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1.
Pediatrics ; 146(3)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32868470

RESUMO

Pediatric care providers, pediatricians, pediatric subspecialty physicians, and other health care providers should be able to recognize children with abnormal head shapes that occur as a result of both synostotic and deformational processes. The purpose of this clinical report is to review the characteristic head shape changes, as well as secondary craniofacial characteristics, that occur in the setting of the various primary craniosynostoses and deformations. As an introduction, the physiology and genetics of skull growth as well as the pathophysiology underlying craniosynostosis are reviewed. This is followed by a description of each type of primary craniosynostosis (metopic, unicoronal, bicoronal, sagittal, lambdoid, and frontosphenoidal) and their resultant head shape changes, with an emphasis on differentiating conditions that require surgical correction from those (bathrocephaly, deformational plagiocephaly/brachycephaly, and neonatal intensive care unit-associated skill deformation, known as NICUcephaly) that do not. The report ends with a brief discussion of microcephaly as it relates to craniosynostosis as well as fontanelle closure. The intent is to improve pediatric care providers' recognition and timely referral for craniosynostosis and their differentiation of synostotic from deformational and other nonoperative head shape changes.


Assuntos
Craniossinostoses/diagnóstico , Acrocefalossindactilia/genética , Fenótipo de Síndrome de Antley-Bixler/genética , Suturas Cranianas/anatomia & histologia , Disostose Craniofacial , Craniossinostoses/classificação , Craniossinostoses/etiologia , Craniossinostoses/cirurgia , Cabeça/anormalidades , Humanos , Lactente , Hipertensão Intracraniana/etiologia , Ilustração Médica , Microcefalia/etiologia , Osteogênese/fisiologia , Fenótipo , Fotografação , Polidactilia/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Procedimentos Cirúrgicos Reconstrutivos , Crânio/anatomia & histologia , Crânio/diagnóstico por imagem , Crânio/crescimento & desenvolvimento , Sinostose/complicações , Sinostose/diagnóstico por imagem
2.
Nat Commun ; 11(1): 4278, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855388

RESUMO

Activation and migration of endogenous mesenchymal stromal cells (MSCs) are critical for bone regeneration. Here, we report a combinational peptide screening strategy for rapid discovery of ligands that not only bind strongly to osteogenic progenitor cells (OPCs) but also stimulate osteogenic cell Akt signaling in those OPCs. Two lead compounds are discovered, YLL3 and YLL8, both of which increase osteoprogenitor osteogenic differentiation in vitro. When given to normal or osteopenic mice, the compounds increase mineral apposition rate, bone formation, bone mass, and bone strength, as well as expedite fracture repair through stimulated endogenous osteogenesis. When covalently conjugated to alendronate, YLLs acquire an additional function resulting in a "tri-functional" compound that: (i) binds to OPCs, (ii) targets bone, and (iii) induces "pro-survival" signal. These bone-targeted, osteogenic peptides are well suited for current tissue-specific therapeutic paradigms to augment the endogenous osteogenic cells for bone regeneration and the treatment of bone loss.


Assuntos
Anabolizantes/farmacologia , Fraturas Ósseas/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Peptídeos/farmacologia , Células-Tronco/efeitos dos fármacos , Anabolizantes/química , Animais , Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Feminino , Fraturas Ósseas/patologia , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Orquiectomia , Osteogênese/fisiologia , Ovariectomia , Peptídeos/química , Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Técnicas de Síntese em Fase Sólida , Células-Tronco/citologia
3.
Small ; 16(38): e2003010, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32815251

RESUMO

Currently, mesenchymal stem cells (MSCs)-based therapies for bone regeneration and treatments have gained significant attention in clinical research. Though many chemical and physical cues which influence the osteogenic differentiation of MSCs have been explored, scaffolds combining the benefits of Zn2+ ions and unique nanostructures may become an ideal interface to enhance osteogenic and anti-infective capabilities simultaneously. In this work, motivated by the enormous advantages of Zn-based metal-organic framework-derived nanocarbons, C-ZnO nanocarbons-modified fibrous scaffolds for stem cell-based osteogenic differentiation are constructed. The modified scaffolds show enhanced expression of alkaline phosphatase, bone sialoprotein, vinculin, and a larger cell spreading area. Meanwhile, the caging of ZnO nanoparticles can allow the slow release of Zn2+ ions, which not only activate various signaling pathways to guide osteogenic differentiation but also prevent the potential bacterial infection of implantable scaffolds. Overall, this study may provide new insight for designing stem cell-based nanostructured fibrous scaffolds with simultaneously enhanced osteogenic and anti-infective capabilities.


Assuntos
Carbono/química , Células-Tronco Mesenquimais/citologia , Nanofibras/química , Osteogênese/fisiologia , Tecidos Suporte/química , Óxido de Zinco/química , Fosfatase Alcalina/metabolismo , Diferenciação Celular/fisiologia , Células Cultivadas , Humanos , Sialoproteína de Ligação à Integrina/metabolismo , Teste de Materiais , Células-Tronco Mesenquimais/metabolismo , Microscopia Eletrônica de Varredura , Nanofibras/ultraestrutura , Transdução de Sinais , Engenharia Tecidual , Vinculina/metabolismo
4.
PLoS One ; 15(8): e0237040, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764823

RESUMO

As type-I-allergies show an increasing prevalence in the general populace, orthodontic patients may also be affected by histamine release during treatment. Human periodontal ligament fibroblasts (PDLF) are regulators of orthodontic tooth movement. However, the impact of histamine on PDLF in this regard is unknown. Therefore PDLF were incubated without or with an orthodontic compressive force of 2g/cm2 with and without additional histamine. To assess the role of histamine-1-receptor (H1R) H1R-antagonist cetirizine was used. Expression of histamine receptors and important mediators of orthodontic tooth movement were investigated. PDLF expressed histamine receptors H1R, H2R and H4R, but not H3R. Histamine increased the expression of H1R, H2R and H4R as well as of interleukin-6, cyclooxygenase-2, and prostaglandin-E2 secretion even without pressure application and induced receptor activator of NF-kB ligand (RANKL) protein expression with unchanged osteoprotegerin secretion. These effects were not observed in presence of H1R antagonist cetirizine. By expressing histamine receptors, PDLF seem to be able to respond to fluctuating histamine levels in the periodontal tissue. Increased histamine concentration was associated with enhanced expression of proinflammatory mediators and RANKL, suggesting an inductive effect of histamine on PDLF-mediated osteoclastogenesis and orthodontic tooth movement. Since cetirizine inhibited these effects, they seem to be mainly mediated via histamine receptor H1R.


Assuntos
Histamina/farmacologia , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/fisiologia , Técnicas de Movimentação Dentária , Células Cultivadas , Cetirizina/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Expressão Gênica/efeitos dos fármacos , Histamina/fisiologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Mediadores da Inflamação/metabolismo , Modelos Biológicos , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligamento Periodontal/citologia , Ligante RANK/genética , Ligante RANK/metabolismo , Receptores Histamínicos H1/fisiologia , Estresse Mecânico
5.
PLoS One ; 15(8): e0238132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853221

RESUMO

Bears do not suffer from osteoporosis during hibernation, which is associated with long-term inactivity, lack of food intake, and cold exposure. However, the mechanisms involved in bone loss prevention have scarcely been elucidated in bears. We investigated the effect of serum from hibernating Japanese black bears (Ursus thibetanus japonicus) on differentiation of peripheral blood mononuclear cells (PBMCs) to osteoclasts (OCs). PBMCs collected from 3 bears were separately cultured with 10% serum of 4 active and 4 hibernating bears (each individual serum type was assessed separately by a bear PBMCs), and differentiation were induced by treatment with macrophage colony stimulating factor (M-CSF) and receptor activator of NF-kB ligand (RANKL). PBMCs that were cultured with the active bear serum containing medium (ABSM) differentiated to multi-nucleated OCs, and were positive for TRAP stain. However, cells supplemented with hibernating bear serum containing medium (HBSM) failed to form OCs, and showed significantly lower TRAP stain (p < 0.001). On the other hand, HBSM induced proliferation of adipose derived mesenchymal stem cells (ADSCs) similarly to ABSM (p > 0.05), indicating no difference on cell growth. It was revealed that osteoclastogenesis of PBMCs is hindered by HBSM, implying an underlying mechanism for the suppressed bone resorption during hibernation in bears. In addition, this study for the first time showed the formation of bears' OCs in-vitro.


Assuntos
Hibernação/fisiologia , Osteoclastos/fisiologia , Osteogênese/fisiologia , Ursidae/fisiologia , Animais , Reabsorção Óssea/metabolismo , Reabsorção Óssea/fisiopatologia , Diferenciação Celular/fisiologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/fisiologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Osteoclastos/metabolismo , Osteoporose/metabolismo , Osteoporose/fisiopatologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Ursidae/metabolismo
6.
Eur J Endocrinol ; 183(4): R95-106, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32621590

RESUMO

Osteogenesis imperfecta (OI) is an inherited skeletal dysplasia characterized by bone fragility and skeletal deformities. While the majority of cases are associated with pathogenic variants in COL1A1 and COL1A2, the genes encoding type I collagen, up to 25% of cases are associated with other genes that function within the collagen biosynthesis pathway or are involved in osteoblast differentiation and bone mineralization. Clinically, OI is heterogeneous in features and variable in severity. In addition to the skeletal findings, it can affect multiple systems including dental and craniofacial abnormalities, muscle weakness, hearing loss, respiratory and cardiovascular complications. A multi-disciplinary approach to care is recommended to address not only the fractures, reduced mobility, growth and bone pain but also other extra-skeletal manifestations. While bisphosphonates remain the mainstay of treatment in OI, new strategies are being explored, such as sclerostin inhibitory antibodies and TGF beta inhibition, to address not only the low bone mineral density but also the inherent bone fragility. Studies in animal models have expanded the understanding of pathomechanisms of OI and, along with ongoing clinical trials, will allow to develop better therapeutic approaches for these patients.


Assuntos
Endocrinologia/tendências , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/terapia , Animais , Endocrinologia/métodos , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Fraturas Ósseas/terapia , Humanos , Osteogênese/fisiologia , Osteogênese Imperfeita/epidemiologia , Osteogênese Imperfeita/patologia
7.
Medicine (Baltimore) ; 99(28): e20906, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664083

RESUMO

Osteoporosis (OP) is a metabolic bone disease that can cause structural changes in bone marrow cavity. Bone marrow is the hematopoietic organ of adults. Accumulating evidence has shown a close connection between bone marrow hematopoietic function and bone formation. Some studies have revealed that OP is associated with hematopoiesis. However, the relationship is not definite.This study aimed to evaluate the association between peripheral blood cell counts (white blood cells [WBC], red blood cells [RBC], platelets [PLT]), hemoglobin [HGB], and bone mineral density [BMD]) in a sample of Chinese postmenopausal women. This is a retrospective study involving 673 postmenopausal women cases. The BMD of lumbar spine and left hip joint were measured by dual-energy X-ray absorptiometry. The levels of blood cell counts and HGB were measured and analyzed.The study results showed the WBC, RBC, PLT, and HGB levels of postmenopausal women in the OP group were all higher than those in the non-osteoporosis group. Spearman linear trend analysis and partial correlation analysis demonstrated that BMD was negatively correlated with WBC, RBC, PLT, and HGB in postmenopausal women.Due to the differences between different countries and races, and there are few studies on the association of BMD with peripheral blood cell counts and HGB in Chinese Postmenopausal Women. Therefore, more large sample studies are needed.


Assuntos
Grupo com Ancestrais do Continente Asiático/etnologia , Contagem de Células Sanguíneas/métodos , Densidade Óssea/fisiologia , Hemoglobinas/análise , Pós-Menopausa/sangue , Absorciometria de Fóton/métodos , Idoso , Contagem de Células Sanguíneas/tendências , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/epidemiologia , Doenças Ósseas Metabólicas/fisiopatologia , Estudos de Casos e Controles , Feminino , Hematopoese/fisiologia , Articulação do Quadril/diagnóstico por imagem , Articulação do Quadril/fisiopatologia , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/fisiopatologia , Pessoa de Meia-Idade , Osteogênese/fisiologia , Osteoporose/diagnóstico , Osteoporose/epidemiologia , Osteoporose/fisiopatologia , Estudos Retrospectivos
8.
Life Sci ; 257: 118055, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634429

RESUMO

AIMS: Human adipose derived mesenchymal stem cells (hAD-MSCs) as the most promising target for cell therapy and regenerative medicine, face senescence as a major drawback resulting in their limited proliferation and differentiation potentials. To evaluate the efficacy of miR-34a silencing as an anti-senescence strategy in hAD-MSCs, in this study common hallmarks of senescence were assessed after transient inhibition of miR-34a in hAD-MSCs. MATERIALS AND METHODS: The expression levels of miR-34a in hAD-MSCs at different passages were evaluated by real-time quantitative PCR. hAD-MSCs at passage 2 and passage 7 were transfected with miR-34a inhibitor. Doubling time assay, colony forming assay, and cell cycle analysis were performed to evaluate cell proliferation rate. The activity of senescence associated ß-galactosidase (SA-ß-gal) was assessed by histochemical staining. Moreover, the senescence associated molecular alterations including that of pro-senescence (P53, P21 and P16) and anti-senescence (SIRT1, HTERT and CD44) genes were examined by quantitative RT-PCR and western blot assays. To evaluate the differentiation potentials of MSCs, following adipogenic and osteogenic induction, the expression levels of lineage specific markers were analyzed by qPCR. KEY FINDINGS: Our results showed that inhibition of miR-34a enhances the proliferation, promotes the adipogenic and osteogenic differentiation potency, reduces the senescence associated-ß gal activity, and reverses the senescence associated molecular alterations in hAD-MSCs. SIGNIFICANCE: In this study, we showed that inhibition of miR-34a reduces the cellular senescence through the activation of SIRT1. Our findings support the silencing of miR-34a as an anti-senescence approach to improve the therapeutic potentials of hAD-MSCs.


Assuntos
Diferenciação Celular/fisiologia , Senescência Celular/fisiologia , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , Sirtuína 1/genética , Adipogenia/fisiologia , Tecido Adiposo/citologia , Inativação Gênica , Humanos , Receptores de Hialuronatos/genética , Osteogênese/fisiologia , Telomerase/genética
9.
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
10.
Life Sci ; 256: 117993, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32574664

RESUMO

Flavonoids are known for their wide range of bioactive properties including beneficial effect on bone formation. Their intense metal ion chelating capacity endorsed their nomination as a new biomaterial for biomedical applications. The present study examined the functional role of Kaemferal-Zinc(II) (Kaem-Zn) complex in bone formation, in vitro and in vivo. The cyto-compatibility assay confirmed that upto 25 µM of Kaem and Kaem-Zn complex was non-toxic. In fact, it facilitates ALP activity and accumulation of calcium in osteoblast; it was confirmed by Alizarin red and von Kossa staining. In addition to this, osteoblast markers, Runx2, type 1 col., ALP mRNAs expression, and osteocalcin and osteonectin secretory proteins level were also induced by the Kaem-Zn complex. Furthermore, bone forming ability of Kaem and Kaem-Zn was assessed by zebrafish model. The optimal concentration of Kaem and Kaem-Zn was determined by the viability assay of Zebrafish larvae. Osteoblasts distribution in scale, vertebrae and caudal fin ossification was studied by alizarin red staining accompanied by confocal imaging were carried out in adult zebrafish exposed to Kaem and Kaem-Zn complex. To sum up, our findings showed that Kaem promotes bone growth, and Kaem-Zn complex has further strengthened it. Kaem-Zn complex could be an effectively explored and used use in bone tissue engineering.


Assuntos
Quempferóis/administração & dosagem , Quempferóis/síntese química , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Zinco/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Peixe-Zebra , Zinco/química
11.
Life Sci ; 256: 117921, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32526288

RESUMO

Estrogen is a hormone responsible for modulating several physiological processes such as immune response and bone homeostasis. Physiological fluctuations of estrogen concentration are one of the defining principles behind its mechanism. In cases of estrogen deficiency, such as in menopausal women, a more intense bone resorption may occur due to an increase in osteoclast activity. One of the main factors that influence osteoclast formation and response is the immune system, mainly through cytokines secreted by B and T cells. The purpose of this review is to highlight how estrogen can modulate the secretion of cytokines that can alter bone physiology, thereby establishing an axis between estrogen, immune cells, and osteoclastogenesis.


Assuntos
Linfócitos B/metabolismo , Citocinas/metabolismo , Estrogênios/metabolismo , Osteogênese/fisiologia , Linfócitos T/metabolismo , Animais , Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Diferenciação Celular , Citocinas/genética , Moduladores de Receptor Estrogênico/metabolismo , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Menopausa/metabolismo , Osteoclastos/metabolismo
12.
Cell Prolif ; 53(5): e12819, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32372504

RESUMO

OBJECTIVE: The objective of this study was to explore characteristics of bone marrow mesenchymal stromal cells (BM-MSCs) derived from patients with myelodysplastic syndrome (MDS) and multiple myeloma (MM). METHODS: BM-MSCs were recovered from 17 of MDS patients, 23 of MM patients and 9 healthy donors and were passaged until proliferation stopped. General characteristics and gene expression profiles of MSCs were analysed. In vitro, ex vivo coculture, immunohistochemistry and knockdown experiments were performed to verify gene expression changes. RESULTS: BM-MSCs failed to culture in 35.0% of patients and 50.0% of recovered BM-MSCs stopped to proliferate before passage 6. MDS- and MM-MSCs shared characteristics including decreased osteogenesis, increased angiogenesis and senescence-associated molecular pathways. In vitro and ex vivo experiments showed disease-specific changes such as neurogenic tendency in MDS-MSCs and cardiomyogenic tendency in MM-MSCs. Although the age of normal control was younger than patients and telomere length was shorter in patient's BM-MSCs, they were not different according to disease category nor degree of proliferation. Specifically, poorly proliferation BM-MSCs showed CDKN2A overexpression and CXCL12 downregulation. Immunohistochemistry of BM biopsy demonstrated that CDKN2A was intensely accumulation in perivascular BM-MSCs failed to culture. Interestingly, patient's BM-MSCs revealed improved proliferation activity after CDKN2A knockdown. CONCLUSION: These results collectively indicate that MDS-MSCs and MM-MSCs have common and different alterations at various degrees. Hence, it is necessary to evaluate their alteration status using representative markers such as CDKN2A expression.


Assuntos
Medula Óssea/patologia , Células-Tronco Mesenquimais/patologia , Mieloma Múltiplo/patologia , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Quimiocina CXCL12/metabolismo , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Síndromes Mielodisplásicas/metabolismo , Osteogênese/fisiologia , Adulto Jovem
13.
Gerontology ; 66(4): 393-400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32454508

RESUMO

INTRODUCTION: Muscle and bone metabolism are both important for the healing of fractures and the regeneration of injured muscle tissue. The aim of this investigation was to evaluate myostatin and other regulating factors in patients with hip fractures who underwent hemi-arthroplasty. METHODS: Serum levels of myostatin (MSTN), follistatin (FSTN), dickkopf-1 (Dkk1), and periostin (PSTN) as well as markers of bone turnover were evaluated in patients with hip fractures before surgery and twice in the 2 weeks after surgery. These parameters were also evaluated in age- and gender-matched subjects without major musculoskeletal injury. RESULTS: MSTN was transiently reduced; its opponent FSTN was transiently increased. Dkk1, the negative regulator of bone mass, and PSTN, a marker of subperiosteal bone formation, increased after surgery. With regard to markers of bone turnover, resorption was elevated during the entire period of observation whereas the early bone formation marker N-terminal propeptide of type I collagen was elevated 12 days after surgery. CONCLUSIONS: Unexpectedly, MSTN, a negative regulator of muscle growth, was reduced after surgery compared with before surgery. As musculoskeletal markers are altered during bone healing, they do not reflect general bone metabolism after fracture or joint arthroplasty. This is important because many elderly patients receive treatment for osteoporosis.


Assuntos
Artroplastia de Quadril , Hemiartroplastia , Fraturas do Quadril/sangue , Miostatina/sangue , Idoso , Idoso de 80 Anos ou mais , Áustria , Biomarcadores/sangue , Proteínas Morfogenéticas Ósseas/sangue , Remodelação Óssea/fisiologia , Estudos de Casos e Controles , Moléculas de Adesão Celular/sangue , Feminino , Folistatina/sangue , Fraturas do Quadril/cirurgia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Osteogênese/fisiologia , Estudos Prospectivos
14.
PLoS One ; 15(5): e0232695, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379794

RESUMO

BACKGROUND: The proliferation and osteogenic differentiation of human bone marrow mesenchymal stem cells (HBMScs) are modulated by a variety of microRNAs (miRNAs). SATB homeobox 2 (SATB2) is a critical transcription factor that contributes to maintain the balance of bone metabolism. However, it remains unclear how the regulatory relationship between miR-103 and SATB2 on HBMScs proliferation and osteogenic differentiation. METHODS: HBMScs were obtained from Cyagen Biosciences and successful induced osteogenic differentiation. The proliferation abilities of HBMScs after treatment with agomiR-103 and antagomiR-103 were assessed using a cell counting Kit-8 (CCK-8) assay, and osteogenic differentiation was determined using alizarin red S staining and alkaline phosphatase (ALP) activity assay. The expression levels of miR-103, SATB2, and associated osteogenic differentiation biomarkers, including RUNX family transcription factor 2 (RUNX2), bone gamma-carboxyglutamate protein (BGLAP), and secreted phosphoprotein 1 (SPP1), were evaluated using real-time qPCR and Western blot. The regulatory sites of miR-103 on SATB2 were predicted using bioinformatics software and validated using a dual luciferase reporter assay. The underlying mechanism of miR-103 on SATB2-medicated HBMScs proliferation and osteogenic differentiation were confirmed by co-transfection of antagomiR-103 and SATB2 siRNA. RESULTS: The expression of miR-103 in HBMScs after induction of osteogenic differentiation was reduced in a time-dependent way. Overexpression of miR-103 by transfection of agomiR-103 suppressed HBMScs proliferation and osteogenic differentiation, while silencing of miR-103 by antagomiR-103 abolished these inhibitory effects. Consistently, RUNX2, BGLAP and SPP1 mRNA and protein expression were decreased in agomiR-103 treated HBMScs compared with those in agomiR-NC group. Meanwhile, antagomiR-103 upregulated the mRNA and protein expression levels of RUNX2, BGLAP and SPP1 in HBMScs. Further studies revealed that SATB2 was a direct target gene of miR-103. BMSCs transfected with agomiR-103 exhibited significantly downregulated protein expression level of SATB2, whereas knockdown of miR-103 promoted it. Additionally, rescue assays confirmed that silencing of SATB2 partially reversed the effects of antagomiR-103 induced HBMScs proliferation and osteogenic differentiation. CONCLUSIONS: The present results suggested that miR-103 negatively regulates SATB2 to serve an inhibitory role in the proliferation and osteogenic differentiation of HBMScs, which sheds light upon a potential therapeutic target for treating bone-related diseases.


Assuntos
Diferenciação Celular/fisiologia , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , MicroRNAs/fisiologia , Osteogênese/fisiologia , Fatores de Transcrição/metabolismo , Células da Medula Óssea , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Células-Tronco Mesenquimais
15.
J Appl Oral Sci ; 28: e20190690, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348445

RESUMO

Objective To investigate the effects of intro-oral injection of parathyroid hormone (PTH) on tooth extraction wound healing in hyperglycemic rats. Methodology 60 male Sprague-Dawley rats were randomly divided into the normal group (n=30) and DM group (n=30). Type 1 diabetes mellitus (DM) was induced by streptozotocin. After extracting the left first molar of all rats, each group was further divided into 3 subgroups (n=10 per subgroup), receiving the administration of intermittent PTH, continuous PTH and saline (control), respectively. The intermittent-PTH group received intra-oral injection of PTH three times per week for two weeks. A thermosensitive controlled-release hydrogel was synthesized for continuous-PTH administration. The serum chemistry was determined to evaluate the systemic condition. All animals were sacrificed after 14 days. Micro-computed tomography (Micro-CT) and histological analyses were used to evaluate the healing of extraction sockets. Results The level of serum glucose in the DM groups was significantly higher than that in the non-DM groups (p<0.05); the level of serum calcium was similar in all groups (p>0.05). Micro-CT analysis showed that the DM group had a significantly lower alveolar bone trabecular number (Tb.N) and higher trabecular separation (Tb.Sp) than the normal group (p<0.05). The histological analyses showed that no significant difference in the amount of new bone (hard tissue) formation was found between the PTH and non-PTH groups (p>0.05). Conclusions Bone formation in the extraction socket of the type 1 diabetic rats was reduced. PTH did not improve the healing of hard and soft tissues. The different PTH administration regimes (continuous vs. intermittent) had similar effect on tissue healing. These results demonstrated that the metabolic characteristics of the hyperglycemic rats produced a condition that was unable to respond to PTH treatment.


Assuntos
Hormônios e Agentes Reguladores de Cálcio/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Hormônio Paratireóideo/farmacologia , Extração Dentária/métodos , Alvéolo Dental/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Glicemia/análise , Cálcio/sangue , Hidrogéis , Masculino , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Ferida Cirúrgica/tratamento farmacológico , Fatores de Tempo , Alvéolo Dental/diagnóstico por imagem , Resultado do Tratamento , Microtomografia por Raio-X
16.
Medicine (Baltimore) ; 99(14): e19684, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32243406

RESUMO

BACKGROUND: Fracture is a common disease; many factors affect fracture healing. Recent studies have confirmed that hydrogen sulfide (H2S) plays an essential role in bone formation, but most of these studies are drawing conclusions based on animal experiment; whether H2S could promote fracture healing in patients is still unclear. We aim to investigate the change of serum H2S in fracture patients, and analyze its effort on fracture healing. METHODS: This is a single-center, prospective cohort study. Patients with spinal or limb fracture will be recruited. Patient's serum and urine will be collected at baseline for examination (serum H2S, ß-CTX, OC, PINP, 25-OH-VitD3, S-CTX, urinary calcium, and urinary creatinine). All patients will be followed-up for 24 months in outpatients settings, the image of X-ray or CT will be reviewed and fracture healing will be judged by 2 experienced orthopedic physicians. The difference in serum parameters especially H2S will be compared between patients with fracture healed within 9 months and those with fracture unhealed at 9 months. DISCUSSION: Results of the trial could provide insight into influence of H2S on fracture healing. ETHICS AND DISSEMINATION: The study was approved by the ethics committee of School of Medicine UESTC & Sichuan Provincial People's Hospital Ethics Committee. All the participants will be asked to provide written informed consent before data collection. The findings of the study will be published in peer-reviewed journals and will be presented at national or international conferences.


Assuntos
Consolidação da Fratura/fisiologia , Fraturas Ósseas/sangue , Sulfeto de Hidrogênio/sangue , Traumatismos do Braço/sangue , Fraturas Ósseas/urina , Humanos , Sulfeto de Hidrogênio/urina , Traumatismos da Perna/sangue , Osteogênese/fisiologia , Estudos Prospectivos , Fraturas da Coluna Vertebral/sangue
17.
Metabolism ; 108: 154250, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32335074

RESUMO

BACKGROUND: Chronic steroid treatment causes an increase in visceral adiposity and osteoporosis. It is believed that steroids may alter a balance between differentiation of mesenchymal stem cells (MSCs) into either adipocytes or osteoblasts; however, the detailed molecular mechanisms are unclear. We previously identified Dexras1 as a critical factor that potentiates adipogenesis in response to glucocorticoids. Thus, in this study, we investigated the role of Dexras1 in maintaining the balance between chronic steroid treatment-associated adipogenesis and osteoporosis. MATERIAL AND METHODS: We treated wild type (WT) and Dexras1 knockout (KO) mice with dexamethasone for five weeks followed by 60% HFD for additional two weeks with dexamethasone. The changes of glucocorticoid-induced body weight gain and osteoporosis were analyzed. Bone marrow derived stromal cells (BMSCs) and mouse embryonic fibroblasts (MEFs) extracted from WT and Dexras1 KO mice, as well as MC3T3-E1 pre-osteoblasts and osteoclasts differentiated from RAW264.7 were analyzed to further define the role of Dexras1 in osteoblasts and osteoclasts. RESULTS: Dual-energy X-ray absorptiometry and micro-computed tomography analyses in murine femurs revealed that Dexras1 deficiency was associated with increased osteogenesis, concurrent with reduced adipogenesis. Furthermore, Dexras1 deficiency promoted osteogenesis of BMSCs and MEFs in vitro, suggesting that Dexras1 deficiency prevents steroid-induced osteoporosis. We also observed that Dexras1 downregulated SMAD signaling pathways, which reduced the osteogenic differentiation capacity of pre-osteoblast MC3T3-E1 cells into mature osteoblasts. CONCLUSION: We propose that Dexras1 is critical for maintaining the equilibrium between adipogenesis and osteogenesis upon steroid treatment.


Assuntos
Adipogenia/fisiologia , Osteogênese/fisiologia , Proteínas ras/metabolismo , Células 3T3 , Adipócitos/metabolismo , Animais , Diferenciação Celular/fisiologia , Linhagem Celular , Fêmur/metabolismo , Glucocorticoides/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporose/metabolismo , Células RAW 264.7 , Transdução de Sinais/fisiologia
18.
PLoS One ; 15(3): e0229127, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32134943

RESUMO

Vibration acceleration through whole body vibration has been reported to promote fracture healing. However, the mechanism responsible for this effect remains unclear. Purpose of this study was to determine whether vibration acceleration directly affects cells around the fracture site and promotes endochondral ossification. Four-week-old female Wistar Hannover rats were divided into two groups (vibration [V group] and control [C group]). The eighth ribs on both sides were cut vertically using scissors. From postoperative day 3 to 11, vibration acceleration using Power Plate® (30 Hz, low amplitude [30-Low], 10 min/day) was applied in the V group. Mature calluses appeared earlier in the V group than in the C group by histological analysis. The GAG content in the fracture callus on day 6 was significantly higher in the V group than in the C group. The mRNA expressions of SOX-9, aggrecan, and Col-II in the fracture callus on day 6 and Col-X on day 9 were significantly higher in the V group than in the C group. For in vitro analysis, four different conditions of vibration acceleration (30 or 50 Hz with low or high amplitude [30-Low, 30-High, 50-Low, and 50-High], 10 min/day) were applied to a prechondrogenic cell (ATDC5) and an undifferentiated cell (C3H10T1/2). There was no significant difference in cell proliferation between the control and any of the four vibration conditions for both cell lines. For both cell lines, alcian blue staining was greater under 30-Low and 50-Low conditions than under control as well as 30-High and 50-High conditions on days 7 and 14. Vibration acceleration under 30-L condition upregulated chondrogenic gene expressions of SOX-9, aggrecan, Col-II, and Col-X. Low-amplitude vibration acceleration can promote endochondral ossification in the fracture healing in vivo and chondrogenic differentiation in vitro.


Assuntos
Diferenciação Celular , Condrócitos/fisiologia , Condrogênese/fisiologia , Consolidação da Fratura/fisiologia , Osteogênese/fisiologia , Vibração , Aceleração , Animais , Fenômenos Biomecânicos/fisiologia , Calo Ósseo/fisiologia , Células Cultivadas , Feminino , Fraturas Ósseas/fisiopatologia , Fraturas Ósseas/terapia , Ratos , Ratos Wistar , Vibração/uso terapêutico
19.
Gene ; 740: 144534, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32145328

RESUMO

The function of tissue cells is strongly depends on the extracellular matrix (ECM) that can guide and support cell structure. This support plays a crucial role in the process of cell proliferation and differentiation. Herein, three different nanofibrous scaffolds that are highly attractive for tissue engineering were selected and then osteogenic related genes and protein expression patterns of human adipose-derived mesenchymal stem cells (AT-MSCs) were investigated when grown on substrates. Polycaprolactone, Poly (L-lactic acid) and Polyvinylidene-fluoride nanofibrous scaffolds were fabricated using Electrospinning method and then AT-MSCs viability and osteogenic differentiation were evaluated while cultured on them. The highest AT-MSCs survival rate when grown on the scaffolds was detected when grown on Polyvinylidene-fluoride. In addition, the highest ALP activity and mineralization were also observed in differentiated AT-MSCs has grown on Polyvinylidene-fluoride. The expression levels of Runx2, osteonectin and osteocalcin genes and osteocalcin protein in the AT-MSCs has grown on the Polyvinylidene-fluoride were also significantly higher than the rest of the scaffolds. Based on the results, it seems that since the studied substrate have a similar structural characteristics, their nature may have an important role in the stem cell's osteogenesis process, where the Polyvinylidene-fluoride piezoelectricity was a most distinguished characteristic.


Assuntos
Células-Tronco Mesenquimais , Nanofibras , Osteogênese , Engenharia Tecidual/métodos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Nanofibras/química , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Osteonectina/metabolismo , Poliésteres , Polivinil
20.
Nat Commun ; 11(1): 1384, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170111

RESUMO

Cells respond in complex ways to their environment, making it challenging to predict a direct relationship between the two. A key problem is the lack of informative representations of parameters that translate directly into biological function. Here we present a platform to relate the effects of cell morphology to gene expression induced by nanotopography. This platform utilizes the 'morphome', a multivariate dataset of cell morphology parameters. We create a Bayesian linear regression model that uses the morphome to robustly predict changes in bone, cartilage, muscle and fibrous gene expression induced by nanotopography. Furthermore, through this model we effectively predict nanotopography-induced gene expression from a complex co-culture microenvironment. The information from the morphome uncovers previously unknown effects of nanotopography on altering cell-cell interaction and osteogenic gene expression at the single cell level. The predictive relationship between morphology and gene expression arising from cell-material interaction shows promise for exploration of new topographies.


Assuntos
Osso e Ossos/citologia , Expressão Gênica , Nanotecnologia/métodos , Osteogênese/genética , Osteogênese/fisiologia , Animais , Teorema de Bayes , Materiais Biocompatíveis , Osso e Ossos/diagnóstico por imagem , Comunicação Celular/fisiologia , Microambiente Celular , Técnicas de Cocultura , Biologia Computacional , Aprendizado de Máquina , Camundongos , Sistema Musculoesquelético/diagnóstico por imagem , Células NIH 3T3 , Nanopartículas
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