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1.
Nat Rev Endocrinol ; 16(3): 147-164, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31974498

RESUMO

The development of the craniofacial skeleton relies on complex temporospatial organization of diverse cell types by key signalling molecules. Even minor disruptions to these processes can result in deleterious consequences for the structure and function of the skull. Thyroid hormone deficiency causes delayed craniofacial and tooth development, dysplastic facial features and delayed development of the ossicles in the middle ear. Thyroid hormone excess, by contrast, accelerates development of the skull and, in severe cases, might lead to craniosynostosis with neurological sequelae and facial hypoplasia. The pathogenesis of these important abnormalities remains poorly understood and underinvestigated. The orchestration of craniofacial development and regulation of suture and synchondrosis growth is dependent on several critical signalling pathways. The underlying mechanisms by which these key pathways regulate craniofacial growth and maturation are largely unclear, but studies of single-gene disorders resulting in craniofacial malformations have identified a number of critical signalling molecules and receptors. The craniofacial consequences resulting from gain-of-function and loss-of-function mutations affecting insulin-like growth factor 1, fibroblast growth factor receptor and WNT signalling are similar to the effects of altered thyroid status and mutations affecting thyroid hormone action, suggesting that these critical pathways interact in the regulation of craniofacial development.


Assuntos
Anormalidades Craniofaciais/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Craniossinostoses/metabolismo , Humanos , Transdução de Sinais/fisiologia , Crânio/metabolismo
2.
ACS Appl Mater Interfaces ; 11(37): 33548-33558, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31436082

RESUMO

Tissue oxygenation is one of the key determining factors in bone repair and bone tissue engineering. Adequate tissue oxygenation is essential for survival and differentiation of the bone-forming cells and ultimately the success of bone tissue regeneration. Two-photon phosphorescence lifetime microscopy (2PLM) has been successfully applied in the past to image oxygen distributions in tissue with high spatial resolution. However, delivery of phosphorescent probes into avascular compartments, such as those formed during early bone defect healing, poses significant problems. Here, we report a multifunctional oxygen-reporting fibrous matrix fabricated through encapsulation of a hydrophilic oxygen-sensitive, two-photon excitable phosphorescent probe, PtP-C343, in the core of fibers during coaxial electrospinning. The oxygen-sensitive fibers support bone marrow stromal cell growth and differentiation and at the same time enable real-time high-resolution probing of partial pressures of oxygen via 2PLM. The hydrophilicity of the probe facilitates its gradual release into the nearby microenvironment, allowing fibers to act as a vehicle for probe delivery into the healing tissue. In conjunction with a cranial defect window chamber model, which permits simultaneous imaging of the bone and neovasculature in vivo via two-photon laser scanning microscopy, the oxygen-reporting fibers provide a useful tool for minimally invasive, high-resolution, real-time 3D mapping of tissue oxygenation during bone defect healing, facilitating studies aimed at understanding the healing process and advancing design of tissue-engineered constructs for enhanced bone repair and regeneration.


Assuntos
Regeneração Óssea , Oximetria , Oxigênio/metabolismo , Crânio , Animais , Camundongos , Camundongos Transgênicos , Oximetria/instrumentação , Oximetria/métodos , Crânio/diagnóstico por imagem , Crânio/lesões , Crânio/metabolismo , Crânio/patologia
3.
PLoS One ; 14(7): e0218899, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291291

RESUMO

Genetic incompatibilities constitute the final stages of reproductive isolation and speciation, but little is known about incompatibilities that occur within recent adaptive radiations among closely related diverging populations. Crossing divergent species to form hybrids can break up coadapted variation, resulting in genetic incompatibilities within developmental networks shaping divergent adaptive traits. We crossed two closely related sympatric Cyprinodon pupfish species-a dietary generalist and a specialized molluscivore-and measured expression levels in their F1 hybrids to identify regulatory variation underlying the novel craniofacial morphology found in this recent microendemic adaptive radiation. We extracted mRNA from eight day old whole-larvae tissue and from craniofacial tissues dissected from 17-20 day old larvae to compare gene expression between a total of seven F1 hybrids and 24 individuals from parental species populations. We found 3.9% of genes differentially expressed between generalists and molluscivores in whole-larvae tissues and 0.6% of genes differentially expressed in craniofacial tissue. We found that 2.1% of genes were misregulated in whole-larvae hybrids whereas 19.1% of genes were misregulated in hybrid craniofacial tissues, after correcting for sequencing biases. We also measured allele specific expression across 15,429 heterozygous sites to identify putative compensatory regulatory mechanisms underlying differential expression between generalists and molluscivores. Together, our results highlight the importance of considering misregulation as an early indicator of genetic incompatibilities in the context of rapidly diverging adaptive radiations and suggests that compensatory regulatory divergence drives hybrid gene misregulation in developing tissues that give rise to novel craniofacial traits.


Assuntos
Quimera , Especiação Genética , Genética Populacional , Peixes Listrados/genética , Larva/genética , Animais , Cruzamentos Genéticos , Comportamento Alimentar , Feminino , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Fluxo Gênico , Heterozigoto , Peixes Listrados/anatomia & histologia , Peixes Listrados/classificação , Peixes Listrados/crescimento & desenvolvimento , Larva/anatomia & histologia , Larva/crescimento & desenvolvimento , Masculino , Fenótipo , Isolamento Reprodutivo , Crânio/anatomia & histologia , Crânio/crescimento & desenvolvimento , Crânio/metabolismo , Simpatria
4.
Biomed Res Int ; 2019: 9051713, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061829

RESUMO

Objective: In this study, we evaluated changes in bone remodeling in an irradiated rat calvarial defect model according to duration of hyperbaric oxygen therapy. Materials and Methods: The 28 rats were divided into four groups. Radiation of 12 Gy was applied to the skull, and 5-mm critical size defects were formed on both sides of the skull. Bone grafts were applied to one side of formed defects. From the day after surgery, HBO was applied for 0, 1, and 3 weeks. At 6 weeks after bone graft, experimental sites were removed and analyzed for radiography, histology, and histomorphometry. Results: Micro-CT analysis showed a significant increase in new bone volume in the HBO-3 group, with or without bone graft. When bone grafting was performed, BV, BS, and BS/TV all significantly increased. Histomorphometric analysis showed significant increases in %NBA and %BVN in the HBO-1 and HBO-3 groups, regardless of bone graft. Conclusion: Hyperbaric oxygen therapy was effective for bone regeneration with only 1 week of treatment.


Assuntos
Regeneração Óssea/efeitos da radiação , Oxigenação Hiperbárica , Lesões Experimentais por Radiação , Crânio , Raios X/efeitos adversos , Animais , Masculino , Lesões Experimentais por Radiação/diagnóstico por imagem , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/terapia , Ratos , Ratos Sprague-Dawley , Crânio/diagnóstico por imagem , Crânio/lesões , Crânio/metabolismo , Crânio/patologia , Microtomografia por Raio-X
5.
Hum Genet ; 138(6): 601-611, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968251

RESUMO

Facial shape differences are one of the most significant phenotypes in humans. It is affected largely by skull shape. However, research into the genetic basis of the craniofacial morphology has rarely been reported. The present study aimed to identify genetic variants influencing craniofacial morphology in northern Han Chinese through whole-exome sequencing (WES). Phenotypic data of the volunteers' faces and skulls were obtained through three-dimensional CT scan of the skull. A total of 48 phenotypes (35 facial and 13 cranial phenotypes) were used for the bioinformatics analysis. Four genetic loci were identified affecting the craniofacial shapes. The four candidate genes are RGPD3, IGSF3, SLC28A3, and USP40. Four single-nucleotide polymorphism (SNP) site mutations in RGPD3, IGSF3, and USP40 were significantly associated with the skull shape (p < 1×10-6), and three SNP site mutations in RGPD3, IGSF3, and SLC28A3 were significantly associated with the facial shape (p < 1×10-6). The rs62152530 site mutation in the RGPD3 gene may be closely associated with the nasal length, ear length, and alar width. The rs647711 site mutation in the IGSF3 gene may be closely associated with the nasal length, mandibular width, and width between the mental foramina. The rs10868138 site mutation in the SLC28A3 gene may be associated with the nasal length, alar width, width between tragus, and width between the mental foramina. The rs1048603 and rs838543 site mutations in the USP40 gene may be closely associated with the pyriform aperture width. Our findings provide useful genetic information for the determination of face morphology.


Assuntos
Ossos Faciais/metabolismo , Loci Gênicos/genética , Polimorfismo de Nucleotídeo Único , Crânio/metabolismo , Sequenciamento Completo do Exoma/métodos , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , China , Anormalidades Craniofaciais/etnologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Ossos Faciais/anatomia & histologia , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Crânio/anatomia & histologia
6.
Endocrinology ; 160(5): 1348-1358, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30916761

RESUMO

Fibroblast growth factor 23 (FGF23) secretion is facilitated by the PTH, particularly in hyperparathyroidism. The PTH also attenuates dentin matrix protein 1 (DMP1), which is produced by osteocytes to contribute to bone mineralization and suppress FGF23 expression. Nevertheless, it remains unknown whether attenuated DMP1 affects FGF23 expression in hyperparathyroidism. We examined their expression in bone tissue using a mouse model of primary hyperparathyroidism (PHPT). PHPT mice increased serum FGF23 levels, along with a high level of serum PTH. Fgf23 expression increased, and Dmp1 decreased significantly in the calvaria of PHPT mice compared with wild-type mice and primary osteoblasts treated with PTH. In UMR106 mature osteoblasts, PTH increased Fgf23 expression and decreased Dmp1 expression, and stimulation of protein kinase A (PKA) signaling by forskolin also increased Fgf23 expression and decreased Dmp1 expression in a dose-dependent manner, whereas inhibition of PKA signaling with 10-5 M H89 reversed the changes in Fgf23 and Dmp1 expression when cells were stimulated with PTH. Silencing Dmp1 along with PTH treatment led to an additive increase in Fgf23 expression, accompanied by additive phosphorylation of the cAMP-response element-binding protein. These results indicate that persistent and high levels of PTH lead to the continuous activation of PKA signaling in osteoblasts/osteocytes, resulting in an increase in FGF23 and a decrease in DMP1 in bone. Moreover, suppression of DMP1 enhanced FGF23 expression in PHPT, besides having a direct effect on PTH. These mechanisms may describe one of the pathogeneses behind the increase in FGF23 transcription in bone tissue in patients with PHPT.


Assuntos
Modelos Animais de Doenças , Proteínas da Matriz Extracelular/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hiperparatireoidismo Primário/metabolismo , Crânio/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Proteínas da Matriz Extracelular/genética , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Hiperparatireoidismo Primário/genética , Camundongos Endogâmicos C57BL , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/farmacologia , Interferência de RNA , Ratos
8.
Macromol Biosci ; 19(5): e1800460, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30821921

RESUMO

Bone is a vascularized tissue that is comprised of collagen fibers and calcium phosphate crystals such as hydroxyapatite (HAp) and whitlockite (WH). HAp and WH are known to elicit bone regeneration by stimulating osteoblast activities and osteogenic commitment of stem cells. In addition, vascular endothelial growth factor (VEGF) is shown to promote osteogenesis and angiogenesis which is considered as an essential process in bone repair by providing nutrients. In this study, VEGF-secreting human adipose-derived stem cells (VEGF-ADSCs) are developed by transducing ADSCs with VEGF-encoded lentivirus. Additionally, WH-reinforced gelatin/heparin cryogels (WH-C) are fabricated by loading WH into gelatin/heparin cryogels. VEGF-ADSC secrete tenfold more VEGF than ADSC and show increased VEGF secretion with cell growth. Also, incorporation of WH into cryogels provides a mineralized environment with ions secreted from WH. When the VEGF-ADSCs are seeded on WH-C, sustained release of VEGF is observed due to the specific affinity of VEGF to heparin. Finally, the synergistic effect of VEGF-ADSC and WH on osteogenesis is successfully confirmed by alkaline phosphatase and real-time polymerase chain reaction analysis. In vivo bone formation is demonstrated via implantation of VEGF-ADSC seeded WH-C into mouse calvarial bone defect model, resulted in enhanced bone development with the highest bone volume/total volume.


Assuntos
Tecido Adiposo/metabolismo , Regeneração Óssea , Células Imobilizadas/transplante , Criogéis/química , Crânio , Transplante de Células-Tronco , Células-Tronco/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Tecido Adiposo/patologia , Animais , Células Imobilizadas/metabolismo , Células Imobilizadas/patologia , Feminino , Células HEK293 , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Crânio/lesões , Crânio/metabolismo , Crânio/patologia , Células-Tronco/patologia
9.
Genesis ; 57(5): e23288, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30801905

RESUMO

The meninges are membranous layers surrounding the central nervous system. In the head, the meninges lie between the brain and the skull, and interact closely with both during development. The cranial meninges originate from a mesenchymal sheath on the surface of the developing brain, called primary meninx, and undergo differentiation into three layers with distinct histological characteristics: the dura mater, the arachnoid mater, and the pia mater. While genetic regulation of meningeal development is still poorly understood, mouse mutants and other models with meningeal defects have demonstrated the importance of the meninges to normal development of the calvaria and the brain. For the calvaria, the interactions with the meninges are necessary for the progression of calvarial osteogenesis during early development. In later stages, the meninges control the patterning of the skull and the fate of the sutures. For the brain, the meninges regulate diverse processes including cell survival, cell migration, generation of neurons from progenitors, and vascularization. Also, the meninges serve as a stem cell niche for the brain in the postnatal life. Given these important roles of the meninges, further investigation into the molecular mechanisms underlying meningeal development can provide novel insights into the coordinated development of the head.


Assuntos
Meninges/embriologia , Meninges/metabolismo , Meninges/fisiologia , Animais , Aracnoide-Máter/embriologia , Aracnoide-Máter/metabolismo , Encéfalo/embriologia , Encéfalo/metabolismo , Diferenciação Celular , Biologia do Desenvolvimento/métodos , Dura-Máter/embriologia , Dura-Máter/metabolismo , Humanos , Pia-Máter/embriologia , Pia-Máter/metabolismo , Crânio/embriologia , Crânio/metabolismo
10.
J Oral Sci ; 61(1): 25-29, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30713263

RESUMO

High-magnitude mechanical strain inhibits bone nodule formation by reducing expression of bone morphogenetic protein-2 (BMP-2), Runt-related transcription factor 2 (Runx2), and muscle segment homeobox 2 (Msx2). Mechanical strain also induces production of proinflammatory factor prostaglandin E2 (PGE2) by osteoblasts. We measured the effect of mechanical strain-induced PGE2 production on bone nodule formation and expression levels of bone formation-related factors. Osteoblast-like cells isolated from fetal rat calvariae were loaded with 18% cyclic tension force (TF) for 48 h in the presence or absence of NS-398, a selective inhibitor of cyclooxygenase-2. To investigate the effect of TF-induced PGE2 on bone formation, bone nodule area on day 21 was measured by von Kossa staining. BMP-2, Runx2, and Msx2 expression levels were examined at 1 day after TF loading. Bone nodule formation was significantly inhibited by TF but was restored to control level by PGE2 inhibition. Furthermore, TF loading-induced reductions in expressions of these factors were restored to control level by PGE2 suppression. These results indicate that PGE2 production induced by high-magnitude mechanical strain inhibits bone nodule formation by reducing expression levels of bone formation-related factors.


Assuntos
Osso e Ossos/patologia , Dinoprostona/biossíntese , Crânio/metabolismo , Células-Tronco/metabolismo , Estresse Mecânico , Animais , Proteína Morfogenética Óssea 2/metabolismo , Osso e Ossos/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Proteínas de Homeodomínio/metabolismo , Nitrobenzenos/farmacologia , Ratos , Crânio/citologia , Sulfonamidas/farmacologia
11.
Int J Biol Sci ; 15(2): 298-311, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30745822

RESUMO

Craniosynostosis, is the premature fusion of one or more cranial sutures which is the second most common cranial facial anomalies. The premature cranial sutures leads to deformity of skull shape and restricts the growth of brain, which might elicit severe neurologic damage. Craniosynostosis exhibit close correlations with a varieties of syndromes. During the past two decades, as the appliance of high throughput DNA sequencing techniques, steady progresses has been made in identifying gene mutations in both syndromic and nonsyndromic cases, which allow researchers to better understanding the genetic roles in the development of cranial vault. As the enrichment of known mutations involved in the pathogenic of premature sutures fusion, multiple signaling pathways have been investigated to dissect the underlying mechanisms beneath the disease. In addition to genetic etiology, environment factors, especially mechanics, have also been proposed to have vital roles during the pathophysiological of craniosynostosis. However, the influence of mechanics factors in the cranial development remains largely unknown. In this review, we present a brief overview of the updated genetic mutations and environmental factors identified in both syndromic and nonsyndromic craniosynostosis. Furthermore, potential molecular signaling pathways and its relations have been described.


Assuntos
Craniossinostoses/genética , Craniossinostoses/fisiopatologia , Humanos , Mutação/genética , Transdução de Sinais/genética , Crânio/metabolismo
12.
Clin Nucl Med ; 44(4): e315-e317, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30762822

RESUMO

A 63-year-old woman was referred to our PET/MRI platform to evaluate the possible relapse of a meningeal metastasis, complicating an invasive ductal carcinoma of the left breast. This metastasis was diagnosed on a left hemiparesis and treated by surgery and radiation therapy. One year later, the same symptoms led to another brain MRI examination that found a contrast-enhanced lesion in the operating site. We decided to perform a F-DOPA PET/MRI to document this lesion, which confirmed the diagnosis of a probable relapse and revealed a focal uptake on the bone flap.


Assuntos
Di-Hidroxifenilalanina , Radioisótopos de Flúor , Imagem por Ressonância Magnética , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/secundário , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva , Crânio/diagnóstico por imagem , Crânio/metabolismo
13.
Mol Cells ; 42(2): 183-188, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30703868

RESUMO

Osteoarthritis (OA) is a naturally occurring, irreversible disorder and a major health burden. The disease is multifactorial, involving both physiological and mechanical processes, but calcium crystals have been associated intimately with its pathogenesis. This study tested the hypothesis that these crystals have a detrimental effect on the differentiation of osteoclasts and bone homeostasis. This study employed an osteoblast-osteoclast coculture system that resembles in vivo osteoblast-dependent osteoclast differentiation along with Ca2+-phosphate-coated culture dishes. The calcium-containing crystals upregulated the expression of RANKL and increased the differentiation of osteoclasts significantly as a result. On the other hand, osteoblast differentiation was unaffected. MicroRNA profiling showed that dual-specificity phosphatases 1 (DUSP1) was associated with the increased RANKL expression. DUSP1 belongs to a family of MAPK phosphatases and is known to inactivate all three groups of MAPKs, p38, JNK, and ERK. Furthermore, knockdown of DUSP1 gene expression suggested that RANKL expression increases significantly in the absence of DUSP1 regulation. Microarray analysis of the DUSP1 mRNA levels in patients with pathological bone diseases also showed that the downregulated DUSP1 expression leads to increased expression of RANKL and consequently to the destruction of the bone observed in these patients. These findings suggest that calcium-containing crystals may play a crucial role in promoting RANKL-induced osteoclastogenesis via DUSP1.


Assuntos
Fosfatos de Cálcio/química , Fosfatos de Cálcio/farmacologia , Regulação para Baixo/genética , Fosfatase 1 de Especificidade Dupla/genética , Ligante RANK/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Técnicas de Cocultura , Cristalização , Regulação para Baixo/efeitos dos fármacos , Fosfatase 1 de Especificidade Dupla/metabolismo , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Regiões Promotoras Genéticas/genética , Ligante RANK/metabolismo , Crânio/metabolismo , Fosfatase Ácida Resistente a Tartarato/metabolismo
14.
Drug Deliv ; 26(1): 137-146, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30799644

RESUMO

The burst release of active osteogenic factors, which is not beneficial to osteogenesis, is commonly encountered in bone tissue engineering. The aims of this study were to prepare naringin-loaded microsphere/sucrose acetate isobutyrate (Ng-m-SAIB) hybrid depots, reduce the burst release of naringin (Ng), and improve osteogenesis. The morphology and size distributions of electrosprayed Ng-microspheres were characterized by scanning electron microscopy (SEM). The Ng-microspheres and Ng-m-SAIB depots were characterized by Fourier transform infrared spectroscopy (FTIR) and in vitro release studies. In vitro osteoblast-microsphere interactions and in vivo osteogenesis were assessed after implantation of Ng-m-SAIB depots. The addition of sucrose acetate isobutyrate (SAIB) to monodisperse Ng-microspheres did not cause a change in the chemical structure. The performances of the microspheres in osteoblast-microsphere interactions were better when the naringin content was 4% than when it was at 2% and 6%. On the first day following the loading of Ng-microspheres (2%, 4%, and 6%) into SAIB depots, the burst release was reduced dramatically from 70.9% to 6.3%, 73.1% to 7.2%, and 73.9% to 9.9%, respectively. In addition, after 8 weeks, the new bone formation rate in the calvarial defects of SD rats receiving Ng-m-SAIB was 53.1% compared to 21.2% for the control group and 16.1% for the microsphere-SAIB group. These results demonstrated that Ng-m-SAIB hybrid depots may have promise in bone regeneration applications.


Assuntos
Modelos Animais de Doenças , Flavanonas/administração & dosagem , Microesferas , Osteogênese/efeitos dos fármacos , Crânio/efeitos dos fármacos , Sacarose/análogos & derivados , Animais , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Flavanonas/síntese química , Flavanonas/metabolismo , Masculino , Camundongos , Osteogênese/fisiologia , Ratos , Ratos Sprague-Dawley , Crânio/metabolismo , Crânio/patologia , Sacarose/administração & dosagem , Sacarose/síntese química , Sacarose/metabolismo
15.
Nat Commun ; 10(1): 357, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664637

RESUMO

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.


Assuntos
Alelos , Loci Gênicos , Variação Genética , RNA Mensageiro/genética , Crânio/metabolismo , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cefalometria , Criança , Grupo com Ancestrais do Continente Europeu , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Frequência do Gene , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Crânio/anatomia & histologia
16.
Macromol Biosci ; 19(4): e1800392, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30645050

RESUMO

Plant derived flavonoids have not been well explored in tissue engineering applications due to difficulties in efficient formulations with biomaterials for controlled presentation. Here, the authors report that surface coating of epigallocatechin gallate (EGCG) on polymeric substrates including poly (L-lactic acid) (PLLA) nanofibers can be performed via oxidative polymerization of EGCG in the presence of cations, enabling regulation of biological functions of multiple cell types implicated in bone regeneration. EGCG coating on the PLLA nanofiber promotes osteogenic differentiation of adipose-derived stem cells (ADSCs) and is potent to suppress adipogenesis of ADSCs while significantly reduces osteoclastic maturation of murine macrophages. Moreover, EGCG coating serves as a protective layer for ADSCs against oxidative stress caused by hydrogen peroxide. Finally, the in vivo implantation of EGCG-coated nanofibers into a mouse calvarial defect model significantly promotes the bone regeneration (61.52 ± 28.10%) as compared to defect (17.48 ± 11.07%). Collectively, the results suggest that EGCG coating is a simple bioinspired surface modification of polymeric biomaterials and importantly can thus serve as a promising interface for tuning activities of multiple cell types associated with bone fracture healing.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Catequina/análogos & derivados , Materiais Revestidos Biocompatíveis , Nanofibras , Poliésteres , Crânio , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Catequina/química , Catequina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Nanofibras/química , Nanofibras/uso terapêutico , Osteoclastos/metabolismo , Osteoclastos/patologia , Poliésteres/química , Poliésteres/farmacologia , Células RAW 264.7 , Crânio/lesões , Crânio/metabolismo , Crânio/patologia , Células-Tronco/metabolismo , Células-Tronco/patologia
17.
Nat Neurosci ; 22(2): 317-327, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30598527

RESUMO

Analysis of entire transparent rodent bodies after clearing could provide holistic biological information in health and disease, but reliable imaging and quantification of fluorescent protein signals deep inside the tissues has remained a challenge. Here, we developed vDISCO, a pressure-driven, nanobody-based whole-body immunolabeling technology to enhance the signal of fluorescent proteins by up to two orders of magnitude. This allowed us to image and quantify subcellular details through bones, skin and highly autofluorescent tissues of intact transparent mice. For the first time, we visualized whole-body neuronal projections in adult mice. We assessed CNS trauma effects in the whole body and found degeneration of peripheral nerve terminals in the torso. Furthermore, vDISCO revealed short vascular connections between skull marrow and brain meninges, which were filled with immune cells upon stroke. Thus, our new approach enables unbiased comprehensive studies of the interactions between the nervous system and the rest of the body.


Assuntos
Meninges/diagnóstico por imagem , Neurônios/metabolismo , Crânio/diagnóstico por imagem , Imagem Corporal Total/métodos , Animais , Meninges/metabolismo , Camundongos , Camundongos Transgênicos , Crânio/metabolismo
18.
J Biomater Sci Polym Ed ; 30(2): 107-121, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30518309

RESUMO

The aim of this study was to evaluate the thermal properties and in vivo interface performance of poly(amino acid) (PAA) and a composite containing PAA, hydroxyapatite (HA), and calcium sulfate (CS), with respect to their suitability for skull repair. Biocompatibility was evaluated by implantation of materials into muscles of rabbits for eight weeks. Skull repair was assessed by implanting PAA, the compact PAA/HA/CS composite (c-PAA/HA/CS), and a one-side-porous PAA/HA/CS composite (p-PAA/HA/CS) into rabbit calvarial defects. The results showed that the PAA/HA/CS composite possessed good heat resistance and possessed excellent biocompatibility and osteoconductivity. Guided bone regeneration and calvarial repair were observed, with excellent integration between calvarial tissue and implant. The p-PAA/HA/CS composite performed best in terms of stability and bone bonding between implant and host bone tissue. Thus, the present work provides new information for the potential use of osteoconductive PAA/HA/CS composites with a macrostructure in calvarial bone repair.


Assuntos
Aminoácidos/química , Substitutos Ósseos/química , Sulfato de Cálcio/química , Durapatita/química , Polímeros/química , Crânio/metabolismo , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Regeneração Óssea , Substitutos Ósseos/metabolismo , Teste de Materiais , Polimerização , Porosidade , Próteses e Implantes , Coelhos , Crânio/cirurgia
19.
Biomed Pharmacother ; 109: 573-581, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30399593

RESUMO

Accumulating evidence suggests that improvements in osteogenesis and angiogenesis play an important role in repairing osteoporotic bone defects. Cinnamomum cassia (C. cassia), a traditional Chinese medicinal herb, is reported to show anabolic effects on osteoblasts. However, whether C. cassia could actually repair bone defects in osteoporotic conditions remains unknown. The purpose of this study was to evaluate the effect of combined treatment with Cinnamaldehyde (main oil isolated from the C. cassia) and ß-tricalcium phosphate (ß-TCP) on bone formation and angiogenesis in critical size calvarial defects in ovariectomized (OVX) rats. Using a previously established OVX model, 5 mm critical size calvarial defect was established in OVX rats. All OVX rats were then randomly divided into OVX group (OVX rats + empty defect), TCP group (OVX rats + ß-TCP), and CTCP group (Cinnamaldehyde 75 mg/kg/day for 12 weeks + ß-TCP). Twelve weeks after treatment, according to Micro-CT and HE staining, combination of Cinnamaldehyde and ß-TCP had an additive effect on bone regeneration compared with other groups (p < 0.05). Based on dynamic fluorochrome-labelling analysis, Cinnamaldehyde+ß-TCP continuously promoted new bone mineralization compared with other groups at each time point (p < 0.05). Microfil perfusion suggested that CTCP group showed more neovascularization compared with other groups (p < 0.05). Immunohistochemical assay supported the findings that Cinnamaldehyde+ß-TCP enhanced expression of OCN, VEGF and CD31. The present study demonstrated that combined treatment with Cinnamaldehyde and ß-TCP promoted bone formation and angiogenesis in osteoporotic bone defects, which provides a promising new strategy for repairing bone defects in osteoporotic conditions.


Assuntos
Acroleína/análogos & derivados , Indutores da Angiogênese/administração & dosagem , Fosfatos de Cálcio/administração & dosagem , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Ovariectomia/efeitos adversos , Acroleína/administração & dosagem , Animais , Materiais Biocompatíveis/administração & dosagem , Quimioterapia Combinada , Feminino , Osteogênese/fisiologia , Osteoporose/diagnóstico por imagem , Osteoporose/metabolismo , Ovariectomia/tendências , Ratos , Ratos Sprague-Dawley , Crânio/diagnóstico por imagem , Crânio/efeitos dos fármacos , Crânio/metabolismo
20.
Genesis ; 57(1): e23249, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30207415

RESUMO

Variation in development mediates phenotypic differences observed in evolution and disease. Although the mechanisms underlying phenotypic variation are still largely unknown, recent research suggests that variation in developmental processes may play a key role. Developmental processes mediate genotype-phenotype relationships and consequently play an important role regulating phenotypes. In this review, we provide an example of how shared and interacting developmental processes may explain convergence of phenotypes in spliceosomopathies and ribosomopathies. These data also suggest a shared pathway to disease treatment. We then discuss three major mechanisms that contribute to variation in developmental processes: genetic background (gene-gene interactions), gene-environment interactions, and developmental stochasticity. Finally, we comment on evolutionary alterations to developmental processes, and the evolution of disease buffering mechanisms.


Assuntos
Desenvolvimento Ósseo/genética , Disostose Craniofacial/genética , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento , Animais , Disostose Craniofacial/metabolismo , Humanos , Processamento de RNA , Ribossomos/genética , Crânio/embriologia , Crânio/metabolismo
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