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1.
Int J Nanomedicine ; 15: 8465-8478, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33149587

RESUMO

Introduction: Decellularized matrix from porcine small intestinal submucosa (SIS) endows scaffolds with an ECM-like surface, which enhances stem cell self-renewal, proliferation, and differentiation. Mesoporous bioactive glass (MBG) is extensively recognized as an excellent bio-ceramic for fabricating bone grafts. Materials and Methods: In the current study, SIS was doped on an MBG scaffold (MBG/SIS) using polyurethane foam templating and polydopamine chemistry method. To mimic the bony environment of a natural bone matrix, an ECM-inspired delivery system was constructed by coupling the BMP2-related peptide P28 to a heparinized MBG/SIS scaffold (MBG/SIS-H-P28). The release of P28 from MBG/SIS-H-P28 and its effects on the proliferation, viability, and osteogenic differentiation of bone marrow stromal stem cells were investigated in vitro and in vivo. Results: Our research indicated that the novel tissue-derived ECM scaffold MBG/SIS has a hierarchical and interconnected porous architecture, and superior biomechanical properties. MBG/SIS-H-P28 released P28 in a controlled manner, with the long-term release time of 40 d. The results of in vitro experiments showed improvements in cell proliferation, cell viability, alkaline phosphatase activity, and mRNA expression levels of osteogenesis-related genes (Runx-2, OCN, OPN, and ALP) compared to those of MBG/SIS or MBG/SIS-P28 and MBG/SIS-H-P28. The in vivo results demonstrated that MBG/SIS-H-P28 scaffolds evidently increased bone formation in rat calvarial critical-sized defect compared to that in controls. Conclusion: MBG/SIS-H-P28 scaffolds show potential as ideal platforms for delivery of P28 and for providing a bony environment for bone regeneration.


Assuntos
Ácido Aspártico/química , Materiais Biocompatíveis/farmacologia , Proteína Morfogenética Óssea 2/farmacologia , Osso e Ossos/efeitos dos fármacos , Cerâmica/farmacologia , Matriz Extracelular/metabolismo , Osteoblastos/efeitos dos fármacos , Peptídeos/farmacologia , Fator de Crescimento Transformador beta/farmacologia , Animais , Regeneração Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Cinética , Masculino , Camundongos , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Porosidade , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Suínos , Tecidos Suporte/química
2.
Maturitas ; 141: 63-70, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33036705

RESUMO

During the last decade, a cascade of evidence has questioned the anti-fracture efficacy of vitamin D supplementation. In general, vitamin D status, reflected by serum 25-hydroxy-vitamin D [25(OH)D] concentrations, seems to predict fracture risk and bone mineral density (BMD). Despite the well-documented detrimental effect of vitamin D deficiency on bones, vitamin D monotherapy does not seem to reduce the risk of fractures. On the other hand, high vitamin D doses, either at monthly (60,000-100,000 IU) or daily intervals (>4000 IU), appear to be harmful with regard to falls, fracture risk and BMD, especially for people without vitamin D deficiency and at low fracture risk. Therefore, a U-shaped effect of vitamin D on the musculoskeletal system may be supported by the current evidence. Vitamin D supplementation could be of value, at daily doses of at least 800 IU, co-supplemented with calcium (1000-1200  mg/day), in elderly populations, especially those with severe vitamin D deficiency [25(OH)D <25-30  nmol/L (<10-12  ng/mL)], although its anti-fracture and anti-fall efficacy is modest. Good compliance and at least 3-5 years of therapy are required.


Assuntos
Densidade Óssea/efeitos dos fármacos , Fraturas Ósseas/prevenção & controle , Vitamina D/administração & dosagem , Acidentes por Quedas , Idoso , Osso e Ossos/efeitos dos fármacos , Cálcio na Dieta/administração & dosagem , Suplementos Nutricionais , Fraturas Ósseas/etiologia , Humanos , Vitamina D/efeitos adversos , Vitamina D/análogos & derivados , Deficiência de Vitamina D/complicações , Vitaminas/uso terapêutico
3.
Internist (Berl) ; 61(11): 1196-1203, 2020 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-32970191

RESUMO

The hype about vitamin D can be traced back to the ubiquitous presence of vitamin D receptors in many organ systems, in addition to the importance for healthy bones. Large observational studies have provided indications that a vitamin D deficiency favors risks for age-associated chronic diseases, such as cancer and cardiovascular diseases. In this article the latest information on bone health in adult persons as well as cancer and cardiovascular diseases is summarized based on the current results of the large vitamin D and omega­3 trial (VITAL).


Assuntos
Osso e Ossos/efeitos dos fármacos , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/administração & dosagem , Vitamina D/uso terapêutico , Densidade Óssea/fisiologia , Doenças Cardiovasculares/prevenção & controle , Suplementos Nutricionais , Humanos , Deficiência de Vitamina D/prevenção & controle , Vitaminas
4.
Acta Odontol Latinoam ; 33(2): 143-152, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920617

RESUMO

The aims of the present study were, first, to identify signs of alveolar bone damage in early stages of experimental periodontitis (EP) and, second, to assess its possible prevention by treatment with cannabinoid receptor 2 agonist HU 308. Experimental periodontitis was induced by injections of lipopolysaccharide (LPS) (1mg/ml) in gums surrounding maxillary and mandibular first molar, 3 days per week, and untreated controls were kept for comparison. Then, a 3-week study was conducted including eighteen new rats (six rats per group): 1) controls; 2) experimental periodontitis rats; and 3) experimental periodontitis rats treated daily with HU 308 (500 ng/ml). After euthanasia, alveolar bone loss was assessed by morphometric and histomorphometric techniques, and the content of prostaglandin E2 (PGE2) in gingival tissue was evaluated by radioimmunoassay. The first signs of alveolar bone loss were apparent at 3 weeks of experimental periodontitis (ρ<0.05) in the mandibular first molar, but there was no detectable change at 1 week, leading us to establish 3 weeks as an early stage of experimental periodontitis. Rats subjected to 3-week experimental periodontitis showed less interradicular bone volume, less whole bone perimeter and fewer bone formation areas, and higher periodontal space height, bone resorption areas, number of osteoclasts and gingival content of prostaglandin E2 than controls, while HU 308 prevented, at least partially, the deleterious effects (ρ<0.001). We can conclude that a 3-week term of lipopolysaccharide-induced periodontitis in rats provides a valid model of the early stage of the disease, as emerging damage is observed in bone tissue. Furthermore, harmful effects at 3 weeks could be prevented by local stimulation of cannabinoid receptor 2, before greater damage is produced.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Osso e Ossos/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Canabinoides/farmacologia , Periodontite , Perda do Osso Alveolar/metabolismo , Animais , Modelos Animais de Doenças , Osteoclastos , Periodontite/metabolismo , Periodontite/prevenção & controle , Ratos
5.
Int J Nanomedicine ; 15: 5027-5042, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764934

RESUMO

Background: Bactericidal capacity, durable inhibition of biofilm formation, and a three-dimensional (3D) porous structure are the emphases of infected bone defect (IBD) treatment via local scaffold implantation strategy. Purpose: In this study, silver nanoparticle (AgNP)-loaded nano-hydroxyapatite (nHA)@ reduced graphene oxide (RGO) 3D scaffolds (AHRG scaffolds) were designed to alleviate bone infection, inhibit biofilm formation, and promote bone repair through the synergistic effects of AgNPs, RGO, and nHA. Materials and Methods: AHRGs were prepared using a one-step preparation method, to create a 3D porous scaffold to facilitate a uniform distribution of AgNPs and nHA. Methicillin-resistant Staphylococcus aureus (MRSA) was used as a model-resistant bacterium, and the effects of different silver loadings on the antimicrobial activity and cytocompatibility of materials were evaluated. Finally, a rabbit IBD model was used to evaluate the therapeutic effect of the AHRG scaffold in vivo. Results: The results showed successful synthesis of the AHRG scaffold. The ideal 3D porous structure was verified using scanning electron microscopy and transmission electron microscopy, and X-ray photoelectron spectroscopy and selected area electron diffraction measurements revealed uniform distributions of AgNP and nHA. In vitro antibacterial and cytocompatibility indicated that the 4% AHRG scaffolds possessed the most favorable balance of bactericidal properties and cytocompatibility. In vivo evaluation of the IBD model showed promising treatment efficacy of AHRG scaffolds. Conclusion: The as-fabricated AHRG scaffolds effectively eliminated infection and inhibited biofilm formation. IBD repair was facilitated by the bactericidal properties and 3D porous structure of the AHRG scaffold, suggesting its potential in the treatment of IBDs.


Assuntos
Antibacterianos/farmacologia , Doenças Ósseas Infecciosas/terapia , Grafite/química , Nanopartículas Metálicas/química , Engenharia Tecidual/métodos , Tecidos Suporte/química , Animais , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Substitutos Ósseos , Osso e Ossos/efeitos dos fármacos , Modelos Animais de Doenças , Durapatita/química , Feminino , Masculino , Teste de Materiais , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Porosidade , Coelhos , Ratos , Prata/química , Prata/farmacologia , Infecções Estafilocócicas/terapia
6.
Int J Nanomedicine ; 15: 5825-5838, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821104

RESUMO

Background and Purpose: The extracellular matrix (ECM) derived from bone marrow mesenchymal stem cells (BMSCs) has been used in regenerative medicine because of its good biological activity; however, its poor mechanical properties limit its application in bone regeneration. The purpose of this study is to construct a three dimensional-printed hydroxyapatite (3D-HA)/BMSC-ECM composite scaffold that not only has biological activity but also sufficient mechanical strength and reasonably distributed spatial structure. Methods: A BMSC-ECM was first extracted and formed into micron-sized particles, and then the ECM particles were modified onto the surface of 3D-HA scaffolds using an innovative linking method to generate composite 3D-HA/BMSC-ECM scaffolds. The 3D-HA scaffolds were used as the control group. The basic properties, biocompatibility and osteogenesis ability of both scaffolds were tested in vitro. Finally, a critical skull defect rat model was created and the osteogenesis effect of the scaffolds was evaluated in vivo. Results: The compressive modulus of the composite scaffolds reached 9.45±0.32 MPa, which was similar to that of the 3D-HA scaffolds (p>0.05). The pore size of the two scaffolds was 305±47 um and 315±34 um (p>0.05), respectively. A CCK-8 assay indicated that the scaffolds did not have cytotoxicity. The composite scaffolds had good cell adhesion ability, with a cell adhesion rate of up to 76.00±6.17% after culturing for 7 hours, while that of the 3D-HA scaffolds was 51.85±4.77% (p<0.01). In addition, the composite scaffold displayed higher alkaline phosphatase (ALP) activity, osteogenesis-related mRNA expression, and calcium nodule formation, thus confirming that the composite scaffolds had good osteogenic activity. The composite scaffolds exhibited good bone repair in vivo and were superior to the 3D-HA scaffolds. Conclusion: We conclude that BMSC-ECM is a good osteogenic material and that the composite scaffolds have good osteogenic ability, which provides a new method and concept for the repair of bone defects.


Assuntos
Durapatita/farmacologia , Matriz Extracelular/metabolismo , Células-Tronco Mesenquimais/citologia , Tecidos Suporte/química , Animais , Regeneração Óssea/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Adesão Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Hidrodinâmica , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/ultraestrutura , Osteogênese/efeitos dos fármacos , Osteogênese/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Cicatrização/efeitos dos fármacos
7.
Medicine (Baltimore) ; 99(27): e21102, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629743

RESUMO

RATIONALE: Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare disease without standard treatments. Tripterygium wilfordii hook f (TwHF) is a traditional Chinese herb with anti-inflammatory effect, and 1.0 mg/(kg·d) dose of Tripterygium glycosides has been reported to significantly improve the disease activity of a SAPHO patient in a case report. However, the optimal dose of TwHF is still unclear. Here, we report the first case of SAPHO patient who achieved rapid remission in clinical symptoms after receiving 1.5 mg/(kg·d) dose of Tripterygium glycosides treatment. PATIENT CONCERNS: A 67-year-old woman noted palmoplantar pustulosis and pain in the anterior chest wall and waist. Bone scintigraphy demonstrated the typical tracer accumulation feature and magnetic resonance images showed bone marrow edema in lumbosacral vertebra. DIAGNOSES: The diagnosis was made by dermatological and osteoarticular manifestations and classical signs in bone scintigraphy in accordance with the diagnostic criteria proposed in 2012. INTERVENTIONS: Tripterygium glycosides was given with a primary dose of 1.5 mg/(kg·d) for 1 month and then reduced at a rate of 10 mg every 2 weeks until 1.0 mg/(kg·d) for a long-term maintenance. OUTCOMES: Fast-induced remission on clinical manifestations was achieved and magnetic resonance imaging abnormality was improved significantly. Additionally, no apparent side effects were observed. LESSONS: 1.5 mg/(kg·d) dose of Tripterygium glycosides seems to have fast-induced remission than 1.0 mg/(kg·d) with reliable safety. Besides, Tripterygium glycosides may also have a pharmacological effect of inhibiting osteolysis and enhancing bone strength.


Assuntos
Síndrome de Hiperostose Adquirida/tratamento farmacológico , Osso e Ossos/patologia , Medicamentos de Ervas Chinesas/uso terapêutico , Glicosídeos/uso terapêutico , Síndrome de Hiperostose Adquirida/patologia , Idoso , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Glicosídeos/administração & dosagem , Humanos , Região Lombossacral/diagnóstico por imagem , Região Lombossacral/patologia , Imagem por Ressonância Magnética/métodos , Osteólise/prevenção & controle , Psoríase/etiologia , Cintilografia/métodos , Indução de Remissão , Resultado do Tratamento , Tripterygium
8.
PLoS One ; 15(7): e0235135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628733

RESUMO

BACKGROUND: In patients on hemodialysis (HD), the various chemical elements in the dialysate may influence survival rates. In particular, calcium modifies mineral and bone metabolism and the vascular calcification rate. We studied the influence of the dialysate calcium concentration and the treatments prescribed for mineral bone disease (MBD) on survival. METHODS: All patients in REIN having initiated HD from 2010 to 2013 were classified according to their exposure to the different dialysate calcium concentrations in their dialysis unit. Data on the individual patients' treatments for MBD were extracted from the French national health database. Cox proportional hazard models were used to estimate mortality hazard ratios (HR) associated with time-dependent exposure to dialysate calcium concentrations and MBD therapies, adjusted for comorbidities, laboratory and technical data. RESULTS: Dialysate calcium concentration of 1.5 mmol/L was used by 81% of the dialysis centers in 2010 and in 83% in 2014. Most centers were using several formulas in up to 78% for 3 formulas in 2010 to 86% in 2014. In full adjusted Cox survival analyses, the percentage of calcium >1.5 mmol/L and <1.5 mmol/l by center and the number of formula used per center were not associated with survival. Depending on the daily dose used, the MBD therapies were associated with survival improvement for calcium, native vitamin D, active vitamin D, sevelamer, lanthanum and cinacalcet in the second and third tertiles of dose. CONCLUSION: No influence of the dialysate calcium concentration was evidenced on survival whereas all MBD therapies were associated with a survival improvement depending on the daily dose used.


Assuntos
Osso e Ossos/efeitos dos fármacos , Cálcio/análise , Soluções para Hemodiálise/análise , Sistema de Registros , Diálise Renal , Insuficiência Renal Crônica/terapia , Idoso , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Calcinose/epidemiologia , Calcinose/metabolismo , Calcinose/fisiopatologia , Cálcio/administração & dosagem , Cálcio/metabolismo , Cinacalcete/análise , Feminino , França/epidemiologia , Soluções para Hemodiálise/administração & dosagem , Soluções para Hemodiálise/química , Humanos , Lantânio/análise , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Sevelamer/análise , Vitamina D/análise , Vitamina D/metabolismo
9.
Proc Natl Acad Sci U S A ; 117(25): 14386-14394, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513693

RESUMO

We report that two widely-used drugs for erectile dysfunction, tadalafil and vardenafil, trigger bone gain in mice through a combination of anabolic and antiresorptive actions on the skeleton. Both drugs were found to enhance osteoblastic bone formation in vivo using a unique gene footprint and to inhibit osteoclast formation. The target enzyme, phosphodiesterase 5A (PDE5A), was found to be expressed in mouse and human bone as well as in specific brain regions, namely the locus coeruleus, raphe pallidus, and paraventricular nucleus of the hypothalamus. Localization of PDE5A in sympathetic neurons was confirmed by coimmunolabeling with dopamine ß-hydroxylase, as well as by retrograde bone-brain tracing using a sympathetic nerve-specific pseudorabies virus, PRV152. Both drugs elicited an antianabolic sympathetic imprint in osteoblasts, but with net bone gain. Unlike in humans, in whom vardenafil is more potent than tadalafil, the relative potencies were reversed with respect to their osteoprotective actions in mice. Structural modeling revealed a higher binding energy of tadalafil to mouse PDE5A compared with vardenafil, due to steric clashes of vardenafil with a single methionine residue at position 806 in mouse PDE5A. Collectively, our findings suggest that a balance between peripheral and central actions of PDE5A inhibitors on bone formation together with their antiresorptive actions specify the osteoprotective action of PDE5A blockade.


Assuntos
Disfunção Erétil/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Inibidores da Fosfodiesterase 5/farmacologia , Envelhecimento/fisiologia , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Diferenciação Celular/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Reposicionamento de Medicamentos , Disfunção Erétil/complicações , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Animais , Modelos Moleculares , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Osteoporose/complicações , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/prevenção & controle , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/uso terapêutico , Cultura Primária de Células , Tadalafila/química , Tadalafila/farmacologia , Tadalafila/uso terapêutico , Dicloridrato de Vardenafila/química , Dicloridrato de Vardenafila/farmacologia , Dicloridrato de Vardenafila/uso terapêutico
10.
J Med Chem ; 63(13): 7355-7368, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32510210

RESUMO

Continuing our search for vitamin D analogues, we explored the modification of the steroidal side chain and inserted a methylene moiety in position C-22 together with either lengthening the side chain or introducing a ring at the terminal end. Our conformational studies confirmed that the presence of a methylene group attached to C-22 restricts the conformational flexibility of the side chain, which can result in changes in biological characteristics of a molecule. All synthesized 1α,25-dihydroxy-2,22-dimethylene-19-norvitamin D3 analogues proved equal to calcitriol in their ability to bind to the vitamin D receptor, and most of them exert significantly higher differentiation and transcriptional activity than calcitriol. The most active compounds were characterized by the presence of an elongated side chain or 26,27-dimethylene bridge. The synthetic strategy was based on the Wittig-Horner coupling of the known A-ring phosphine oxide with the corresponding Grundmann ketones prepared from a 20-epi-Inhoffen-Lythgoe diol derived from vitamin D2.


Assuntos
Calcitriol/análogos & derivados , Cálcio/metabolismo , Animais , Ligação Competitiva , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Calcitriol/farmacologia , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Intestinos/efeitos dos fármacos , Luciferases/genética , Masculino , Conformação Molecular , Ratos Sprague-Dawley , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Relação Estrutura-Atividade , Transcrição Genética
11.
J Vis Exp ; (159)2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32478748

RESUMO

Osteochondral defects in middle-aged patients might be treated with focal metallic implants. First developed for defects in the knee joint, implants are now available for the shoulder, hip, ankle and the first metatarsalphalangeal joint. While providing pain reduction and clinical improvement, progressive degenerative changes of the opposing cartilage are observed in many patients. The mechanisms leading to this damage are not fully understood. This protocol describes a tribological experiment to simulate a metal-on-cartilage pairing and comprehensive analysis of the articular cartilage. Metal implant material is tested against bovine osteochondral cylinders as a model for human articular cartilage. By applying different loads and sliding speeds, physiological loading conditions can be imitated. To provide a comprehensive analysis of the effects on the articular cartilage, histology, metabolic activity and gene expression analysis are described in this protocol. The main advantage of tribological testing is that loading parameters can be adjusted freely to simulate in vivo conditions. Furthermore, different testing solutions might be used to investigate the influence of lubrication or pro-inflammatory agents. By using gene expression analysis for cartilage-specific genes and catabolic genes, early changes in the metabolism of articular chondrocytes in response to mechanical loading might be detected.


Assuntos
Cartilagem Articular/fisiologia , Metais/farmacologia , Próteses e Implantes , Animais , Osso e Ossos/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Bovinos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , DNA Complementar/biossíntese , Fricção , Regulação da Expressão Gênica , Fatores de Tempo
12.
Proc Natl Acad Sci U S A ; 117(22): 12029-12040, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32404427

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is a uniformly fatal condition that is especially prevalent in skin, cardiovascular, and musculoskeletal systems. A wide gap exists between our knowledge of the disease and a promising treatment or cure. The aim of this study was to first characterize the musculoskeletal phenotype of the homozygous G608G BAC-transgenic progeria mouse model, and to determine the phenotype changes of HGPS mice after a five-arm preclinical trial of different treatment combinations with lonafarnib, pravastatin, and zoledronic acid. Microcomputed tomography and CT-based rigidity analyses were performed to assess cortical and trabecular bone structure, density, and rigidity. Bones were loaded to failure with three-point bending to assess strength. Contrast-enhanced µCT imaging of mouse femurs was performed to measure glycosaminoglycan content, thickness, and volume of the femoral head articular cartilage. Advanced glycation end products were assessed with a fluorometric assay. The changes demonstrated in the cortical bone structure, rigidity, stiffness, and modulus of the HGPS G608G mouse model may increase the risk for bending and deformation, which could result in the skeletal dysplasia characteristic of HGPS. Cartilage abnormalities seen in this HGPS model resemble changes observed in the age-matched WT controls, including early loss of glycosaminoglycans, and decreased cartilage thickness and volume. Such changes might mimic prevalent degenerative joint diseases in the elderly. Lonafarnib monotherapy did not improve bone or cartilage parameters, but treatment combinations with pravastatin and zoledronic acid significantly improved bone structure and mechanical properties and cartilage structural parameters, which ameliorate the musculoskeletal phenotype of the disease.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Modelos Animais de Doenças , Lamina Tipo A/genética , Progéria , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Fêmur/efeitos dos fármacos , Fêmur/patologia , Glicosaminoglicanos/análise , Articulações/efeitos dos fármacos , Articulações/patologia , Lamina Tipo A/metabolismo , Camundongos , Camundongos Transgênicos , Mutação , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Fenótipo , Piperidinas/uso terapêutico , Pravastatina/uso terapêutico , Progéria/tratamento farmacológico , Progéria/genética , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Piridinas/uso terapêutico , Microtomografia por Raio-X , Ácido Zoledrônico/uso terapêutico
13.
Eur J Endocrinol ; 183(2): 181-189, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32454455

RESUMO

Objective: Long-term androgen deprivation therapy (ADT) negatively influences bone. The short-term effects on bone and mineral homeostasis are less known. Therefore, we aimed to investigate the early effects of ADT on calcium/phosphate homeostasis and bone turnover. Design: Prospective cohort study. Methods: Eugonadal adult, male sex offenders, who were referred for ADT to the endocrine outpatient clinic, received cyproterone acetate. Changes in blood markers of calcium/phosphate homeostasis and bone turnover between baseline and first follow-up visit were studied. Results: Of 26 screened patients, 17 were included. The median age was 44 (range 20-75) years. The median time interval between baseline and first follow-up was 13 (6-27) weeks. Compared to baseline, an 81% decrease was observed for median total testosterone (to 3.4 nmol/L (0.4-12.2); P < 0.0001) and free testosterone (to 0.06 nmol/L (0.01-0.18); P < 0.0001). Median total estradiol decreased by 71% (to 17.6 pmol/L (4.7-35.6); P < 0.0001). Increased serum calcium (P < 0.0001) and phosphate (P = 0.0016) was observed, paralleled by decreased PTH (P = 0.0156) and 1,25-dihydroxyvitamin D3 (P = 0.0134). The stable calcium isotope ratio (δ44/42Ca) decreased (P = 0.0458), indicating net calcium loss from bone. Bone-specific alkaline phosphatase and osteocalcin decreased (P < 0.0001 and P = 0.0056, respectively), periostin tended to decrease (P = 0.0500), whereas sclerostin increased (P < 0.0001), indicating suppressed bone formation. Serum bone resorption markers (TRAP, CTX) were unaltered. Conclusions: In adult men, calcium release from the skeleton occurs early following sex steroid deprivation, reflecting early bone resorption. The increase of sclerostin and reduction of bone formation markers, without changes in resorption markers, suggests a dominant negative effect on bone formation in the acute phase.


Assuntos
Antagonistas de Androgênios/farmacologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Calcificação Fisiológica/efeitos dos fármacos , Acetato de Ciproterona/farmacologia , Adulto , Idoso , Bélgica , Remodelação Óssea/efeitos dos fármacos , Cálcio/sangue , Estudos de Coortes , Homeostase/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Estudos Prospectivos , Delitos Sexuais , Testosterona/sangue
14.
Internist (Berl) ; 61(6): 535-540, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-32458373

RESUMO

Vitamin D deficiency is widespread in geriatric patients. While vitamin D deficiency is prevalent in about 50% of healthy older adults, the prevalence in geriatric patients with hip fracture increases to over 80%. This is partly due to the fact that sunlight is unreliable as the main source of vitamin D. In addition to insufficient sun intensity from November to April, skin aging plays an important role; it causes a 4-fold reduction in the skin's own vitamin D production during sunshine exposure in older adults compared with younger people. Immobility and institutionalization are additional risk factors for vitamin D deficiency in geriatric patients. At the same time, vitamin D deficiency (< 20 ng/ml) increases parathyroid hormone levels and thus promotes bone loss and the risk of fracture. Severe vitamin D deficiency (< 10 ng/ml) may also lead to reversible muscle weakness resulting in an increased risk of falling. Since falls affect at least every second geriatric patient and hip fractures increase exponentially after the age of 75, the correction of vitamin D deficiency is an important medical and public health effort in these patients. Several randomized intervention trials, comparing 800-1000 IU vitamin D/day versus placebo or calcium, showed a significant reduction in falls and hip fractures in adults ≥65 years of age who had an increased risk of vitamin D deficiency and of falls or fractures. In geriatric patients, implementing vitamin D supplementation at this dosage is currently preferred. A bolus dose of over 24,000 IU/month should be avoided due to the increased risk of falls and fractures. These recommendations remain relevant after a critical review of the four most recent meta-analyses.


Assuntos
Osso e Ossos/efeitos dos fármacos , Fraturas Ósseas/prevenção & controle , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem , Acidentes por Quedas/prevenção & controle , Idoso , Densidade Óssea/fisiologia , Suplementos Nutricionais , Fraturas do Quadril/prevenção & controle , Humanos , Osteoporose/prevenção & controle , Vitamina D/sangue , Vitamina D/uso terapêutico , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/prevenção & controle
15.
Life Sci ; 255: 117827, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32450170

RESUMO

AIMS: Data suggest pharmacological treatment of depression with selective serotonin reuptake inhibitors (SSRI) may impair bone health. Our group has previously modeled compromised craniofacial healing after treatment with sertraline, a commonly prescribed SSRI, and hypothesized potential culprits: alterations in bone cells, collagen, and/or inflammation. Here we interrogate bone lineage cell alterations due to sertraline treatment as a potential cause of the noted compromised bone healing. MAIN METHODS: Murine pre-osteoblast, pre-osteoclast, osteoblast, and osteoclast cells were treated with clinically relevant concentrations of the SSRI. Studies focused on serotonin pathway targets, cell viability, apoptosis, differentiation, and the osteoblast/osteoclast feedback loop. KEY FINDINGS: All cells studied express neurotransmitters (e.g. serotonin transporter, SLC6A4, SSRI target) and G-protein-coupled receptors associated with the serotonin pathway. Osteoclasts presented the greatest native expression of Slc6a4 with all cell types exhibiting decreases in Slc6a4 expression after SSRI treatment. Pre-osteoclasts exhibited alteration to their differentiation pathway after treatment. Pre-osteoblasts and osteoclasts showed reduced apoptosis after treatment but showed no significant differences in functional assays. RANKL: OPG mRNA and protein ratios were decreased in the osteoblast lineage. Osteoclast lineage cells treated with sertraline demonstrated diminished TRAP positive cells when pre-exposed to sertraline prior to RANKL-induced differentiation. SIGNIFICANCE: These data suggest osteoclasts are a likely target of bone homeostasis disruption due to sertraline treatment, most potently through the osteoblast/clast feedback loop.


Assuntos
Osso e Ossos/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Inibidores de Captação de Serotonina/toxicidade , Células 3T3 , Animais , Apoptose/efeitos dos fármacos , Osso e Ossos/citologia , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Osteoblastos/citologia , Osteoclastos/citologia , Ligante RANK/metabolismo , Células RAW 264.7 , RNA Mensageiro/metabolismo
16.
Nutrients ; 12(1)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32284510

RESUMO

Studies investigating the effect of the caudal-type homeobox protein 2 (Cdx2) polymorphism in the vitamin D receptor gene and calcium intake on bone mass have shown inconsistent results. This study investigated whether the effect of calcium intake on peak bone mass is affected by Cdx2 polymorphism in young Japanese women. A cross-sectional study of 500 young women was conducted. Dietary intake was assessed by the Food Frequency Questionnaire. The osteo sono-assessment index (OSI), assessed by the qualitative ultrasound method, was used as a bone mass index. The subjects were divided into two groups by the median calcium intake. The OSI was not different among Cdx2 genotypes and between calcium groups (p = 0.960, p = 0.191, respectively). The interaction between calcium and Cdx2 genotypes on the OSI approached significance (GG versus GA and AA genotypes, p = 0.092). The difference in the OSI between calcium groups was significant in the GG genotype (p = 0.028), but not in the GA or AA genotypes (p = 0.501, p = 0.306, respectively). Adjustment for covariates (body mass index and physical activity) did not change the results. In conclusion, the relationship between dietary calcium intake and peak bone mass may vary according to Cdx2 polymorphism.


Assuntos
Densidade Óssea/genética , Osso e Ossos/efeitos dos fármacos , Fator de Transcrição CDX2/genética , Cálcio na Dieta/farmacologia , Cálcio/farmacologia , Polimorfismo Genético , Receptores de Calcitriol/metabolismo , Adulto , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Estudos Transversais , Feminino , Genótipo , Humanos , Japão , Adulto Jovem
17.
Nat Rev Endocrinol ; 16(8): 437-447, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32286516

RESUMO

Glucocorticoids are widely used to suppress inflammation or the immune system. High doses and long-term use of glucocorticoids lead to an important and common iatrogenic complication, glucocorticoid-induced osteoporosis, in a substantial proportion of patients. Glucocorticoids mainly increase bone resorption during the initial phase (the first year of treatment) by enhancing the differentiation and maturation of osteoclasts. Glucocorticoids also inhibit osteoblastogenesis and promote apoptosis of osteoblasts and osteocytes, resulting in decreased bone formation during long-term use. Several indirect effects of glucocorticoids on bone metabolism, such as suppression of production of insulin-like growth factor 1 or growth hormone, are involved in the pathogenesis of glucocorticoid-induced osteoporosis. Fracture risk assessment for all patients with long-term use of oral glucocorticoids is required. Non-pharmacological interventions to manage the risk of fracture should be prescribed to all patients, while pharmacological management is reserved for patients who have increased fracture risk. Various treatment options can be used, ranging from bisphosphonates to denosumab, as well as teriparatide. Finally, appropriate monitoring during treatment is also important.


Assuntos
Glucocorticoides/efeitos adversos , Osteoporose/induzido quimicamente , Osteoporose/terapia , Apoptose/efeitos dos fármacos , Reabsorção Óssea/induzido quimicamente , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Feminino , Fraturas Ósseas , Humanos , Masculino , Pessoa de Meia-Idade , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteócitos/efeitos dos fármacos , Osteoporose/complicações , Fraturas por Osteoporose/prevenção & controle , Pós-Menopausa , Medição de Risco
18.
Georgian Med News ; (299): 43-47, 2020 Feb.
Artigo em Russo | MEDLINE | ID: mdl-32242843

RESUMO

The purpose of this review is the study of literature for the current data on the metabolism of vitamin D and its role in development of bone tissue in children. The role of the main marker enabling assessing 25(OH)D concentration in the body the reference values has been analyzed. Summarizing the literature data, we may say that vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a mayor impact on health of infants, children and adolescents.


Assuntos
Osso e Ossos/efeitos dos fármacos , Cálcio/administração & dosagem , Osteomalacia , Raquitismo , Deficiência de Vitamina D/complicações , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Adolescente , Criança , Humanos , Lactente , Osteomalacia/diagnóstico , Osteomalacia/tratamento farmacológico , Osteomalacia/etiologia , Raquitismo/diagnóstico , Raquitismo/tratamento farmacológico , Raquitismo/etiologia , Resultado do Tratamento , Vitamina D/administração & dosagem , Vitamina D/sangue , Deficiência de Vitamina D/prevenção & controle , Vitaminas/administração & dosagem , Vitaminas/sangue
19.
Gene ; 749: 144703, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32339623

RESUMO

The repair of segmental bone defects and bone fractures is a clinical challenge involving high risk and postsurgical morbidity. Bone injury and partial bone tumor resection via traditional bone grafting result in high complications. Growth factors have been proposed as alternatives to promote bone repair and formation and circumvent these limitations. In this study, we classified different lengths of mechano growth factor (MGF) E peptides in different species and analyzed their effects on MC3T3-E1 cell proliferation, cell cycle, alkaline phosphatase (ALP) activity, differentiation-related factor expression, and cell mineralization. A rabbit bone injury model was constructed, and the repair function of MGF E peptide was verified by injecting the candidate MGF E peptide. We analyzed 52 different MGF-E peptides and classified them into the following four categories: T-MGF-25E, M-MGF-25E, T-MGF-19E, and M-MGF-19E. These peptides were synthesized for further study. T-MGF-19E peptide obviously promoted cell proliferation by regulating cell cycle after MGF E peptide treatment at 72 h. T-MGF-25E and T-MGF-19E peptide significantly promoted the differentiation of osteoblasts on day 14, and M-MGF-25E peptide promoted cell differentiation on day 7. T-MGF-19E, T-MGF-25E, and M-MGF-19E significantly promoted osteoblast mineralization, with T-MGF19E showing the most significant effect. These results implied that T-MGF19E peptide could remarkably promote MC3T3-E1 cell proliferation, differentiation, and mineralization. The rabbit bone defect model showed that the low-dose T-MGF-19E peptide significantly promoted bone injury healing, suggesting its promoting effect on the healing of bone injury.


Assuntos
Osso e Ossos/efeitos dos fármacos , Calcificação Fisiológica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Osteogênese/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Animais , Osso e Ossos/fisiologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese/genética
20.
Sci Rep ; 10(1): 5889, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32246003

RESUMO

Platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum (195mPt-BP) complexes to confirm preferential accumulation of these Pt-based drugs in metabolically active bone. In vitro NMR studies revealed that release of Pt from Pt BP complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. These Pt-BP complexes formed less Pt-DNA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of Pt from Pt-BP complexes proceeded relatively slow. Subsequently, radioactive 195mPt-BP complexes were synthesized using 195mPt(NO3)2(en) as precursor and injected intravenously into mice. Specific accumulation of 195mPt-BP was observed at skeletal sites with high metabolic activity using micro-SPECT/CT imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195mPt BP co-localized with calcium in the trabeculae of mice tibia.


Assuntos
Antineoplásicos/administração & dosagem , Osso e Ossos/metabolismo , Difosfonatos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Compostos de Platina/administração & dosagem , Animais , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Osso e Ossos/efeitos dos fármacos , Difosfonatos/uso terapêutico , Injeções Intravenosas , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Compostos de Platina/uso terapêutico , Radioisótopos , Tíbia/metabolismo , Peixe-Zebra
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