currently, anti-resorptive agents, including estrogen, bisphosphonates, and selective estrogen receptor modulators (SERMs), are the drugs of choice for osteoporosis. Other treatments include parathyroid hormone (PTH) as well as the nutritional support of calcium and vitamin D. New treatments such as tissue-selective estrogen receptor complexes (TSECs) are currently in use too. This review, which is based on a systematic appraisal of the current literature, provides current molecular and genetic opinions on osteoporosis and its medical treatment. It offers evidence-based information to help researchers and clinicians with osteoporosis assessment. However, many issues regarding osteoporosis and its treatment remain unknown or controversial and warrant future investigation.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Osteoporose/tratamento farmacológico , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Conservadores da Densidade Óssea/farmacologia , Hormônios e Agentes Reguladores de Cálcio/farmacologia , Humanos , Osteoporose/genética , Osteoporose/metabolismo
6.
Life Sci ; 228: 208-214, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31055087

RESUMO

AIMS: Current study aimed to investigate the effects of lncRNA SNHG1 on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and explore the underlying mechanisms. MAIN METHODS: Mouse model of osteoporosis was created by ovariectomy (OVX). The BMD of mice spine, the serum level of ß-CTX and the ALP activity were measured. The expression of SNHG1, JNK, p-JNK, p-38, p-p38 and Osterix were examined by qRT-PCR and Western blot. Co-IP assay was used to verify the effect of SNHG1 on the interaction between p-p38 and Nedd4. Ubiquitination assay was used to evaluate the roles of SNHG1 in ubiquitination of p-p38. KEY FINDINGS: In the mice with osteoporosis, BMD was decreased and ß-CTX concentration and SNHG1 expression were increased. ALP activity and p-p38 protein level were elevated and SNHG1 expression was down-regulated in BMSCs stimulated by osteogenic inducer, while the effects were reversed by SNHG1 over-expression. SNHG1 over-expression enhanced the interaction between Nedd4 and p-p38, disrupted protein stability of p-p38, and promoted the ubiquitination of p-p38. In addition, pcDNA-SNHG1 down-regulated p-p38 protein level, and sh-Nedd4 removed the trend. Nedd4 silencing elevated ALP activity and Osterix protein level, while p-38 inhibitor abrogated the effects. In vivo, SNHG1 silence increased BMD and Osterix protein level, and decreased endogenous SNHG1 expression in mice with OVX. SIGNIFICANCE: This study proved the regulation mechanism that lncRNA SNHG1 negatively regulates p38 MAPK signal pathway through ubiquitination mediated by Nedd4, and thus inhibits osteogenic differentiation of BMSCs.


Assuntos
Células-Tronco Mesenquimais/citologia , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Osteogênese , Osteoporose/genética , RNA Longo não Codificante/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Osteoporose/metabolismo , Osteoporose/patologia , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Ubiquitinação
7.
Mol Med Rep ; 20(1): 270-280, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115543

RESUMO

Osteoporosis (OP) seriously affects the health and quality of life of elderly individuals and postmenopausal women, and the need to identify drugs that can prevent or treat OP remains urgent. Recently, several miRNAs have been reported to be involved in the differentiation of mesenchymal stem cells and osteoblasts; however, the role of miRNA (miR)­144 in regulating OP remains to be elucidated. In the present study, the expression levels of miR­144, secreted frizzled­related protein 1 (Sfrp1) and TNF­α in clinical samples were detected by the reverse transcription­quantitative polymerase chain reaction analysis and ELISA, respectively. 5­Ethynyl­2'­deoxyuridine staining, Hoechst 33258 staining, flow cytometry, a clone formation assay and Alizarin red staining were used to assess the effects of miR­144 combined with or without Sfrp1 small interfering RNA on the proliferation, apoptosis and osteoblastic differentiation of primary mesenchymal stem cells isolated from rats. Western blot assays were performed to assess the relevant mechanisms, and a dual luciferase reporter assay was used to detect the interaction between miR­144 and Sfrp1. The results showed that the levels of miR­144, Sfrp1 and TNF­α in clinical serum samples obtained from patients with postmenopausal OP were higher than those in serum samples obtained from postmenopausal women with normal bone density. There was a significant positive correlation between miR­144 and Sfrp1. Functional experiments demonstrated that miR­144 promoted proliferation, inhibited apoptosis and induced the osteoblastic differentiation of bone marrow­derived mesenchymal stem cells by targeting Sfrp1. It was also shown that miR­144 may help regulate OP by activating the Wnt/ß­catenin pathway. These data suggest miR­144 as a novel target for preventing and treating OP.


Assuntos
Osso e Ossos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , MicroRNAs/genética , Osteoporose/genética , Animais , Desenvolvimento Ósseo/genética , Osso e Ossos/patologia , Diferenciação Celular/genética , Proliferação de Células/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/metabolismo , Osteoporose/patologia , Ratos , Fator de Necrose Tumoral alfa/genética
8.
Mol Med Rep ; 20(1): 401-408, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115574

RESUMO

Osteoblast apoptosis has been identified as an important event in the development of glucocorticoid (GC)­induced osteoporosis and osteonecrosis of the femoral head. Crocin, a bioactive ingredient of saffron, has been demonstrated to induce antiapoptotic effects on numerous types of cell in vitro; however, the effects of crocin on the dexamethasone (Dex)­induced apoptosis of osteoblasts remain unclear. In the present study, the protective effects of crocin during Dex­induced apoptosis of MC3T3­E1 osteoblasts, and the underlying mechanisms, were investigated. MTT and Annexin V­FITC/PI flow cytometry assays were performed to evaluate the viability and apoptosis of cells, respectively. The mitochondrial transmembrane potential, reactive oxygen species (ROS), intracellular Ca2+ levels and apoptosis­associated protein expression were assessed via flow cytometry, fluorescence microscopy and western blotting. It was demonstrated that crocin pretreatment inhibited Dex­induced apoptosis of osteoblasts in a dose­dependent manner. Crocin reversed Dex­induced decreases in the mitochondrial transmembrane potential, and increases in ROS and intracellular Ca2+ levels. Furthermore, crocin upregulated the expression levels of B­cell lymphoma-2 (Bcl­2) and mitochondrial cytochrome c (Cyt C), and downregulated those of cleaved caspase­9, cleaved caspase­3, Bcl­2­associated X protein and cytoplasmic Cyt C. N­acetylcysteine, a ROS inhibitor, and 1,2­bis(2­aminophenoxy)ethane­N,N,N',N'­tetraacetic acid, a calcium chelator, attenuated Dex­induced osteoblast apoptosis, whereas H2O2 and ionomycin, a calcium ionophore that increases intracellular calcium levels, reversed the antiapoptotic effects of crocin on Dex­treated osteoblasts. These results indicated that crocin may protect osteoblasts from Dex­induced apoptosis by inhibiting the ROS/Ca2+­mediated mitochondrial pathway, thus suggesting that crocin has potential value as a treatment for GC­induced bone diseases.


Assuntos
Apoptose/efeitos dos fármacos , Carotenoides/farmacologia , Glucocorticoides/metabolismo , Osteonecrose/tratamento farmacológico , Osteoporose/tratamento farmacológico , Acetilcisteína/farmacologia , Animais , Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dexametasona/toxicidade , Fraturas do Fêmur/tratamento farmacológico , Fraturas do Fêmur/genética , Fraturas do Fêmur/patologia , Humanos , Peróxido de Hidrogênio/farmacologia , Ionomicina/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Osteonecrose/induzido quimicamente , Osteonecrose/genética , Osteonecrose/patologia , Osteoporose/induzido quimicamente , Osteoporose/genética , Osteoporose/patologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
9.
Int J Mol Sci ; 20(8)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003519

RESUMO

Bone is a dynamic tissue, whose homeostasis is maintained by a fine balance between osteoclast (OC) and osteoblast (OB) activity. The endocannabinoid/endovanilloid (EC/EV) system's receptors are the cannabinoid receptor type 1 (CB1), the cannabinoid receptor type 2 (CB2), and the transient receptor potential cation channel subfamily V member 1 (TRPV1). Their stimulation modulates bone formation and bone resorption. Bone diseases are very common worldwide. Osteoporosis is the principal cause of bone loss and it can be caused by several factors such as postmenopausal estrogen decrease, glucocorticoid (GC) treatments, iron overload, and chemotherapies. Studies have demonstrated that CB1 and TRPV1 stimulation exerts osteoclastogenic effects, whereas CB2 stimulation has an anti-osteoclastogenic role. Moreover, the EC/EV system has been demonstrated to have a role in cancer, favoring apoptosis and inhibiting cell proliferation. In particular, in bone cancer, the modulation of the EC/EV system not only reduces cell growth and enhances apoptosis but it also reduces cell invasion and bone pain in mouse models. Therefore, EC/EV receptors may be a useful pharmacological target in the prevention and treatment of bone diseases. More studies to better investigate the biochemical mechanisms underlining the EC/EV system effects in bone are needed, but the synthesis of hybrid molecules, targeting these receptors and capable of oppositely regulating bone homeostasis, seems to be a promising and encouraging prospective in bone disease management.


Assuntos
Endocanabinoides/genética , Osteogênese/genética , Osteoporose/genética , Osteossarcoma/genética , Apoptose/genética , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Proliferação de Células/genética , Endocanabinoides/metabolismo , Glucocorticoides/genética , Humanos , Osteoporose/patologia , Osteossarcoma/patologia , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/genética , Canais de Cátion TRPV/genética
10.
PLoS Genet ; 15(4): e1008060, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31022172

RESUMO

The promise of personalized genomic medicine is that knowledge of a person's gene sequences and activity will facilitate more appropriate medical interventions, particularly drug prescriptions, to reduce the burden of disease. Early successes in oncology and pediatrics have affirmed the power of positive diagnosis and are mostly based on detection of one or a few mutations that drive the specific pathology. However, genetically more complex diseases require the development of polygenic risk scores (PRSs) that have variable accuracy. The rarity of events often means that they have necessarily low precision: many called positives are actually not at risk, and only a fraction of cases are prevented by targeted therapy. In some situations, negative prediction may better define the population at low risk. Here, I review five conditions across a broad spectrum of chronic disease (opioid pain medication, hypertension, type 2 diabetes, major depression, and osteoporotic bone fracture), considering in each case how genetic prediction might be used to target drug prescription. This leads to a call for more research designed to evaluate genetic likelihood of response to therapy and a call for evaluation of PRS, not just in terms of sensitivity and specificity but also with respect to potential clinical efficacy.


Assuntos
Herança Multifatorial , Medicina de Precisão/métodos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Masculino , Mutação , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Osteoporose/genética , Osteoporose/prevenção & controle , Testes Farmacogenômicos/métodos , Medicina Preventiva/métodos , Fatores de Risco
11.
In Vitro Cell Dev Biol Anim ; 55(5): 376-386, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31025251

RESUMO

Osteoporosis results from the imbalance between osteogenesis and bone resorption mediated by osteoblasts and osteoclasts. During the disease process of osteoporosis, the alteration of gene expression occurs, which lead to the disease progression. MicroRNAs (miRNAs) have been previously demonstrated to be modulators for bone metabolism via regulation of osteoblast and osteoclast differentiation. In the present study, we detected the expression levels of five osteoporosis-related miRNAs in bone and serum samples of patient with or without osteoporosis. The downstream molecular mechanism of miR-363-3p was analyzed and detected by using bioinformatics analysis and mechanism experiment. The upstream transcription factor of miR-363-3p was analyzed by applying bioinformatics analysis and ChIP assay and luciferase reporter assay. The role of this pathway in osteoclastogenesis was demonstrated by functional assays. MiR-363-3p was significantly highly expressed in osteoporotic samples. Mechanistically, miR-363-3p promotes osteoclastogenesis and inhibits osteogenic differentiation by targeting PTEN and therefore activating PI3K/AKT signaling pathway. MiR-363-3p was activated by its upstream transcription activator MYB. This study revealed that MYB-induced upregulation of miR-363-3p regulates osteoporosis pathogenesis via PTEN/PI3K/AKT signaling pathway.


Assuntos
Reabsorção Óssea/genética , MicroRNAs/genética , Osteoporose/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-myb/genética , Reabsorção Óssea/sangue , Reabsorção Óssea/patologia , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Diferenciação Celular/genética , Biologia Computacional , Regulação da Expressão Gênica/genética , Humanos , MicroRNAs/sangue , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese/genética , Osteoporose/sangue , Osteoporose/patologia , Pacientes , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética
12.
Med Sci Monit ; 25: 2289-2295, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30923307

RESUMO

BACKGROUND The essence of osteoporosis is mainly the imbalance of bone formation and absorption. Previous studies indicated that SIRT1 is closely related to bone metabolism and bone mass as a regulator of bone mass. The literature reports that microRNAs are significant regulators of osteoblast proliferation and differentiation. MATERIAL AND METHODS In this study, SIRT1 protein and mRNA levels were examined by Western blot and RT-PCR. Osteogenic proliferation was examined by CCK8 assay and osteogenic markers, including ALP, OCN, and RUNX2, were examined by ELISA. The target of miR-132-3p was identified by luciferase reporter assay. RESULTS LPS downregulated the SIRT1 protein level and ß-glycerophosphate upregulated the SIRT1 protein level. The results demonstrated that SIRT1 overexpression promoted the proliferation and differentiation in MC3T3-E1 cells, and SIRT1 interference had the opposite effect. Luciferase reporter assay revealed that miR-132-3p inhibited the reporter gene activity of SIRT1. LPS upregulated the mRNA level of miR-132-3p, and ß-glycerophosphate downregulated the mRNA level of miR-132-3p. CONCLUSIONS miR-132-3p is a pivotal regulator in osteogenic proliferation and differentiation by targeting SIRT1.


Assuntos
MicroRNAs/genética , Osteoporose/genética , Sirtuína 1/metabolismo , Células 3T3 , Fosfatase Alcalina/metabolismo , Animais , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células/genética , Células Cultivadas , China , Regulação da Expressão Gênica/genética , Lipopolissacarídeos/farmacologia , Camundongos , MicroRNAs/fisiologia , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Sirtuína 1/genética
13.
Nat Commun ; 10(1): 1260, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890710

RESUMO

Osteoporosis is a devastating disease with an essential genetic component. GWAS have discovered genetic signals robustly associated with bone mineral density (BMD), but not the precise localization of effector genes. Here, we carry out physical and direct variant to gene mapping in human mesenchymal progenitor cell-derived osteoblasts employing a massively parallel, high resolution Capture C based method in order to simultaneously characterize the genome-wide interactions of all human promoters. By intersecting our Capture C and ATAC-seq data, we observe consistent contacts between candidate causal variants and putative target gene promoters in open chromatin for ~ 17% of the 273 BMD loci investigated. Knockdown of two novel implicated genes, ING3 at 'CPED1-WNT16' and EPDR1 at 'STARD3NL', inhibits osteoblastogenesis, while promoting adipogenesis. This approach therefore aids target discovery in osteoporosis, here on the example of two relevant genes involved in the fate determination of mesenchymal progenitors, and can be applied to other common genetic diseases.


Assuntos
Densidade Óssea/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Osteoporose/genética , Regiões Promotoras Genéticas/genética , Adipogenia/genética , Adulto , Diferenciação Celular/genética , Mapeamento Cromossômico , Feminino , Técnicas de Silenciamento de Genes , Loci Gênicos/genética , Células Hep G2 , Proteínas de Homeodomínio/genética , Humanos , Masculino , Proteínas de Membrana/genética , Células-Tronco Mesenquimais , Proteínas de Neoplasias/genética , Osteoblastos/fisiologia , Osteogênese/genética , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Wnt/genética , Adulto Jovem
14.
Int J Mol Sci ; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875838

RESUMO

This study evaluated whether bergapten and methoxsalen could prevent diabetes-induced osteoporosis and its underlying mechanism. For 10 weeks, bergapten or methoxsalen (0.02%, w/w) was applied to diabetic mice that were provided with a high-fat diet and streptozotocin. Bone mineral density (BMD) and microarchitecture quality were significantly reduced in the diabetic control group; however, both bergapten and methoxsalen reversed serum osteocalcin, bone-alkaline phosphatase and femur BMD. These coumarin derivatives significantly increased bone volume density and trabecular number, whereas they decreased the structure model index of femur tissue in diabetic mice. Conversely, tartrate-resistant acid phosphatase 5 (TRAP) staining revealed that these derivatives reduced osteoclast numbers and formation in diabetic bone tissue. Additionally, both bergapten and methoxsalen tended to downregulate the expression of osteoclast-related genes such as receptor activator of nuclear factor kappa-B ligand (RANKL), nuclear of activated T-cells, cytoplasmic 1 (NFATc1) and TRAP in diabetic femurs, with NFATc1 and TRAP expression showing significant reductions. Our data suggest that both bergapten and methoxsalen prevent diabetic osteoporosis by suppressing bone resorption.


Assuntos
5-Metoxipsoraleno/administração & dosagem , Diabetes Mellitus Experimental/complicações , Metoxaleno/administração & dosagem , Osteogênese/efeitos dos fármacos , Osteoporose/prevenção & controle , 5-Metoxipsoraleno/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Densidade Óssea/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Metoxaleno/farmacologia , Camundongos , Fatores de Transcrição NFATC/genética , Osteocalcina/sangue , Osteoporose/genética , Ligante RANK/genética , Estreptozocina , Fosfatase Ácida Resistente a Tartarato/genética
15.
Nat Rev Endocrinol ; 15(6): 356-365, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30899100

RESUMO

The principal role of prolactin in mammals is the regulation of lactation. Prolactin is a hormone that is mainly synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin signalling occurs via a unique transmembrane prolactin receptor (PRL-R). The structure of the PRL-R has now been elucidated and is similar to that of many biologically fundamental receptors of the class 1 haematopoietic cytokine receptor family such as the growth hormone receptor. The PRL-R is expressed in a wide array of tissues, and a growing number of biological processes continue to be attributed to prolactin. In this Review, we focus on the newly discovered roles of prolactin in human health and disease, particularly its involvement in metabolic homeostasis including body weight control, adipose tissue, skin and hair follicles, pancreas, bone, the adrenal response to stress, the control of lactotroph cell homeostasis and maternal behaviour. New data concerning the pathological states of hypoprolactinaemia and hyperprolactinaemia will also be presented and discussed.


Assuntos
Pleiotropia Genética/fisiologia , Nível de Saúde , Hiperprolactinemia/metabolismo , Osteoporose/metabolismo , Prolactina/metabolismo , Animais , Feminino , Homeostase/fisiologia , Humanos , Hiperprolactinemia/genética , Osteoporose/genética , Prolactina/deficiência , Prolactina/genética , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo
16.
PLoS One ; 14(2): e0212464, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794634

RESUMO

Bone mineral density (BMD) and lipid levels are two of the most extensively studied risk factors for common diseases of aging, such as cardiovascular disease (CVD) and osteoporosis (OP). These two risk factors are also correlated with each other, but little is known about the molecular mechanisms behind this correlation. Recent studies revealed that circulating levels of several metabolites involved in the biosynthesis of androsterone correlate significantly with BMD and have the capacity to affect cholesterol and lipids levels. A main aim of the present study was to investigate the hypothesis that androsterone-related metabolites could provide a link between CVD and OP, as a common cause of lipid levels and BMD. The present study employed data from the NIHR BRC TwinsUK BioResource, comprising 1909 and 1994 monozygotic and dizygotic twin pairs, respectively, to address the causal relationships among BMD and lipids, and their associated metabolites, using reciprocal causation twin modelling, as well as Mendelian randomization (MR) using large publicly-available GWAS datasets on lipids and BMD, in conjunction with TwinsUK metabolite data. While results involving the twin modelling and MR analyses with metabolites were unable to establish a causal link between metabolite levels and either lipids or BMD, MR analyses of BMD and lipids suggest that lipid levels have a causal impact on BMD, which is consistent with findings from clinical trials of lipid-lowering drugs, which have also increased BMD.


Assuntos
Densidade Óssea/fisiologia , Lipídeos/sangue , Androsterona/metabolismo , Densidade Óssea/genética , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Causalidade , Estudo de Associação Genômica Ampla , Humanos , Lipídeos/genética , Osteoporose/etiologia , Osteoporose/genética , Osteoporose/metabolismo , Fenótipo , Fatores de Risco , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Reino Unido
17.
Mol Biol Rep ; 46(2): 1667-1674, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30788762

RESUMO

Osteoporosis is a multifactorial disease in which genetic factors and epigenetic modifications play a major role. DNA methylation is known for gene silencing and its effect on BMP2 promoter has been studied here to understand its regulatory activity in osteoporosis pathogenicity. CpG methylation in the BMP2 promoter was analyzed by performing bisulfite specific PCR on the gDNA samples extracted from whole blood of osteoporotic (n = 24) and healthy (n = 24) individuals. Disproportionate allele frequency of CpG sites was calculated statistically. Differential BMP2 expression was estimated using quantitative RT-PCR technique. Luciferase reporter assay was performed to determine and confirm differential transcriptional activity of BMP2 promoter due to methylation. Total of 14 CpG sites were reporter in the BMP2 promoter of which, CpG site at - 267th position upstream to TSS was found to have disproportionate allele frequency among osteoporotic and healthy individuals and was found to be significantly associated with osteoporosis condition. Functional and gene expression analysis of this methylated site using luciferase reporter vector and Real Time PCR approach, suggested reduced transcriptional activity of BMP2 promoter as well as decreased gene expression in disease condition. BMP2 is being a central signaling molecule, aberrant methylation in the promoter region may result into down regulation of osteoblast markers involved in bone formation.


Assuntos
Proteína Morfogenética Óssea 2/genética , Osteoporose/genética , Adulto , Idoso , Alelos , Proteína Morfogenética Óssea 2/fisiologia , Linhagem Celular Tumoral , Ilhas de CpG/genética , Metilação de DNA/genética , Regulação para Baixo , Epigênese Genética/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Frequência do Gene/genética , Inativação Gênica , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Processamento de Proteína Pós-Traducional/genética
18.
J Physiol Biochem ; 75(1): 11-18, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30706289

RESUMO

Lamin A/C is the major architectural protein of cell nucleus in charge of the nuclear mechanosensing. By integrating extracellular mechanical and biochemical signals, lamin A/C regulates multiple intracellular events including mesenchymal stem cell (MSC) fate determination. Herein, we review the recent findings about the effects and mechanisms of lamin A/C in governing MSC lineage commitment, with a special focus on osteogenesis and adipogenesis. Better understanding of MSC differentiation regulated by lamin A/C could provide insights into pathogenesis of age-related osteoporosis.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Lamina Tipo A/genética , Células-Tronco Mesenquimais/metabolismo , Osteoporose/genética , Tretinoína/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adipócitos/citologia , Diferenciação Celular , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Regulação da Expressão Gênica , Humanos , Lamina Tipo A/metabolismo , Mecanotransdução Celular , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteogênese/genética , Osteoporose/metabolismo , Osteoporose/patologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Fator de Resposta Sérica/genética , Fator de Resposta Sérica/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Int J Biol Macromol ; 129: 579-587, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30735778

RESUMO

A homogenous polysaccharide (DAP), with a molecular weight of 2.61 × 104 Da, was isolated from the roots of Dipsacus asper Wall. Gas chromatography (GC) indicated that DAP was composed of galactose and mannose with a molar ratio of 1:1. The purpose of this study was to evaluate the effect of DAP on the progress of bone loss in the ovariectomized (OVX) rat model of osteoporosis. Administration of DAP (50 and 200 mg/kg/body wt. day) for 12 weeks significantly prevented OVX-induced bone loss, biomechanical reduction, the body weight gain, the loss of the uterus weight, as well as increased U-Ca/Cr, U-P/Cr, ALP, TRAP, OC and DPD/Cr levels in rats, which was further supported by the histopathological examinations. Furthermore, we found that the mechanism by which DAP elicited anti-osteoporotic effects was mediated by up-regulation of VEGF and OPG, but down-regulation of RANK and RANKL in both protein and mRNA expression in OVX rats, as well as the activation of PI3K/Akt/eNOS signaling pathway, indicating that DAP can be clinically used as a potential alternative medicine for the prevention and treatment of postmenopausal osteoporosis.


Assuntos
Dipsacaceae/química , Osteoporose/tratamento farmacológico , Polissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ovariectomia , Fosfatidilinositol 3-Quinases/metabolismo , Raízes de Plantas/química , Polissacarídeos/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Útero/efeitos dos fármacos , Útero/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Nat Genet ; 51(2): 258-266, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30598549

RESUMO

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.


Assuntos
Densidade Óssea/genética , Predisposição Genética para Doença/genética , Osteoporose/genética , Adulto , Idoso , Animais , Feminino , Fraturas Ósseas/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
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