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1.
Yi Chuan ; 42(9): 889-897, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32952123

RESUMO

Osteoporosis is a typical polygenic disease, and its heritability is as high as 85%. The incidence of osteoporosis has jumped to the fifth among the common diseases. Although a large number of osteoporosis-susceptible SNPs have been identified, most of them are in the non-coding regions of the genome and the functional mechanisms are unknown. The purpose of this study was to explore the function of non-coding osteoporosis-susceptible SNP rs4325274 and dissect the molecular regulatory mechanisms through integrating bioinformatics analysis and functional experiments. Firstly, we found the SNP rs4325274 resided in a putative enhancer element through functional annotation. eQTL and Hi-C analysis found that the SOX6 gene might be a potential distal target of rs4325274. We conducted the motif prediction using multiple databases and verified the result using ChIP-seq data from GEO database. The result showed that the transcription factor HNF1A could preferentially bind to SNP rs4325274-G allele. We further demonstrated that SNP rs4325274 acted as an enhancer regulating SOX6 gene expression by using dual-luciferase reporter assays. Knockdown of HNF1A decreased the SOX6 gene expression. Taken together, our results uncovered a new mechanism of a non-coding functional SNP rs4325274 as a distal enhancer to modulate SOX6 expression, which provides new insights into deciphering molecular regulatory mechanisms underlying non-coding susceptibility SNPs on complex diseases.


Assuntos
Osteoporose , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição SOXD/genética , Alelos , Predisposição Genética para Doença , Humanos , Osteoporose/genética , Locos de Características Quantitativas
2.
PLoS Med ; 17(7): e1003152, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32614825

RESUMO

BACKGROUND: Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program. METHODS AND FINDINGS: A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N = 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r2 = 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk. CONCLUSIONS: Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention.


Assuntos
Programas de Rastreamento/métodos , Herança Multifatorial , Fraturas por Osteoporose/genética , Fraturas por Osteoporose/prevenção & controle , Medição de Risco/métodos , Idoso , Densidade Óssea , Calcâneo/diagnóstico por imagem , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Calcanhar/diagnóstico por imagem , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Osteoporose/genética , Fatores de Risco , Ultrassonografia , Reino Unido
3.
Proc Natl Acad Sci U S A ; 117(32): 19276-19286, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719141

RESUMO

Bone homeostasis requires continuous remodeling of bone matrix to maintain structural integrity. This involves extensive communication between bone-forming osteoblasts and bone-resorbing osteoclasts to orchestrate balanced progenitor cell recruitment and activation. Only a few mediators controlling progenitor activation are known to date and have been targeted for intervention of bone disorders such as osteoporosis. To identify druggable pathways, we generated a medaka (Oryzias latipes) osteoporosis model, where inducible expression of receptor-activator of nuclear factor kappa-Β ligand (Rankl) leads to ectopic formation of osteoclasts and excessive bone resorption, which can be assessed by live imaging. Here we show that upon Rankl induction, osteoblast progenitors up-regulate expression of the chemokine ligand Cxcl9l. Ectopic expression of Cxcl9l recruits mpeg1-positive macrophages to bone matrix and triggers their differentiation into osteoclasts. We also demonstrate that the chemokine receptor Cxcr3.2 is expressed in a distinct subset of macrophages in the aorta-gonad-mesonephros (AGM). Live imaging revealed that upon Rankl induction, Cxcr3.2-positive macrophages get activated, migrate to bone matrix, and differentiate into osteoclasts. Importantly, mutations in cxcr3.2 prevent macrophage recruitment and osteoclast differentiation. Furthermore, Cxcr3.2 inhibition by the chemical antagonists AMG487 and NBI-74330 also reduced osteoclast recruitment and protected bone integrity against osteoporotic insult. Our data identify a mechanism for progenitor recruitment to bone resorption sites and Cxcl9l and Cxcr3.2 as potential druggable regulators of bone homeostasis and osteoporosis.


Assuntos
Matriz Óssea/metabolismo , Quimiocina CXCL9/metabolismo , Proteínas de Peixes/metabolismo , Oryzias/metabolismo , Osteoclastos/metabolismo , Osteoporose/metabolismo , Receptores CXCR3/metabolismo , Células-Tronco/metabolismo , Animais , Matriz Óssea/crescimento & desenvolvimento , Diferenciação Celular , Quimiocina CXCL9/genética , Modelos Animais de Doenças , Proteínas de Peixes/genética , Humanos , Macrófagos/metabolismo , Oryzias/genética , Oryzias/crescimento & desenvolvimento , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteoclastos/citologia , Osteoporose/genética , Osteoporose/fisiopatologia , Ligação Proteica , Receptores CXCR3/genética , Células-Tronco/citologia
4.
Proc Natl Acad Sci U S A ; 117(29): 17187-17194, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32636266

RESUMO

Osteoprotegerin (OPG), a secreted decoy receptor for receptor activator of nuclear factor B ligand (RANKL), plays an essential role in regulating bone resorption. While much is known about the function of the N-terminal domains of OPG, which is responsible for binding to RANKL, the exact biological functions of the three C-terminal domains of OPG remain uncertain. We have previously shown that one likely function of the C-terminal domains of OPG is to bind cell surface heparan sulfate (HS), but the in vivo evidence was lacking. To investigate the biological significance of OPG-HS interaction in bone remodeling, we created OPG knock-in mice (opg AAA ). The mutated OPG is incapable of binding to HS but binds RANKL normally. Surprisingly, opg AAA/AAA mice displayed a severe osteoporotic phenotype that is very similar to opg-null mice, suggesting that the antiresorption activity of OPG requires HS. Mechanistically, we propose that the HS immobilizes secreted OPG at the surface of osteoblasts lineage cells, which facilitates binding of OPG to membrane-anchored RANKL. To further support this model, we altered the structure of osteoblast HS genetically to make it incapable of binding to OPG. Interestingly, osteocalcin-Cre;Hs2st f/f mice also displayed osteoporotic phenotype with similar severity to opg AAA/AAA mice. Combined, our data provide strong genetic evidence that OPG-HS interaction is indispensable for normal bone homeostasis.


Assuntos
Conservadores da Densidade Óssea/metabolismo , Conservadores da Densidade Óssea/farmacologia , Heparitina Sulfato/metabolismo , Osteoprotegerina/metabolismo , Osteoprotegerina/farmacologia , Animais , Sítios de Ligação , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Osso e Ossos/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese/genética , Osteogênese/fisiologia , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Osteoprotegerina/genética , Ligante RANK/metabolismo , Transcriptoma
5.
DNA Cell Biol ; 39(9): 1691-1699, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32700968

RESUMO

Long noncoding RNAs (lncRNAs) contribute toward regulating gene expression and cell differentiation and may be involved in the pathogenesis of several diseases. The objective of this study was to determine the expression patterns of lncRNAs in bone marrow mesenchymal stem cells (BMSCs) derived from patients with osteoporotic fractures and their relevance to osteogenic function. The BMSCs were isolated from the femoral head of patients with hip fractures (FRX) and controls with osteoarthritis (OA). We found 74 differentially expressed genes between FRX and OA, of which 33 were of the lncRNA type. Among them, 52 genes (20 lncRNAs) were replicated in another independent dataset. The differentially expressed lncRNAs were over-represented among those correlated with differentially expressed protein-coding genes. In addition, the comparison of pre- and post-differentiated paired samples revealed 163 differentially expressed genes, of which 99 were of the lncRNA type. Among them, the overexpression of LINC00341 induced an upregulation of typical osteoblastic genes. In conclusion, the analysis of lncRNA expression in BMSCs shows specific patterns in patients with osteoporotic fractures, as well as changes associated with osteogenic differentiation. The regulation of bone genes through lncRNAs might bring new opportunities for designing bone anabolic therapies in systemic and localized bone disorders.


Assuntos
Células da Medula Óssea/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteoporose/genética , RNA Longo não Codificante/metabolismo , Células da Medula Óssea/citologia , Diferenciação Celular , Células Cultivadas , Células HEK293 , Humanos , Células-Tronco Mesenquimais/citologia , Osteogênese , Osteoporose/patologia , RNA Longo não Codificante/genética , Transcriptoma
6.
J Biol Regul Homeost Agents ; 34(2): 345-355, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32548991

RESUMO

Osteoporosis is defined as an aging-related skeletal disorder involving deterioration of bone mass and bone structure, and consequently, increased risk of fractures. Emerging evidence indicates the dysregulation of microRNAs (miRNAs) in the progression of osteoporosis. However, whether such associated miRNAs control osteoblast differentiation or constitute therapeutic targets remains elusive. In the present study, we found elevated circulating miR-374b-5p level associated with postmenopausal osteoporosis. miR-374b-5p served as a critical suppressor of osteoblast differentiation. We further identified that miR-374b-5p directly targeted Wnt family member 3 (Wnt3) and Runt-related transcription factor 2 (Runx2) through its 3'-untranslated regions (3'UTRs). Moreover, the antagonist of miR-374b-5p could promote bone formation in ovariectomy (OVX)-induced mice. Together, our results revealed that miR-374b-5p directly targeted Wnt3 and Runx2, negatively regulating osteoblast differentiation and bone formation. Collectively, circulating miR-374b-5p in the serum might serve as a potential diagnostic and therapeutic strategy for osteoporosis.


Assuntos
Diferenciação Celular , Subunidade alfa 1 de Fator de Ligação ao Core/genética , MicroRNAs/sangue , Osteoblastos/citologia , Osteoporose/genética , Proteína Wnt3/genética , Animais , Células Cultivadas , Feminino , Humanos , Camundongos , Osteogênese
7.
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
8.
Hum Cell ; 33(3): 569-581, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32253621

RESUMO

Osteoporosis (OP) is a systemic bone metabolic disorder, which negatively affects the quality of life in the elders and postmenopausal females. Healthy volunteers and postmenopausal females with OP were enrolled in the present study. Bone densitometry (BMD) was detected by dual-energy X-ray absorptiometry (DXA). CD14+PBMCs and C2C12 cells were cultured to induce osteoclast differentiation and osteoblast differentiation, respectively. The interaction between miR­140-3p and PTEN was predicted and verified by TargetScan 7.2 and dual luciferase reporter assay, respectively. miRNA/RNA level and protein level were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. Cell proliferation and apoptosis were detected by 5-ethynyl-2'-deoxyuridine (EdU) staining and flow cytometry, respectively. Cell differentiation of CD14+PBMCs and C2C12 cells were detected by tartrate-resistant acid phosphatase (TRAP) staining and alizarin red staining, respectively. The activity of alkaline phosphatase (ALP) was detected by ALP assay. Differences were observed in age, body mass index (BMI), and BMD between the OP group and the control group. Higher miR­140-3p level and lower PTEN level were found in PBMCs of OP group compared to control group; there was a negative correlation between them in the serum of OP group. miR-140-3p targeted and downregulated the expression of PTEN. miR-140-3p inhibitor inhibited cell proliferation, differentiation, and promoted cell apoptosis of CD14+PBMCs; while promoted cell proliferation, differentiation and inhibited cell apoptosis of C2C12 cells, by targeting PTEN and inactivating PTEN/PI3K/AKT signaling pathway. These findings suggested a potential therapeutic role of miR-140-3p in the treatment of patients with OP.


Assuntos
Osteoporose/genética , Osteoporose/patologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Apoptose , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Células HEK293 , Humanos , Terapia de Alvo Molecular , Osteoblastos , Osteoclastos , Osteoporose/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo
9.
Arch Oral Biol ; 113: 104713, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32229339

RESUMO

OBJECTIVE: This work was aimed to investigate the effect of microRNA-141 (miR-141) overexpression in the jawbones of ovariectomized-induced osteoporosis rats and investigate the role of miR-141 in the Wnt/ß-catenin pathway. METHODS: Twenty-four female rats were randomly divided into the sham group, ovariectomized osteoporosis group (OP), miR-141 agonist group (miR-141), and miR-141 scramble group (Scramble). Bone mineral density (BMD) and pathological changes of the jaw were detected. Serum receptor activator of nuclear factor-B ligand (RANKL), osteoprotegerin, tartrate-resistant acid phosphatase (TRAP), and bone gla protein (BGP) levels were tested by ELISA. The expression of Runt-related transcription factor 2 (Runx2), and Osterix measured by immunohistochemistry and the expression of Wnt, ß-catenin, and Dickkopf1 (DKK1) proteins was measured by Western blot. Furhter, the Wnt agonist DKK2-C2, Wnt inhibitor Endostar were used to verify the effect of miR-141 overexpression on the Wnt/ß-catenin pathway. RESULT: Compared with the OP group, the content of osteoprotegerin increased while the levels of RANKL, BGP, TRAP decreased in the miR-141 and DKK2-C2 groups (p < 0.05). The levels of Runx2 and Osterix increased significantly in the miR-141 and DKK2-C2 groups when compared to the OP group (p < 0.05). Interestingly, the protein expression of Wnt and ß-catenin increased while DKK1 was remarkably down-regulated in the miR-141 and DKK2-C2 groups when compared to the OP group (p < 0.05). In contrast to the miR-141 group, the above results were reversed after treatment with the Endostar (p < 0.05). CONCLUSION: Overexpression of miR-141 could inhibit the osteoporosis of jawbones in ovariectomized rats by activating the Wnt/ß-catenin pathway.


Assuntos
Arcada Osseodentária/patologia , MicroRNAs/genética , Osteoporose/genética , Via de Sinalização Wnt , Animais , Feminino , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Osteoporose/patologia , Ovariectomia , Ratos , Ratos Sprague-Dawley , beta Catenina/metabolismo
10.
Hum Genet ; 139(8): 1023-1035, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32239398

RESUMO

Aiming to uncover a shared genetic basis of abdominal obesity and osteoporosis, we performed a bivariate GWAS meta-analysis of femoral neck BMD (FNK-BMD) and trunk fat mass adjusted by trunk lean mass (TFMadj) in 11,496 subjects from 6 samples, followed by in silico replication in the large-scale UK Biobank (UKB) cohort. A series of functional investigations were conducted on the identified variants. Bivariate GWAS meta-analysis identified two novel pleiotropic loci 12q15 (lead SNP rs73134637, p = 3.45 × 10-7) and 10p14 (lead SNP rs2892347, p = 2.63 × 10-7) that were suggestively associated and that were replicated in the analyses of related traits in the UKB sample (osteoporosis p = 0.06 and 0.02, BMI p = 0.03 and 4.61 × 10-3, N up to 499,520). Cis-eQTL analysis demonstrated that allele C at rs73134637 was positively associated with IFNG expression in whole blood (N = 369, p = 0.04), and allele A at rs11254759 (10p14, p = 9.49 × 10-7) was negatively associated with PRKCQ expression in visceral adipose tissue (N = 313, p = 0.04) and in lymphocytes (N = 117, p = 0.03). As a proof-of-principle experiment, the function of rs11254759, which is 235 kb 5'-upstream from PRKCQ gene, was investigated by the dual-luciferase reporter assay, which clearly showed that the haplotype carrying rs11254759 regulated PRKCQ expression by upregulating PRKCQ promoter activity (p = 4.60 × 10-7) in an allelic specific manner. Mouse model analysis showed that heterozygous PRKCQ deficient mice presented decreased fat mass compared to wild-type control mice (p = 3.30 × 10-3). Mendelian randomization analysis demonstrated that both FNK-BMD and TFMadj were causally associated with fracture risk (p = 1.26 × 10-23 and 1.18 × 10-11). Our findings may provide useful insights into the genetic association between osteoporosis and abdominal obesity.


Assuntos
Pleiotropia Genética/genética , Interferon gama/genética , Obesidade Abdominal/genética , Osteoporose/genética , Proteína Quinase C-theta/genética , Locos de Características Quantitativas/genética , Animais , Índice de Massa Corporal , Estudos de Coortes , Feminino , Colo do Fêmur/fisiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Análise da Randomização Mendeliana , Camundongos , Camundongos Knockout , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética
11.
BMC Med Genet ; 21(1): 21, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005172

RESUMO

BACKGROUND: More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. The disorder is caused by mutations in a single gene and the disease severity in affected individuals can be quite variable. Specific MECP2 mutations may lead phenotypic variability and different degrees of disease severity. It is known that low bone mass is a frequent and early complication of subjects with Rett syndrome. As a consequence of the low bone mass Rett girls are at an increased risk of fragility fractures. This study aimed to investigate if specific MECP2 mutations may affects the degree of involvement of the bone status in Rett subjects. METHODS: In 232 women with Rett syndrome (mean age 13.8 ± 8.3 yrs) we measured bone mineral density at whole body and at femur (BMD-FN and BMD-TH) by using a DXA machine (Hologic QDR 4500). QUS parameters were assessed at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT). Moreover, ambulation capacity (independent or assisted), fracture history and presence of scoliosis were assessed. We divided the subjects with the most common point mutations in two group based on genotype-phenotype severity; in particular, there has been consensus in recognising that the mutations R106T, R168X, R255X, R270X are considered more severe. RESULTS: As aspect, BMD-WB, BMD-FN and BMD-TH were lower in subjects with Rett syndrome that present the most severe mutations with respect to subjects with Rett syndrome with less severe mutations, but the difference was statistically significant only for BMD-FN and BMD-TH (p < 0.05). Also both AD-SoS and BTT values were lower in subjects that present the most severe mutations with respect to less severe mutations but the difference was not statistically significant. Moreover, subjects with Rett syndrome with more severe mutations present a higher prevalence of scoliosis (p < 0.05) and of inability to walk (p < 0.05). CONCLUSION: This study confirms that MECP2 mutation type is a strong predictor of disease severity in subjects with Rett syndrome. In particular, the subjects with more severe mutation present a greater deterioration of bone status, and a higher prevalence of scoliosis and inability to walk.


Assuntos
Doenças Ósseas/genética , Proteína 2 de Ligação a Metil-CpG/genética , Osteoporose/genética , Síndrome de Rett/genética , Adolescente , Adulto , Densidade Óssea/genética , Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/fisiopatologia , Criança , Pré-Escolar , Feminino , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/genética , Fraturas Ósseas/fisiopatologia , Humanos , Masculino , Mutação , Osteoporose/diagnóstico por imagem , Osteoporose/fisiopatologia , Síndrome de Rett/diagnóstico por imagem , Síndrome de Rett/fisiopatologia , Escoliose/diagnóstico por imagem , Escoliose/genética , Escoliose/fisiopatologia , Índice de Gravidade de Doença , Adulto Jovem
12.
Medicine (Baltimore) ; 99(8): e19120, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080087

RESUMO

Osteoporosis (OP) is a disease characterized by bone mass loss, bone microstructure damage, increased bone fragility, and easy fracture. The molecular mechanism underlying OP remains unclear.In this study, we identified 217 genes associated with OP, and formed a gene set [OP-related genes gene set (OPgset)].The highly enriched GOs and pathways showed OPgset genes were significantly involved in multiple biological processes (skeletal system development, ossification, and osteoblast differentiation), and several OP-related pathways (Wnt signaling pathway, osteoclast differentiation, steroid hormone biosynthesis, and adipocytokine signaling pathway). Besides, pathway crosstalk analysis indicated three major modules, with first module consisted of pathways mainly involved in bone development-related signaling pathways, second module in Wnt-related signaling pathway and third module in metabolic pathways. Further, we calculated degree centrality of a node and selected ten key genes/proteins, including TGFB1, IL6, WNT3A, TNF, PTH, TP53, WNT1, IGF1, IL10, and SERPINE1. We analyze the K-core and construct three k-core sub-networks of OPgset genes.In summary, we for the first time explored the molecular mechanism underlying OP via network- and pathway-based methods, results from our study will improve our understanding of the pathogenesis of OP. In addition, these methods performed in this study can be used to explore pathogenesis and genes related to a specific disease.


Assuntos
Osso e Ossos/patologia , Fraturas Ósseas/etiologia , Osteoporose/genética , Adipocinas/genética , Densidade Óssea/genética , Osso e Ossos/metabolismo , Osso e Ossos/ultraestrutura , Diferenciação Celular/genética , Biologia Computacional/métodos , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Humanos , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Osteogênese/genética , Osteoporose/complicações , Osteoporose/epidemiologia , Prevalência , Via de Sinalização Wnt/genética
13.
Biochem Biophys Res Commun ; 524(4): 890-894, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32057362

RESUMO

Osteoporosis is a disease of low bone mass that places individuals at enhanced risk for fracture, disability, and death. Osteoporosis rates are expected to rise significantly in the coming decades yet there are limited pharmacological treatment options, particularly for long-term management of this chronic condition. The drug development pipeline is relatively bereft of new strategies, causing an urgent and unmet need for developing new strategies and targets for treating osteoporosis. Here, we examine a lesser-studied bone remodeling pathway, Neuromedin U (NMU), which is expressed in the bone microenvironment along with its cognate receptors NMU receptor 1 (NMUR1) and 2 (NMUR2). We independently corroborate a prior report that global loss of NMU expression leads to high bone mass and test the hypothesis that NMU negatively regulates osteoblast differentiation. Consistent with this, in vitro studies reveal NMU represses osteoblastic differentiation of osteogenic precursors but, in contrast, promotes osteoblastic marker expression, proliferation and activity of osteoblast-like cells. Phospho-profiling arrays were used to detail differential signaling outcomes that may underlie the opposite responses of these cell types. Collectively, our findings indicate that NMU exerts cell-type-specific responses to regulate osteoblast differentiation and activity.


Assuntos
Neuropeptídeos/genética , Osteoblastos/metabolismo , Osteoporose/genética , Fosfoproteínas/genética , Receptores Acoplados a Proteínas-G/genética , Receptores de Neuropeptídeos/genética , Receptores de Neurotransmissores/genética , Animais , Densidade Óssea , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Diferenciação Celular , Linhagem Celular , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Neuropeptídeos/metabolismo , Osteoblastos/patologia , Osteogênese/genética , Osteoporose/metabolismo , Osteoporose/patologia , Fosfoproteínas/classificação , Fosfoproteínas/metabolismo , Fosforilação , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Receptores de Neurotransmissores/metabolismo , Transdução de Sinais
14.
Biochem Biophys Res Commun ; 524(4): 883-889, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32057365

RESUMO

Disuse osteoporosis (DOP) is a common complication resulting from the lack of or disuse of mechanical loading and has been unsatisfactorily treated. We hypothesized that exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSCs) could reduce bone marrow mesenchymal stem cell (BMSC) apoptosis in rat DOP via the miR-1263/Mob1/Hippo signaling pathway. To evaluate the function of exosomes derived from HUCMSCs (HUCMSC-Exos) in DOP, hind limb unloading (HLU)-induced DOP rat models were prepared. In vitro, the proliferation of BMSCs were evaluated using CCK-8 assays. Further, the apoptosis of BMSCs were evaluated using annexin V-FITC assay and Western blots. In vivo, the protective effects of HUCMSC-Exos were evaluated using HE staining and microCT analysis. The underlying molecular mechanism of exosome action on BMSC apoptosis through the miR-1263/Mob1/Hippo pathway was also investigated by high-throughput RNA sequencing, luciferase reporter assays, RNA-pull down assays and Western blots. The RNA-seq and q-PCR results showed that the level of miR-1263 was most abundant among differentially expressed microRNAs. Exosomal miR-1263 could bind to the 3'untranslated region (3' UTR) of Mob1 and exert its function by directly targeting Mob1 in recipient cells. The inhibition of Mob1 could activate YAP expression. Hippo inhibition reversed the in vitro HLU-induced apoptotic effect on BMSCs. The microCT and HE staining results indicated that HUCMSC-Exos ameliorated DOP in vivo. Exosomes derived from HUCMSCs are effective at inhibiting BMSC apoptosis and preventing rat DOP. This mechanism is mediated by the miR-1263/Mob1/Hippo signaling pathway.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Exossomos/transplante , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Osteoporose/prevenção & controle , Proteínas Serina-Treonina Quinases/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proliferação de Células , Exossomos/genética , Exossomos/metabolismo , Regulação da Expressão Gênica , Elevação dos Membros Posteriores/efeitos adversos , Elevação dos Membros Posteriores/métodos , Humanos , Células-Tronco Mesenquimais/citologia , MicroRNAs/metabolismo , Osteoporose/etiologia , Osteoporose/genética , Osteoporose/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Cordão Umbilical/citologia , Cordão Umbilical/metabolismo
15.
Genet Sel Evol ; 52(1): 13, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093603

RESUMO

BACKGROUND: Skeletal damage is a challenge for laying hens because the physiological adaptations required for egg laying make them susceptible to osteoporosis. Previously, we showed that genetic factors explain 40% of the variation in end of lay bone quality and we detected a quantitative trait locus (QTL) of large effect on chicken chromosome 1. The aim of this study was to combine data from the commercial founder White Leghorn population and the F2 mapping population to fine-map this QTL and understand its function in terms of gene expression and physiology. RESULTS: Several single nucleotide polymorphisms on chromosome 1 between 104 and 110 Mb (galGal6) had highly significant associations with tibial breaking strength. The alternative genotypes of markers of large effect that flanked the region had tibial breaking strengths of 200.4 vs. 218.1 Newton (P < 0.002) and, in a subsequent founder generation, the higher breaking strength genotype was again associated with higher breaking strength. In a subsequent generation, cortical bone density and volume were increased in individuals with the better bone genotype but with significantly reduced medullary bone quality. The effects on cortical bone density were confirmed in a further generation and was accompanied by increased mineral maturity of the cortical bone as measured by infrared spectrometry and there was evidence of better collagen cross-linking in the cortical bone. Comparing the transcriptome of the tibia from individuals with good or poor bone quality genotypes indicated four differentially-expressed genes at the locus, one gene, cystathionine beta synthase (CBS), having a nine-fold higher expression in the genotype for low bone quality. The mechanism was cis-acting and although there was an amino-acid difference in the CBS protein between the genotypes, there was no difference in the activity of the enzyme. Plasma homocysteine concentration, the substrate of CBS, was higher in the poor bone quality genotype. CONCLUSIONS: Validated markers that predict bone strength have been defined for selective breeding and a gene was identified that may suggest alternative ways to improve bone health in addition to genetic selection. The identification of how genetic variants affect different aspects of bone turnover shows potential for translational medicine.


Assuntos
Galinhas/genética , Osteoporose/veterinária , Doenças das Aves Domésticas/genética , Locos de Características Quantitativas , Animais , Densidade Óssea , Osso e Ossos/fisiopatologia , Galinhas/fisiologia , Cromossomos/genética , Feminino , Genótipo , Osteoporose/genética , Osteoporose/fisiopatologia , Oviposição , Polimorfismo de Nucleotídeo Único , Doenças das Aves Domésticas/fisiopatologia
16.
Nat Commun ; 11(1): 282, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941964

RESUMO

Wolff's law and the Utah Paradigm of skeletal physiology state that bone architecture adapts to mechanical loads. These models predict the existence of a mechanostat that links strain induced by mechanical forces to skeletal remodeling. However, how the mechanostat influences bone remodeling remains elusive. Here, we find that Piezo1 deficiency in osteoblastic cells leads to loss of bone mass and spontaneous fractures with increased bone resorption. Furthermore, Piezo1-deficient mice are resistant to further bone loss and bone resorption induced by hind limb unloading, demonstrating that PIEZO1 can affect osteoblast-osteoclast crosstalk in response to mechanical forces. At the mechanistic level, in response to mechanical loads, PIEZO1 in osteoblastic cells controls the YAP-dependent expression of type II and IX collagens. In turn, these collagen isoforms regulate osteoclast differentiation. Taken together, our data identify PIEZO1 as the major skeletal mechanosensor that tunes bone homeostasis.


Assuntos
Reabsorção Óssea/patologia , Canais Iônicos/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Animais , Reabsorção Óssea/genética , Diferenciação Celular , Colágeno Tipo II/metabolismo , Colágeno Tipo IX/metabolismo , Feminino , Fraturas Ósseas/genética , Fraturas Ósseas/patologia , Elevação dos Membros Posteriores , Homeostase , Canais Iônicos/genética , Masculino , Camundongos Knockout , Osteoclastos/citologia , Osteoporose/genética , Estresse Mecânico
17.
J Biomed Sci ; 27(1): 10, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900164

RESUMO

Siglec-15 is a member of the Siglec family of glycan-recognition proteins, primarily expressed on a subset of myeloid cells. Siglec-15 has been known to be involved in osteoclast differentiation, and is considered to be a potential therapeutic target for osteoporosis. Recent studies revealed unexpected roles of Siglec-15 in microbial infection and the cancer microenvironment, expanding the potential pathophysiological roles of Siglec-15. Chemical biology has advanced our understanding of the nature of Siglec-15 ligands, but the exact nature of Siglec-15 ligand depends on the biological context, leaving plenty of room for further exploration.


Assuntos
Doenças Transmissíveis/genética , Imunoglobulinas/genética , Proteínas de Membrana/genética , Neoplasias/genética , Osteoporose/genética , Doenças Transmissíveis/patologia , Doenças Transmissíveis/terapia , Regulação da Expressão Gênica/genética , Humanos , Ligantes , Neoplasias/patologia , Neoplasias/terapia , Osteoclastos/metabolismo , Osteoporose/patologia , Osteoporose/terapia , Microambiente Tumoral/genética
18.
Immunol Med ; 43(2): 61-64, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31999934

RESUMO

The adaptor protein 3BP2 (SH3-domain binding protein 2), which is encoded by the SH3BP2 locus, nucleates a signaling complex comprising ABL, SRC, VAV, and SYK, and facilitates an open active configuration of these proteins, leading to their kinase activation. Gain-of-function missense mutations in the SH3BP2 gene cause cherubism, an autosomal dominant disorder associated with severe craniofacial developmental defects in children. Previous studies have demonstrated that 3BP2 and its degradation pathway regulate bone metabolism, energy metabolism, and inflammation and that dysregulation of the 3BP2 degradation pathway is associated with human disorders. Herein, we discussed lessons from cherubism indicating that 3BP2 studies could elucidate the pathogenesis of bone loss caused by inflammation and identify suitable therapeutic targets.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Osso e Ossos/metabolismo , Proteínas de Ligação a RNA/genética , Doenças Raras , Querubismo/genética , Metabolismo Energético/genética , Humanos , Inflamação/genética , Osteoblastos , Osteoporose/genética , Proteólise , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
19.
Exp Mol Pathol ; 113: 104366, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31891679

RESUMO

The increasing level of osteogenic (OS) differentiation of bone marrow derived mesenchymal stem cells (MSCs) could be potentially used to relieve the signs and symptoms associated with osteoporosis (OP). Inhibition of osteoprotegerin (OPG)/Receptor Activator of Nuclear factor-Kappa B Ligand (RANKL) pathway plays an important role in OS differentiation, leading to excessive osteoclasts and reduction of osteoblasts, and finally causing OP. Recent studies revealed that microRNAs exert an essential role in regulating OS differentiation. Here, we investigated the dysregulation of miR-212 and miR-384 and the mechanism by which they are involved in OS differentiation-induced MSCs. Quantitative real-time PCR revealed that miR-212 and miR-384 were significantly upregulated in an OP animal model, but markedly downregulated in OS differentiation-induced MSCs. Interference of miR-212 and miR-384 promoted OS differentiation and alleviated OP by targeting RUNX2 in vitro and in vivo. Notably, the inhibition of miR-212 and miR-384 promoted OS differentiation via upregulating RUNX2, and activating OPG/RANKL pathway. Together, our findings demonstrated that interference of miR-212 and miR-384 alleviated OP via RUNX2/OPG/RANKL pathway, providing a novel target of treating OP.


Assuntos
Diferenciação Celular/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , MicroRNAs/genética , Osteogênese/genética , Osteoporose/genética , Animais , Sequência de Bases , Modelos Animais de Doenças , Regulação para Baixo/genética , Feminino , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , MicroRNAs/sangue , MicroRNAs/metabolismo , Osteoporose/sangue , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Regulação para Cima/genética
20.
J Microbiol Biotechnol ; 30(3): 448-458, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-31752063

RESUMO

We investigated the therapeutic effects of microRNA-139-5p in relation to osteoporosis of bone marrow-derived mesenchymal stem cell (BMSCs) and its underlying mechanisms. In this study we used a dexamethasone-induced in vivo model of osteoporosis and BMSCs were used for the in vitro model. Real-time quantitative polymerase chain reaction (RT-PCR) and gene chip were used to analyze the expression of microRNA-139-5p. In an osteoporosis rat model, the expression of microRNA-139-5p was increased, compared with normal group. Downregulation of microRNA-139-5p promotes cell proliferation and osteogenic differentiation in BMSCs. Especially, up-regulation of microRNA-139-5p reduced cell proliferation and osteogenic differentiation in BMSCs. Overexpression of miR-139-5p induced Wnt/ß-catenin and down-regulated NOTCH1 signaling in BMSCs. Down-regulation of miR-139-5p suppressed Wnt/ß-catenin and induced NOTCH1 signaling in BMSCs. The inhibition of NOTCH1 reduced the effects of anti-miR-139-5p on cell proliferation and osteogenic differentiation in BMSCs. Activation of Wnt/ß-catenin also inhibited the effects of anti-miR-139-5p on cell proliferation and osteogenic differentiation in BMSCs. Taken together, our results suggested that the inhibition of microRNA-139-5p promotes osteogenic differentiation of BMSCs via targeting Wnt/ß-catenin signaling pathway by NOTCH1.


Assuntos
Medula Óssea/metabolismo , MicroRNAs/genética , Osteoporose/metabolismo , Receptor Notch1/metabolismo , Via de Sinalização Wnt , Animais , Medula Óssea/patologia , Células Cultivadas , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteogênese , Osteoporose/genética , Osteoporose/patologia , beta Catenina/metabolismo
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