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1.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199016

RESUMO

Paeonia suffruticosa is a magnificent and long-lived woody plant that has traditionally been used to treat various diseases including inflammatory, neurological, cancer, and cardiovascular diseases. In the present study, we demonstrated the biological mechanisms of paeonoside (PASI) isolated from the dried roots of P. suffruticosa in pre-osteoblasts. Herein, we found that PASI has no cytotoxic effects on pre-osteoblasts. Migration assay showed that PASI promoted wound healing and transmigration in osteoblast differentiation. PASI increased early osteoblast differentiation and mineralized nodule formation. In addition, PASI enhanced the expression of Wnt3a and bone morphogenetic protein 2 (BMP2) and activated their downstream molecules, Smad1/5/8 and ß-catenin, leading to increases in runt-related transcription factor 2 (RUNX2) expression during osteoblast differentiation. Furthermore, PASI-mediated osteoblast differentiation was attenuated by inhibiting the BMP2 and Wnt3a pathways, which was accompanied by reduction in the expression of RUNX2 in the nucleus. Taken together, our findings provide evidence that PASI enhances osteoblast differentiation and mineralized nodules by regulating RUNX2 expression through the BMP2 and Wnt3a pathways, suggesting a potential role for PASI targeting osteoblasts to treat bone diseases including osteoporosis and periodontitis.


Assuntos
Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Glicosídeos/farmacologia , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Extratos Vegetais/farmacologia , Biomarcadores , Proteína Morfogenética Óssea 2/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Glicosídeos/química , Humanos , Imuno-Histoquímica , Espectroscopia de Ressonância Magnética/efeitos adversos , Osteogênese/efeitos dos fármacos , Extratos Vegetais/química , Via de Sinalização Wnt
2.
Molecules ; 26(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203711

RESUMO

Inflammation and stiffness in the arteries is referred to as vascular calcification. This process is a prevalent yet poorly understood consequence of cardiovascular disease and diabetes mellitus, comorbidities with few treatments clinically available. Because this is an active process similar to bone formation, it is hypothesized that osteoclasts (OCs), bone-resorbing cells in the body, could potentially work to reverse existing calcification by resorbing bone material. The receptor activator of nuclear kappa B-ligand (RANKL) is a molecule responsible for triggering a response in monocytes and macrophages that allows them to differentiate into functional OCs. In this study, OC and RANKL delivery were employed to determine whether calcification could be attenuated. OCs were either delivered via direct injection, collagen/alginate microbeads, or collagen gel application, while RANKL was delivered via injection, through either a porcine subdermal model or aortic injury model. While in vitro results yielded a decrease in calcification using OC therapy, in vivo delivery mechanisms did not provide control or regulation to keep cells localized long enough to induce calcification reduction. However, these results do provide context and direction for the future of OC therapy, revealing necessary steps for this treatment to effectively reduce calcification in vivo. The discrepancy between in vivo and in vitro success for OC therapy points to the need for a more stable and time-controlled delivery mechanism that will allow OCs not only to remain at the site of calcification, but also to be regulated so that they are healthy and functioning normally when introduced to diseased tissue.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Osteoclastos/fisiologia , Calcificação Vascular/terapia , Animais , Reabsorção Óssea/metabolismo , Proteínas de Transporte/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Elastina/metabolismo , Elastina/fisiologia , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana , Monócitos/metabolismo , Miócitos de Músculo Liso/metabolismo , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Ligante RANK/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Suínos , Calcificação Vascular/metabolismo
3.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208563

RESUMO

Bone exhibits piezoelectric properties. Thus, electrical stimulations such as pulsed electromagnetic fields (PEMFs) and stimuli-responsive piezoelectric properties of scaffolds have been investigated separately to evaluate their efficacy in supporting osteogenesis. However, current understanding of cells responding under the combined influence of PEMF and piezoelectric properties in scaffolds is still lacking. Therefore, in this study, we fabricated piezoelectric scaffolds by functionalization of polycaprolactone-tricalcium phosphate (PCL-TCP) films with a polyvinylidene fluoride (PVDF) coating that is self-polarized by a modified breath-figure technique. The osteoinductive properties of these PVDF-coated PCL-TCP films on MC3T3-E1 cells were studied under the stimulation of PEMF. Piezoelectric and ferroelectric characterization demonstrated that scaffolds with piezoelectric coefficient d33 = -1.2 pC/N were obtained at a powder dissolution temperature of 100 °C and coating relative humidity (RH) of 56%. DNA quantification showed that cell proliferation was significantly enhanced by PEMF as low as 0.6 mT and 50 Hz. Hydroxyapatite staining showed that cell mineralization was significantly enhanced by incorporation of PVDF coating. Gene expression study showed that the combination of PEMF and PVDF coating promoted late osteogenic gene expression marker most significantly. Collectively, our results suggest that the synergistic effects of PEMF and piezoelectric scaffolds on osteogenesis provide a promising alternative strategy for electrically augmented osteoinduction. The piezoelectric response of PVDF by PEMF, which could provide mechanical strain, is particularly interesting as it could deliver local mechanical stimulation to osteogenic cells using PEMF.


Assuntos
Fosfatos de Cálcio , Materiais Revestidos Biocompatíveis , Campos Eletromagnéticos , Osteogênese , Poliésteres , Polivinil , Tecidos Suporte , Regeneração Óssea , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Materiais Revestidos Biocompatíveis/química , Expressão Gênica , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Osteogênese/efeitos da radiação , Poliésteres/química , Poliésteres/farmacologia , Polivinil/química , Solventes , Engenharia Tecidual , Difração de Raios X
4.
Int J Nanomedicine ; 16: 4321-4332, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211273

RESUMO

Background: As commonly bone defect is a disease of jaw that can seriously affect implant restoration, the bioactive scaffold can be used as potential systems to provide effective repair for bone defect. Purpose: A osteoinductive bone tissue engineering scaffold has been prepared in order to explore the effect of bioactive materials on bone tissue engineering. Methods: In this study, NELL-1 nanoparticles (Chi/NNP) and nano hydroxyapatite were incorporated in composite scaffolds by electrospinning and characterized using TEM, SEM, contact angle, tensile tests and in vitro drug release. In vitro biological activities such as MC3T3-E1 cell attachment, proliferation and osteogenic activity were studied. Results: With the addition of nHA and nanoparticles, the fiber diameter of PCL/BNPs group, PCL/NNPs group and PCL/nHA/NNPs group was significantly increased. Moreover, the hydrophilic hydroxyl group and amino group presented in nHA and nanoparticles had improved the hydrophilicity of the composite fibers. The composite electrospun containing Chi/NNPs can form a double protective barrier which can effectively prolong the release time of NELL-1 growth factor. In addition, the hydroxyapatite/NELL-1 nanoparticles electrospun fibers can promote attachment, proliferation, differentiation of MC3T3-E1 cells and good cytocompatibility, indicating better ability of inducing osteogenic differentiation. Conclusion: A multi-functional PCL/nHA/NNPs composite fiber with long-term bioactivity and osteoinductivity was successfully prepared by electrospinning. This potential composite could be used as scaffolds in bone tissue engineering application after in vivo studies.


Assuntos
Proteínas de Ligação ao Cálcio/farmacologia , Durapatita/química , Nanofibras/química , Osteogênese/efeitos dos fármacos , Engenharia Tecidual/métodos , Osso e Ossos , Proteínas de Ligação ao Cálcio/química , Proteínas de Ligação ao Cálcio/farmacocinética , Diferenciação Celular/efeitos dos fármacos , Quitosana/química , Liberação Controlada de Fármacos , Humanos , Microscopia Eletrônica de Varredura , Nanopartículas/química , Poliésteres/química , Soroalbumina Bovina/química , Tecidos Suporte
5.
J Med Life ; 14(2): 181-197, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34104241

RESUMO

The present study investigated the capacity of Suprathel® (a copolymer membrane, so far validated for skin regeneration) to also regenerate oral tissue - mucosa and bone, by comparing this biomaterial, in a split-mouth rabbit model, to Mucoderm®, a xenogeneic collagen matrix certified for keratinized oral mucosa healing. The clinical reason behind this experimental animal model was to determine whether the benefits of this advanced skin regeneration product (Suprathel®) could be conveyed for future evaluation in clinical trials of oral tissue regeneration in humans. The outcomes of this study validated the use of Suprathel®, a terpolymer of polylactide with trimethylene carbonate and ε-caprolactone, for stimulation of oral epithelium and alveolar bone regeneration in rabbits. Both Suprathel® and Mucoderm® exhibited comparable results and the null hypothesis stating a comparable regenerating effect of these two materials could not be rejected.


Assuntos
Osso e Ossos/patologia , Epitélio/patologia , Boca/fisiologia , Poliésteres/química , Regeneração , Cicatrização , Animais , Materiais Biocompatíveis/farmacologia , Regeneração Óssea/efeitos dos fármacos , Regeneração Óssea/fisiologia , Osso Esponjoso/patologia , Regeneração Tecidual Guiada , Masculino , Mucosa Bucal/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Coelhos , Cicatrização/efeitos dos fármacos
6.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072216

RESUMO

Cheonggukjang (CGJ, fermented soybean paste), a traditional Korean fermented dish, has recently emerged as a functional food that improves blood circulation and intestinal regulation. Considering that excessive consumption of refined salt is associated with increased incidence of gastric cancer, high blood pressure, and stroke in Koreans, consuming CGJ may be desirable, as it can be made without salt, unlike other pastes. Soybeans in CGJ are fermented by Bacillus strains (B. subtilis or B. licheniformis), Lactobacillus spp., Leuconostoc spp., and Enterococcus faecium, which weaken the activity of putrefactive bacteria in the intestines, act as antibacterial agents against pathogens, and facilitate the excretion of harmful substances. Studies on CGJ have either focused on improving product quality or evaluating the bioactive substances contained in CGJ. The fermentation process of CGJ results in the production of enzymes and various physiologically active substances that are not found in raw soybeans, including dietary fiber, phospholipids, isoflavones (e.g., genistein and daidzein), phenolic acids, saponins, trypsin inhibitors, and phytic acids. These components prevent atherosclerosis, oxidative stress-mediated heart disease and inflammation, obesity, diabetes, senile dementia, cancer (e.g., breast and lung), and osteoporosis. They have also been shown to have thrombolytic, blood pressure-lowering, lipid-lowering, antimutagenic, immunostimulatory, anti-allergic, antibacterial, anti-atopic dermatitis, anti-androgenetic alopecia, and anti-asthmatic activities, as well as skin improvement properties. In this review, we examined the physiological activities of CGJ and confirmed its potential as a functional food.


Assuntos
Produtos Biológicos , Fermentação , Alimento Funcional , Soja , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Ingredientes de Alimentos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Estrutura Molecular , Avaliação Nutricional , Osteogênese/efeitos dos fármacos , Probióticos , Soja/química , Soja/metabolismo , Soja/microbiologia
7.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063742

RESUMO

Three-dimensional (3D) printing is perceived as an innovative tool for change in tissue engineering and regenerative medicine based on research outcomes on the development of artificial organs and tissues. With advances in such technology, research is underway into 3D-printed artificial scaffolds for tissue recovery and regeneration. In this study, we fabricated artificial scaffolds by coating bone demineralized and decellularized extracellular matrix (bdECM) onto existing 3D-printed polycaprolactone/tricalcium phosphate (PCL/TCP) to enhance osteoconductivity and osteoinductivity. After injecting adipose-derived stem cells (ADSCs) in an aggregate form found to be effective in previous studies, we examined the effects of the scaffold on ossification during mandibular reconstruction in beagle dogs. Ten beagles were divided into two groups: group A (PCL/TCP/bdECM + ADSC injection; n = 5) and group B (PCL/TCP/bdECM; n = 5). The results were analyzed four and eight weeks after intervention. Computed tomography (CT) findings showed that group A had more diffuse osteoblast tissue than group B. Evidence of infection or immune rejection was not detected following histological examination. Goldner trichrome (G/T) staining revealed rich ossification in scaffold pores. ColI, Osteocalcin, and Runx2 gene expressions were determined using real-time polymerase chain reaction. Group A showed greater expression of these genes. Through Western blotting, group A showed a greater expression of genes that encode ColI, Osteocalcin, and Runx2 proteins. In conclusion, intervention group A, in which the beagles received the additional ADSC injection together with the 3D-printed PCL/TCP coated with bdECM, showed improved mandibular ossification in and around the pores of the scaffold.


Assuntos
Tecido Adiposo/citologia , Fosfatos de Cálcio/química , Matriz Extracelular/fisiologia , Mandíbula/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Poliésteres/química , Células-Tronco/citologia , Tecidos Suporte/química , Adipócitos/citologia , Animais , Regeneração Óssea/efeitos dos fármacos , Cães , Osteoblastos/efeitos dos fármacos , Impressão Tridimensional , Engenharia Tecidual/métodos
8.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066458

RESUMO

Paeonia suffruticosa has been extensively used as a traditional medicine with various beneficial effects; paeonolide (PALI) was isolated from its dried roots. This study aimed to investigate the novel effects and mechanisms of PALI in pre-osteoblasts. Here, cell viability was evaluated using an MTT assay. Early and late osteoblast differentiation was examined by analyzing the activity of alkaline phosphatase (ALP) and by staining it with Alizarin red S (ARS). Cell migration was assessed using wound healing and Boyden chamber assays. Western blot and immunofluorescence analyses were used to examine the intracellular signaling pathways and differentiation proteins. PALI (0.1, 1, 10, 30, and 100 µM) showed no cytotoxic or proliferative effects in pre-osteoblasts. In the absence of cytotoxicity, PALI (1, 10, and 30 µM) promoted wound healing and transmigration during osteoblast differentiation. ALP staining demonstrated that PALI (1, 10, and 30 µM) promoted early osteoblast differentiation in a dose-dependent manner, and ARS staining showed an enhanced mineralized nodule formation, a key indicator of late osteoblast differentiation. Additionally, low concentrations of PALI (1 and 10 µM) increased the bone morphogenetic protein (BMP)-Smad1/5/8 and Wnt-ß-catenin pathways in osteoblast differentiation. Particularly, PALI (1 and 10 µM) increased the phosphorylation of ERK1/2 compared with BMP2 treatment, an FDA-approved drug for bone diseases. Furthermore, PALI-mediated early and late osteoblast differentiation was abolished in the presence of the ERK1/2 inhibitor U0126. PALI-induced RUNX2 (Cbfa1) expression and nuclear localization were also attenuated by blocking the ERK1/2 pathway during osteoblast differentiation. We suggest that PALI has biologically novel activities, such as enhanced osteoblast differentiation and bone mineralization mainly through the intracellular ERK1/2-RUNX2 signaling pathway, suggesting that PALI might have therapeutic action and aid the treatment and prevention of bone diseases, such as osteoporosis and periodontitis.


Assuntos
Acetofenonas/farmacologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Osteoblastos/metabolismo , Osteogênese , Animais , Proteína Morfogenética Óssea 2/metabolismo , Calcificação Fisiológica/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Proteína Wnt3/metabolismo
9.
Molecules ; 26(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070157

RESUMO

After tooth loss, bone resorption is irreversible, leaving the area without adequate bone volume for successful implant treatment. Bone grafting is the only solution to reverse dental bone loss and is a well-accepted procedure required in one in every four dental implants. Research and development in materials, design and fabrication technologies have expanded over the years to achieve successful and long-lasting dental implants for tooth substitution. This review will critically present the various dental bone graft and substitute materials that have been used to achieve a successful dental implant. The article also reviews the properties of dental bone grafts and various dental bone substitutes that have been studied or are currently available commercially. The various classifications of bone grafts and substitutes, including natural and synthetic materials, are critically presented, and available commercial products in each category are discussed. Different bone substitute materials, including metals, ceramics, polymers, or their combinations, and their chemical, physical, and biocompatibility properties are explored. Limitations of the available materials are presented, and areas which require further research and development are highlighted. Tissue engineering hybrid constructions with enhanced bone regeneration ability, such as cell-based or growth factor-based bone substitutes, are discussed as an emerging area of development.


Assuntos
Substitutos Ósseos/farmacologia , Transplante Ósseo/tendências , Odontologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Osteogênese/efeitos dos fármacos
10.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072888

RESUMO

Hybrid biomaterials allow for the improvement of the biological properties of materials and have been successfully used for implantology in medical applications. The covalent and selective functionalization of materials with bioactive peptides provides favorable results in tissue engineering by supporting cell attachment to the biomaterial through biochemical cues and interaction with membrane receptors. Since the functionalization with bioactive peptides may alter the chemical and physical properties of the biomaterials, in this study we characterized the biological responses of differently functionalized chitosan analogs. Chitosan analogs were produced through the reaction of GRGDSPK (RGD) or FRHRNRKGY (HVP) sequences, both carrying an aldehyde-terminal group, to chitosan. The bio-functionalized polysaccharides, pure or "diluted" with chitosan, were chemically characterized in depth and evaluated for their antimicrobial activities and biocompatibility toward human primary osteoblast cells. The results obtained indicate that the bio-functionalization of chitosan increases human-osteoblast adhesion (p < 0.005) and proliferation (p < 0.005) as compared with chitosan. Overall, the 1:1 mixture of HVP functionalized-chitosan:chitosan is the best compromise between preserving the antibacterial properties of the material and supporting osteoblast differentiation and calcium deposition (p < 0.005 vs. RGD). In conclusion, our results reported that a selected concentration of HVP supported the biomimetic potential of functionalized chitosan better than RGD and preserved the antibacterial properties of chitosan.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Transplante Ósseo/métodos , Quitosana/química , Osteogênese/efeitos dos fármacos , Engenharia Tecidual , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Regeneração Óssea/genética , Osso e Ossos/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quitosana/análogos & derivados , Quitosana/síntese química , Quitosana/farmacologia , Durapatita/química , Durapatita/farmacologia , Humanos , Oligopeptídeos/síntese química , Oligopeptídeos/química , Osteoblastos/efeitos dos fármacos , Tecidos Suporte/química
11.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069142

RESUMO

Bone healing is a complex, well-organized process. Multiple factors regulate this process, including growth factors, hormones, cytokines, mechanical stimulation, and aging. One of the most important signaling pathways that affect bone healing is the Notch signaling pathway. It has a significant role in controlling the differentiation of bone mesenchymal stem cells and forming new bone. Interventions to enhance the healing of critical-sized bone defects are of great importance, and stem cell transplantations are eminent candidates for treating such defects. Understanding how Notch signaling impacts pluripotent stem cell differentiation can significantly enhance osteogenesis and improve the overall healing process upon transplantation. In Rancourt's lab, mouse embryonic stem cells (ESC) have been successfully differentiated to the osteogenic cell lineage. This study investigates the role of Notch signaling inhibition in the osteogenic differentiation of mouse embryonic and induced pluripotent stem cells (iPS). Our data showed that Notch inhibition greatly enhanced the differentiation of both mouse embryonic and induced pluripotent stem cells.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Diferenciação Celular/efeitos dos fármacos , Osteogênese/genética , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Animais , Osso e Ossos/metabolismo , Proteínas de Ciclo Celular/genética , Diferenciação Celular/fisiologia , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Dexametasona/farmacologia , Diaminas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/fisiologia , Mesoderma/citologia , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/efeitos dos fármacos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteogênese/efeitos dos fármacos , Células-Tronco Pluripotentes/metabolismo , Receptores Notch/metabolismo , Tiazóis/farmacologia , Fatores de Transcrição HES-1/genética , Vitamina D/farmacologia
12.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069280

RESUMO

The use of human dental pulp stromal cells (hDPSCs) has gained increasing attention as an alternative stem cell source for bone tissue engineering. The modification of the cells' epigenetics has been found to play an important role in regulating differentiation, with the inhibition of histone deacetylases 3 (HDAC3) being linked to increased osteogenic differentiation. This study aimed to induce epigenetic reprogramming using the HDAC2 and 3 selective inhibitor, MI192 to promote hDPSCs osteogenic capacity for bone regeneration. MI192 treatment caused a time-dose-dependent change in hDPSC morphology and reduction in viability. Additionally, MI192 successfully augmented hDPSC epigenetic functionality, which resulted in increased histone acetylation and cell cycle arrest at the G2/M phase. MI192 pre-treatment exhibited a dose-dependent effect on hDPSCs alkaline phosphatase activity. Quantitative PCR and In-Cell Western further demonstrated that MI192 pre-treatment significantly upregulated hDPSCs osteoblast-related gene and protein expression (alkaline phosphatase, bone morphogenic protein 2, type I collagen and osteocalcin) during osteogenic differentiation. Importantly, MI192 pre-treatment significantly increased hDPSCs extracellular matrix collagen production and mineralisation. As such, for the first time, our findings show that epigenetic reprogramming with the HDAC2 and 3 selective inhibitor MI192 accelerates the osteogenic differentiation of hDPSCs, demonstrating the considerable utility of this MSCs engineering approach for bone augmentation strategies.


Assuntos
Polpa Dentária/citologia , Inibidores de Histona Desacetilases/farmacologia , Osteogênese/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/administração & dosagem , Histonas/metabolismo , Humanos , Dente Serotino/citologia , Osteogênese/fisiologia , Células Estromais/metabolismo
13.
ACS Appl Mater Interfaces ; 13(27): 31527-31541, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34181398

RESUMO

It is significant to use functional biomaterials to rationally engineer microenvironments for in situ bone regeneration in the field of bone tissue engineering. To this end, we constructed the gypsum-coated ß-tricalcium phosphate (G-TCP) scaffolds by combing a three-dimensional printing technique and an epitaxial gypsum growth method. In vitro simulation experiments showed that the as-prepared scaffolds could establish a dynamic and weakly acidic microenvironment in a simulated body liquid, in which the pH and the calcium ion concentration always changed due to the gypsum degradation and growth of bone-like apatite nanoplates on the scaffold surfaces. The cell experiments confirmed that the microenvironment established by the G-TCP surfaces promoted rapid osteogenic differentiation and proliferation of bone marrow mesenchymal stem cells (BM-MSCs). In vivo experiments confirmed that the G-TCP scaffolds had high bioactivity in modulating in situ regeneration of bone, and the bioactivity of the G-TCP scaffolds was endowed by correct pore structures, degradation of gypsum, and growth of a bone-like apatite layer. The microenvironment established by the gypsum degradation could stimulate tissue inflammation and recruit white blood cells and BM-MSCs and thus accelerating native healing cascades of the bone defects via a bone growth/remodeling-absorption cycle process. Furthermore, in vivo experiments demonstrated that after the bone defects had healed completely, the as-prepared scaffolds also degraded completely within 24 weeks.


Assuntos
Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Regeneração Óssea/efeitos dos fármacos , Sulfato de Cálcio/química , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Coelhos
14.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062885

RESUMO

The present in vivo study analyses both the inflammatory tissue reactions and the bone healing capacity of a newly developed bone substitute material (BSM) based on xenogeneic bone substitute granules combined with hyaluronate (HY) as a water-binding molecule. The results of the hyaluronate containing bone substitute material (BSM) were compared to a control xenogeneic BSM of the same chemical composition and a sham operation group up to 16 weeks post implantationem. A major focus of the study was to analyze the residual hyaluronate and its effects on the material-dependent healing behavior and the inflammatory tissue responses. The study included 63 male Wistar rats using the calvaria implantation model for 2, 8, and 16 weeks post implantationem. Established and Good Laboratory Practice (GLP)-conforming histological, histopathological, and histomorphometrical analysis methods were conducted. The results showed that the new hyaluronate containing BSM was gradually integrated within newly formed bone up to the end of the study that ended in a condition of complete bone defect healing. Thereby, no differences to the healing capacity of the control BSM were found. However, the bone formation in both groups was continuously significantly higher compared to the sham operation group. Additionally, no differences in the (inflammatory) tissue response that was analyzed via qualitative and (semi-) quantitative methods were found. Interestingly, no differences were found between the numbers of pro- and anti-inflammatory macrophages between the three study groups over the entire course of the study. No signs of the HY as a water-binding part of the BSM were histologically detectable at any of the study time points, altogether the results of the present study show that HY allows for an optimal material-associated bone tissue healing comparable to the control xenogeneic BSM. The added HY seems to be degraded within a very short time period of less than 2 weeks so that the remaining BSM granules allow for a gradual osteoconductive bone regeneration. Additionally, no differences between the inflammatory tissue reactions in both material groups and the sham operation group were found. Thus, the new hyaluronate containing xenogeneic BSM and also the control BSM have been shown to be fully biocompatible without any differences regarding bone regeneration.


Assuntos
Substitutos Ósseos/farmacologia , Transplante Ósseo , Osteogênese/efeitos dos fármacos , Crânio/crescimento & desenvolvimento , Animais , Regeneração Óssea/efeitos dos fármacos , Substitutos Ósseos/química , Interface Osso-Implante/crescimento & desenvolvimento , Interface Osso-Implante/patologia , Humanos , Ácido Hialurônico/farmacologia , Hidroxiapatitas/farmacologia , Teste de Materiais , Ratos , Ratos Wistar , Crânio/efeitos dos fármacos , Água/química , Cicatrização/efeitos dos fármacos
15.
Molecules ; 26(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070497

RESUMO

Chronic inflammation and oxidative stress are two major mechanisms leading to the imbalance between bone resorption and bone formation rate, and subsequently, bone loss. Thus, functional foods and dietary compounds with antioxidant and anti-inflammatory could protect skeletal health. This review aims to examine the current evidence on the skeletal protective effects of propolis, a resin produced by bees, known to possess antioxidant and anti-inflammatory activities. A literature search was performed using Pubmed, Scopus, and Web of Science to identify studies on the effects of propolis on bone health. The search string used was (i) propolis AND (ii) (bone OR osteoporosis OR osteoblasts OR osteoclasts OR osteocytes). Eighteen studies were included in the current review. The available experimental studies demonstrated that propolis could prevent bone loss due to periodontitis, dental implantitis, and diabetes in animals. Combined with synthetic and natural grafts, it could also promote fracture healing. Propolis protects bone health by inhibiting osteoclastogenesis and promoting osteoblastogenesis, partly through its antioxidant and anti-inflammatory actions. Despite the promising preclinical results, the skeletal protective effects of propolis are yet to be proven in human studies. This research gap should be bridged before nutraceuticals based on propolis with specific health claims can be developed.


Assuntos
Osso e Ossos/efeitos dos fármacos , Periodonto/efeitos dos fármacos , Própole/farmacologia , Animais , Antioxidantes/farmacologia , Abelhas , Reabsorção Óssea , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos
16.
Molecules ; 26(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062884

RESUMO

Osteoporosis is a systemic metabolic bone disorder that is caused by an imbalance in the functions of osteoclasts and osteoblasts and is characterized by excessive bone resorption by osteoclasts. Targeting osteoclast differentiation and bone resorption is considered a good fundamental solution for overcoming bone diseases. ß-boswellic acid (ßBA) is a natural compound found in Boswellia serrata, which is an active ingredient with anti-inflammatory, anti-rheumatic, and anti-cancer effects. Here, we explored the anti-resorptive effect of ßBA on osteoclastogenesis. ßBA significantly inhibited the formation of tartrate-resistant acid phosphatase-positive osteoclasts induced by receptor activator of nuclear factor-B ligand (RANKL) and suppressed bone resorption without any cytotoxicity. Interestingly, ßBA significantly inhibited the phosphorylation of IκB, Btk, and PLCγ2 and the degradation of IκB. Additionally, ßBA strongly inhibited the mRNA and protein expression of c-Fos and NFATc1 induced by RANKL and subsequently attenuated the expression of osteoclast marker genes, such as OC-STAMP, DC-STAMP, ß3-integrin, MMP9, ATP6v0d2, and CtsK. These results suggest that ßBA is a potential therapeutic candidate for the treatment of excessive osteoclast-induced bone diseases such as osteoporosis.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Reabsorção Óssea , Regulação da Expressão Gênica , Osteoclastos/metabolismo , Fosfolipase C gama/metabolismo , Ligante RANK , Triterpenos/farmacologia , Animais , Boswellia , Diferenciação Celular , Técnicas de Cocultura , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Fosforilação , Transdução de Sinais
17.
Int J Nanomedicine ; 16: 3633-3648, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079254

RESUMO

Purpose: The deposition of hydroxyapatite (HAp) crystals plays an important role in the development of vascular calcification (VC). This study aimed to demonstrate the effects of nanosized HAp (nHAp) on vascular smooth muscle cells (VSMCs) and VC progression. Methods: Transmission electron microscopy (TEM) was used to examine cellular uptake of nHAp. Cell viability was determined using CCK-8 assay kit. Mitochondrial impairment and reactive oxygen species were detected by TEM and fluorescence dye staining, respectively. Cell apoptosis was detected by Western blot analysis and Annexin V staining. Mouse model of VC was built via applying nHAp on the surface of abdominal aorta. Calcification was visualized by Alizarin red and von Kossa staining. Results: We found that nHAp could promote osteogenic transformation of VSMCs by elevating expression of runt-related factor 2 (Runx2), osteopontin (OPN) and alkaline phosphatase (ALP), impairing function and morphology of mitochondria and inducing apoptosis of VSMCs. More phosphorylation of c-Jun N-terminal protein kinase/c-JUN (JNK/c-JUN) in VSMCs was detected after mixing nHAp with VSMCs. HAp-induced osteogenic transformation of VSMCs was blocked by JNK inhibitor SP600125, resulted in decreased ALP activity, less Runx2 and OPN expressions. SP600125 also inhibited apoptosis of VSMCs. Application of nHAp to outside of aorta induced osteogenic transformation and apoptosis of VSMCs, and significant deposition of calcium on the vessel walls of mice, which can be effectively attenuated by SP600125. Conclusion: JNK/c-JUN signaling pathway is critical for nHAp-induced calcification, which could be a potential therapeutic target for controlling the progression of VC.


Assuntos
Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Durapatita/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Músculo Liso Vascular/citologia , Nanoestruturas/química , Osteogênese/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Durapatita/química , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Osteopontina/metabolismo , Espécies Reativas de Oxigênio/metabolismo
18.
Int J Nanomedicine ; 16: 3473-3485, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34040373

RESUMO

Background: Synthetic biomaterials have played an increasingly prominent role in the substitution of naturally derived biomaterials in current surgery practice. In vitro and in vivo characterization studies of new synthetic biomaterials are essential to analyze their physicochemical properties and the underlying mechanisms associated with the modulation of the inflammatory process and bone healing. Purpose: This study compares the in vivo tissue behavior of a synthetic biomaterial nano-hydroxyapatite/beta-tricalcium phosphate (nano-HA/ß-TCP mixture) and deproteinized bovine bone mineral (DBBM) in a rat calvarial defect model. The innovation of this work is in the comparative analysis of the effect of new synthetic and commercially xenogenic biomaterials on the inflammatory response, bone matrix gain, and stimulation of osteoclastogenesis and osteoblastogenesis. Methods: Both biomaterials were inserted in rat defects. The animals were divided into three groups, in which calvarial defects were filled with xenogenic biomaterials (group 1) and synthetic biomaterials (group 2), or left unfilled (group 3, controls). Sixty days after calvarial bone defects filled with biomaterials, periodic acid Schiff (PAS) and Masson's trichrome staining, immunohistochemistry tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase-9 (MMP-9), and electron microscopy analyses were conducted. Results: Histomorphometric analysis revealed powerful effects such as a higher amount of proteinaceous matrix and higher levels of TNF-α and MMP-9 in bone defects treated with alloplastic nano-HA/ß-TCP mixture than xenogenicxenogic biomaterial, as well as collagen-proteinaceous material in association with hydroxyapatite crystalloids. Conclusion: These data indicate that the synthetic nano-HA/ß-TCP mixture enhanced bone formation/remodeling in rat calvarial bone defects. The nano-HA/ß-TCP did not present risks of cross-infection/disease transmission. The synthetic nano-hydroxyapatite/beta-tricalcium phosphate mixture presented adequate properties for guided bone regeneration and guided tissue regeneration for dental surgical procedures.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Hidroxiapatitas/química , Hidroxiapatitas/farmacologia , Nanoestruturas/química , Crânio/efeitos dos fármacos , Crânio/fisiologia , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Colágeno/metabolismo , Masculino , Osteogênese/efeitos dos fármacos , Ratos , Crânio/metabolismo , Crânio/patologia
19.
Nat Commun ; 12(1): 2885, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001887

RESUMO

Despite the widespread observations on the osteogenic effects of magnesium ion (Mg2+), the diverse roles of Mg2+ during bone healing have not been systematically dissected. Here, we reveal a previously unknown, biphasic mode of action of Mg2+ in bone repair. During the early inflammation phase, Mg2+ contributes to an upregulated expression of transient receptor potential cation channel member 7 (TRPM7), and a TRPM7-dependent influx of Mg2+ in the monocyte-macrophage lineage, resulting in the cleavage and nuclear accumulation of TRPM7-cleaved kinase fragments (M7CKs). This then triggers the phosphorylation of Histone H3 at serine 10, in a TRPM7-dependent manner at the promoters of inflammatory cytokines, leading to the formation of a pro-osteogenic immune microenvironment. In the later remodeling phase, however, the continued exposure of Mg2+ not only lead to the over-activation of NF-κB signaling in macrophages and increased number of osteoclastic-like cells but also decelerates bone maturation through the suppression of hydroxyapatite precipitation. Thus, the negative effects of Mg2+ on osteogenesis can override the initial pro-osteogenic benefits of Mg2+. Taken together, this study establishes a paradigm shift in the understanding of the diverse and multifaceted roles of Mg2+ in bone healing.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Fêmur/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Macrófagos/metabolismo , Magnésio/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Cátion TRPM/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Fêmur/metabolismo , Fêmur/patologia , Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Macrófagos/citologia , Macrófagos/imunologia , Magnésio/administração & dosagem , Magnésio/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Proteínas Serina-Treonina Quinases/genética , Ratos Sprague-Dawley , Células THP-1 , Canais de Cátion TRPM/genética
20.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946862

RESUMO

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.


Assuntos
Reabsorção Óssea/fisiopatologia , Lumicana/farmacologia , Osteoclastos/metabolismo , Osteogênese/fisiologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Fusão Celular , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Lumicana/fisiologia , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Osteogênese/efeitos dos fármacos , Osteoprotegerina/biossíntese , Ligante RANK/biossíntese , Ligante RANK/farmacologia , Proteínas Recombinantes/farmacologia
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