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1.
Int J Mol Med ; 47(4): 1, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33537804

RESUMEN

Quercetin (Quer) is a typical antioxidant flavonoid from plants that is involved in bone metabolism, as well as in the progression of inflammatory diseases. Elevated levels of tumor necrosis factor­α (TNF­α), a typical pro­inflammatory cytokine, can affect osteogenesis. In the present study, TNF­α was used to establish an in vitro model of periodontitis. The effects of Quer on, as well as its potential role in the osteogenic response of human periodontal ligament stem cells (hPDLSCs) under TNF­α­induced inflammatory conditions and the underlying mechanisms were then investigated. Within the appropriate concentration range, Quer did not exhibit any cytotoxicity. More importantly, Quer significantly attenuated the TNF­α induced the suppression of osteogenesis­related genes and proteins, alkaline phosphatase (ALP) activity and mineralized matrix in the hPDLSCs. These findings were associated with the fact that Quer inhibited the activation of the NF­κB signaling pathway, as well as the expression of NLRP3 inflammation­associated proteins in the inflammatory microenvironment. Moreover, the silencing of NLRP3 by small interfering RNA (siRNA) was found to protect the hPDLSCs against TNF­α­induced osteogenic damage, which was in accordance with the effects of Quer. On the whole, the present study demonstrates that Quer reduces the impaired osteogenesis of hPDLSCs under TNF­α­induced inflammatory conditions by inhibiting the NF­κB/NLRP3 inflammasome pathway. Thus, Quer may prove to be a potential remedy against periodontal bone defects.


Asunto(s)
Inflamasomas/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Osteogénesis/efectos de los fármacos , Ligamento Periodontal/patología , Quercetina/farmacología , Células Madre/patología , Factor de Necrosis Tumoral alfa/toxicidad , Adolescente , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Humanos , Mediadores de Inflamación/metabolismo , Sustancias Protectoras/farmacología , Transducción de Señal/efectos de los fármacos , Células Madre/efectos de los fármacos , Adulto Joven
2.
Int J Nanomedicine ; 16: 61-73, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33442250

RESUMEN

Objective: Cell sheet technology (CST) is advantageous for repairing alveolar bone defects in clinical situations, and osteogenic induction before implantation may result in enhanced bone regeneration. Herein, we observed the effect of gold nanoparticles (AuNPs) on osteogenic differentiation of periodontal ligament stem cell (PDLSC) sheets and explored their potential mechanism of action. Methods: PDLSCs were cultured in cell sheet induction medium to obtain cell sheets. PDLSC sheets were treated with or without AuNPs. Alkaline phosphatase, alizarin red S, von Kossa, and immunofluorescence staining were used to observe the effects of AuNPs on the osteogenic differentiation of PDLSC sheets. Western blotting was performed to evaluate the osteogenic effects and autophagy activity. The cell sheets were transplanted into the dorsa of nude mice, and bone regeneration was analyzed by micro-CT and histological staining. Results: AuNPs could promote the osteogenic differentiation of PDLSC sheets by upregulating bone-related protein expression and mineralization. The 45-nm AuNPs were more effective than 13-nm AuNPs. Additional analysis demonstrated that their ability to promote differentiation could depend on activation of the autophagy pathway through upregulation of microtubule-associated protein light chain 3 and downregulation of sequestosome 1/p62. Furthermore, AuNPs significantly promoted the bone regeneration of PDLSC sheets in ectopic models. Conclusion: AuNPs enhance the osteogenesis of PDLSC sheets by activating autophagy, and 45-nm AuNPs were more effective than 13-nm AuNPs. This study may provide an AuNP-based pretreatment strategy for improving the application of CST in bone repair and regeneration.


Asunto(s)
Autofagia/efectos de los fármacos , Regeneración Ósea/efectos de los fármacos , Oro/farmacología , Nanopartículas del Metal/química , Ligamento Periodontal/fisiología , Células Madre/citología , Fosfatasa Alcalina/metabolismo , Animales , Fosfatos de Calcio/farmacología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Masculino , Nanopartículas del Metal/ultraestructura , Ratones Desnudos , Osteocalcina/metabolismo , Osteogénesis/efectos de los fármacos , Osteopontina/metabolismo , Osteoprotegerina/metabolismo , Ligamento Periodontal/efectos de los fármacos , Células Madre/efectos de los fármacos , Microtomografía por Rayos X
3.
Int J Nanomedicine ; 16: 147-159, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33456309

RESUMEN

Background: There is still a big challenge to achieve a balance between mechanical characteristics and biological properties in biphasic calcium phosphate (BCP) ceramics. Purpose: The present study focused on the in-situ whisker growth on BCP ceramics via different hydrothermal treatments and investigated the influences of these whiskers on the mechanical property and biological performance of the ceramics. Methods: Five kinds of BCP ceramics with in-situ whisker growth, ie, BCP-C, BCP-HNO3, BCP-Citric, BCP-NaOH, BCP-CaCl2 and BCP-Na3PO4 were fabricated by different hydrothermal treatments. The phase compositions, morphologies, crystal structures and mechanical strengths of the obtained BCP ceramics were firstly characterized. Then, the in vitro cell adhesion, proliferation and alkaline  phosphatase (ALP) activity of bone marrow stromal cells (BMSCs) on the BCP ceramics were evaluated. Lastly, the effects of in-situ whisker growth on the bone-like apatite formation abilities of BCP ceramics were also investigated by immersing them in simulated body fluid (SBF). Results: The results demonstrated that the hydrothermal conditions, especially the hydrothermal media, were crucial to determine the phase composition and morphology of the in-situ whisker. Especially among the five media used (HNO3, Citric, NaOH, CaCl2 and Na3PO4), the Na3PO4 treatment resulted in the shortest whisker with a unique hollow structure, and kept the original biphasic composition. All five kinds of whiskers increased the mechanical strength of BCP ceramics to some extent, and showed the good ability of bone-like apatite formation. The in vitro cell study demonstrated that the in-situ whisker growth had no adverse but even positive effect on the adhesion, proliferation and ALP activity of BMSCs. Conclusion: Due to the growth of in-situ whiskers, the mechanical property and biological performance of the obtained BCP ceramics could increase simultaneously. Therefore, in-situ whiskers growth offers a promising strategy for the expanded application of BCP ceramics to meet the requirements of regenerative medicine.


Asunto(s)
Fosfatos de Calcio/química , Cerámica/química , Temperatura , Agua/química , Fosfatasa Alcalina/metabolismo , Animales , Apatitas/metabolismo , Adhesión Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayo de Materiales , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/ultraestructura , Ratones , Osteogénesis/efectos de los fármacos , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos X
4.
Nat Commun ; 12(1): 421, 2021 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-33462210

RESUMEN

Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on bone marrow mesenchymal stromal cells (MSCs). MM-MSCs exhibit abnormal transcriptomes, suggesting the involvement of epigenetic mechanisms governing their tumor-promoting functions and prolonged osteoblast suppression. Here, we identify widespread DNA methylation alterations of bone marrow-isolated MSCs from distinct MM stages, particularly in Homeobox genes involved in osteogenic differentiation that associate with their aberrant expression. Moreover, these DNA methylation changes are recapitulated in vitro by exposing MSCs from healthy individuals to MM cells. Pharmacological targeting of DNMTs and G9a with dual inhibitor CM-272 reverts the expression of hypermethylated osteogenic regulators and promotes osteoblast differentiation of myeloma MSCs. Most importantly, CM-272 treatment prevents tumor-associated bone loss and reduces tumor burden in a murine myeloma model. Our results demonstrate that epigenetic aberrancies mediate the impairment of bone formation in MM, and its targeting by CM-272 is able to reverse MBD.


Asunto(s)
Antineoplásicos/farmacología , Enfermedades Óseas/tratamiento farmacológico , Metilación de ADN/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/uso terapéutico , Enfermedades Óseas/diagnóstico , Enfermedades Óseas/genética , Enfermedades Óseas/patología , Médula Ósea/patología , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Femenino , Fémur/diagnóstico por imagen , Fémur/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antígenos de Histocompatibilidad/metabolismo , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Masculino , Células Madre Mesenquimatosas/patología , Ratones , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Int J Nanomedicine ; 16: 331-343, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33488075

RESUMEN

Purpose: Redox homeostasis plays an important role in the osteogenic differentiation of human mesenchymal stem cells (hMSCs) for bone engineering. Oxidative stress (OS) is believed to induce osteoporosis by changing bone homeostasis. Selenium nanoparticles (SeNPs), an antioxidant with pleiotropic pharmacological activity, prevent bone loss. However, the molecular mechanism underlying the osteogenic activity during hMSC-SeNP interaction is unclear. Methods: This study assessed the effects of different concentrations (25, 50, 100, and 300 ng/mL) of SeNPs on the cell viability and differentiation ability of human embryonic stem cell-derived hMSCs. In addition, we analyzed OS markers and their effect on mitogen-activated protein kinase (MAPK) and Forkhead box O3 (FOXO3) during osteogenesis. Results: SeNPs increased the cell viability of hMSCs and induced their differentiation toward an osteogenic over an adipogenic lineage by enhancing osteogenic transcription and mineralization, while inhibiting Nile red staining and adipogenic gene expression. By preventing excessive reactive oxygen species accumulation, SeNPs increased antioxidant levels in hMSCs undergoing osteogenesis compared to untreated cells. In addition, SeNPs significantly upregulated the gene and protein expression of phosphorylated c-Jun N-terminal kinase (JNK) and FOXO3a, with no significant change in the expression levels of extracellular signal-related kinase (ERK) and p38 MAPK. Conclusion: The results approved that low concentrations of SeNPs might enhance the cell viability and osteogenic potential of hMSCs by moderating OS. Increased JNK and FOXO3a expression shows that SeNPs might enhance osteogenesis via activation of the JNK/FOXO3 pathway. In addition, SeNP co-supplementation might prevent bone loss by enhancing osteogenesis and, thus, can be an effective candidate for treating osteoporosis through cell-based therapy.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Nanopartículas , Osteoblastos/citología , Estrés Oxidativo/efectos de los fármacos , Selenio/química , Selenio/farmacología , Adipogénesis/efectos de los fármacos , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
6.
Cell Prolif ; 54(2): e12973, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33382502

RESUMEN

OBJECTIVES: NLRP3 inflammasome is a critical part of the innate immune system and plays an important role in a variety of inflammatory diseases. However, the effects of NLRP3 inflammasome on periodontitis have not been fully studied. MATERIALS AND METHODS: We used ligature-induced periodontitis models of NLRP3 knockout mice (NLRP3KO ) and their wildtype (WT) littermates to compare their alveolar bone phenotypes. We further used Lysm-Cre/RosanTnG mouse to trace the changes of Lysm-Cre+ osteoclast precursors in ligature-induced periodontitis with or without MCC950 treatment. At last, we explored MCC950 as a potential drug for the treatment of periodontitis in vivo and in vitro. RESULTS: Here, we showed that the number of osteoclast precursors, osteoclast differentiation and alveolar bone loss were reduced in NLRP3KO mice compared with WT littermates, by using ligature-induced periodontitis model. Next, MCC950, a specific inhibitor of the NLRP3 inflammasome, was used to inhibit osteoclast precursors differentiation into osteoclast. Further, we used Lysm-Cre/RosanTnG mice to demonstrate that MCC950 decreases the number of Lysm-Cre+ osteoclast precursors in ligature-induced periodontitis. At last, treatment with MCC950 significantly suppressed alveolar bone loss with reduced IL-1ß activation and osteoclast differentiation in ligature-induced periodontitis. CONCLUSION: Our findings reveal that NLRP3 regulates alveolar bone loss in ligature-induced periodontitis by promoting osteoclastic differentiation.


Asunto(s)
Pérdida de Hueso Alveolar/patología , Diferenciación Celular , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Osteoclastos/citología , Periodontitis/patología , Pérdida de Hueso Alveolar/metabolismo , Pérdida de Hueso Alveolar/prevención & control , Animales , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Inflamasomas/efectos de los fármacos , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos , Periodontitis/tratamiento farmacológico , Periodontitis/etiología , Células Madre/citología , Células Madre/metabolismo , Sulfonas/farmacología , Sulfonas/uso terapéutico
7.
Cell Prolif ; 54(2): e12969, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33332682

RESUMEN

OBJECTIVES: Various factors could interfere the biological performance of DPSCs during post-thawed process. Yet, little has been known about optimization of the recovery medium for DPSCs. Thus, our study aimed to explore the effects of adding recombinant bFGF on DPSCs after 3-month cryopreservation as well as the underlying mechanisms. MATERIALS AND METHODS: DPSCs were extracted from impacted third molars and purified by MACS. The properties of CD146+ DPSCs (P3) were identified by CCK-8 and flow cytometry. After cryopreservation for 3 months, recovered DPSCs (P4) were immediately supplied with a series of bFGF and analysed cellular proliferation by CCK-8. Then, the optimal dosage of bFGF was determined to further identify apoptosis and TRPC1 channel through Western blot. The succeeding passage (P5) from bFGF pre-treated DPSCs was cultivated in bFGF-free culture medium, cellular proliferation and stemness were verified, and pluripotency was analysed by neurogenic, osteogenic and adipogenic differentiation. RESULTS: It is found that adding 20 ng/mL bFGF in culture medium could significantly promote the proliferation of freshly thawed DPSCs (P4) through suppressing apoptosis, activating ERK pathway and up-regulating TRPC1. Such proliferative superiority could be inherited to the succeeding passage (P5) from bFGF pre-stimulated DPSCs, meanwhile, stemness and pluripotency have not been compromised. CONCLUSIONS: This study illustrated a safe and feasible cell culture technique to rapidly amplify post-thawed DPSCs with robust regenerative potency, which brightening the future of stem cells banking and tissue engineering.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Pulpa Dental/metabolismo , Factor 2 de Crecimiento de Fibroblastos/farmacología , Adipogénesis/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antígeno CD146/metabolismo , Diferenciación Celular/efectos de los fármacos , Criopreservación , Medios de Cultivo/química , Pulpa Dental/citología , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína Homeótica Nanog/metabolismo , Osteogénesis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Células Madre/citología , Células Madre/metabolismo , Canales Catiónicos TRPC/antagonistas & inhibidores , Canales Catiónicos TRPC/metabolismo , Factores de Tiempo , Regulación hacia Arriba/efectos de los fármacos
8.
Nat Rev Endocrinol ; 17(1): 31-46, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33149262

RESUMEN

Over the past three decades, the mainstay of treatment for osteoporosis has been antiresorptive agents (such as bisphosphonates), which have been effective with continued administration in lowering fracture risk. However, the clinical landscape has changed as adherence to these medications has declined due to perceived adverse effects. As a result, decreases in hip fracture rates that followed the introduction of bisphosphonates have now levelled off, which is coincident with a decline in the use of the antiresorptive agents. In the past two decades, two types of anabolic agents (including three new drugs), which represent a novel approach to improving bone quality by increasing bone formation, have been approved. These therapies are expected to lead to a new clinical paradigm in which anabolic agents will be used either alone or in combination with antiresorptive agents to build new bone and reduce fracture risk. This Review examines the mechanisms of action for these anabolic agents by detailing their receptor-activating properties for key cell types in the bone and marrow niches. Using these advances in bone biology as context, the comparative effectiveness of these anabolic agents is discussed in relation to other therapeutic options for osteoporosis to better guide their clinical application in the future.


Asunto(s)
Anabolizantes/uso terapéutico , Osteoporosis/tratamiento farmacológico , Anabolizantes/farmacología , Animales , Conservadores de la Densidad Ósea/uso terapéutico , Remodelación Ósea/efectos de los fármacos , Humanos , Osteogénesis/efectos de los fármacos , Osteoporosis/metabolismo , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento
9.
Gene ; 771: 145347, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33333228

RESUMEN

BACKGROUND: Pre-licensing mesenchymal stromal cells (MSCs) with IFN-γ and TNF-α can empower their immune fate and induce a more effective immune regulation. However, the cellular heterogeneity of MSCs limits our understanding of this inflammatory licensing. METHODS: The publicly available Gene Expression Omnibus single-cell RNA sequencing (scRNA-seq) data of human bone marrow-derived MSCs with or without IFN-γ and TNF-α licensing were analyzed. Based on the scRNA-seq data and related marker genes, the cell-cycle, stemness, differentiative potencies, and immunomodulate capability of unlicensed and licensed MSCs were compared. RESULTS: After removing low-quality cells and regressing out the ribosomal gene effects, high-quality data reflecting IFN-γ and TNF-α effect on MSCs were chosen for further analysis. Despite the heterogeneity, pre-licensing didn't influence the cell-cycle and stemness of human bone marrow-derived MSCs. The osteogenesis potencies were decreased, the chondrogenesis potencies were increased while the adipogenesis potencies were stable in licensed MSCs. Licensed MSCs also showed more effective immunomodulate capability including expression of related chemokines, cytokines, surface molecules, and receptors. CONCLUSION: Collectively, our study showed the expression profiles of human bone marrow-derived unlicensed and licensed MSCs about the cell cycle, stemness, differentiative potencies, and immunomodulate capability at single-cell resolution, which may help the comprehensive understanding about the inflammatory licensing of human bone marrow-derived MSCs and their further clinical application.


Asunto(s)
Redes Reguladoras de Genes/efectos de los fármacos , Interferón gamma/farmacología , Células Madre Mesenquimatosas/citología , Análisis de la Célula Individual/métodos , Factor de Necrosis Tumoral alfa/farmacología , Ciclo Celular/efectos de los fármacos , Diferenciación Celular , Células Cultivadas , Condrogénesis/efectos de los fármacos , Bases de Datos Genéticas , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/inmunología , Osteogénesis/efectos de los fármacos , Análisis de Secuencia de ARN
10.
Gene ; 766: 145128, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32911026

RESUMEN

BACKGROUND: The pathogenesis of osteonecrosis of the femoral head (ONFH) is unclear. Our previous study demonstrated that upregulated miR-335 in bone microvascular endothelial cells (BMECs) might be associated with the disease of steroid-induced ONFH. Here, we study the preventive effect of ICA on steroid-induced ONFH in rats. METHOD: 90 rats were separated into three groups: control group, methylprednisolone (MPS) group, and MPS + Icariin (ICA) group. Four weeks later, histological analyses were performed. Thrombomodulin (TM) and vascular endothelial growth factor (VEGF) were tested. MiRNA-335 expression was screened in the three groups using Agilent Gene Spring GX software. Target genes of miRNA-335 were detected by bioinformatics analysis. The functions of BMECs were analyzed by scratch, angiogenesis and cell survival rate. RESULTS: ICA can prevent the occurrence of steroid-associated ONFH in rats and reduce the amount of TM and VEGF in serum induced by glucocorticoids. ICA could regulate the overexpression of miRNA-335 induced by glucocorticoids. We predicted the Gene ontology (GO) and signaling pathways of target genes. At 24 hours, we found that ICA significantly promoted BMECs migration abilities. We also found that ICA could promote the angioplasty ability of BMECs. ICA could improve the survival rate of BMECs after steroid-induced injury. CONCLUSIONS: ICA is effective to prevent the occurrence of steroidinduced ONFH. ICA has a protective effect against steroid-induced BMECs injury. ICA regulated the imbalance of miRNA-335 expression induced by the glucocorticoid in BMECs, which provides a new viewpoint to explore the mechanism of ICA in preventing steroid-induced ONFH.


Asunto(s)
Células Endoteliales/efectos de los fármacos , Necrosis de la Cabeza Femoral/tratamiento farmacológico , Cabeza Femoral/efectos de los fármacos , Flavonoides/farmacología , MicroARNs/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Sustancias Protectoras/farmacología , Adipogénesis/efectos de los fármacos , Animales , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Cabeza Femoral/metabolismo , Necrosis de la Cabeza Femoral/inducido químicamente , Necrosis de la Cabeza Femoral/metabolismo , Glucocorticoides/metabolismo , Metilprednisolona/farmacología , Neovascularización Patológica/metabolismo , Osteocitos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Esteroides/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo
11.
Phytomedicine ; 80: 153377, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33126167

RESUMEN

BACKGROUND: Osteoporosis is a threat to aged people who have excessive osteoclast activation and bone resorption, subsequently causing fracture and even disability. Inhibiting osteoclast differentiation and absorptive functions has become an efficient approach to treat osteoporosis, but osteoclast-targeting inhibitors available clinically remain rare. Kirenol (Kir), a bioactive diterpenoid derived from an antirheumatic Chinese herbal medicine Herba Siegesbeckiae, can treat collagen-induced arthritis in vivo and promote osteoblast differentiation in vitro, while the effects of Kir on osteoclasts are still unclear. PURPOSE: We explore the role of Kir on RANKL-induced osteoclastogenesis in vitro and bone loss in vivo. METHODS: The in vitro effects of Kir on osteoclast differentiation, bone resorption and the underlying mechanisms were evaluated with bone marrow-derived macrophages (BMMs). In vivo experiments were performed using an ovariectomy (OVX)-induced osteoporosis model. RESULTS: We found that Kir remarkably inhibited osteoclast generation and bone resorption in vitro. Mechanistically, Kir significantly inhibited F-actinring formation and repressed RANKL-induced NF-κB p65 activation and p-p38, p-ERK and c-Fos expression. Moreover, Kir inhibited both the expression and nuclear translocation of NFATc1. Ca2+ oscillation and caveolin-1 (Cav-1) were also reduced by Kir during osteoclastogenesis in vitro. Consistent with these findings, 2-10 mg/kg Kir attenuated OVX-induced osteoporosis in vivo as evidenced by decreased osteoclast numbers and downregulated Cav-1 and NFATc1 expression. CONCLUSIONS: Kir suppresses osteoclastogenesis and the Cav-1/NFATc1 signaling pathway both in vitro and in vivo and protects against OVX-induced osteoporosis. Our findings reveal Kir as a potential safe oral treatment for osteoporosis.


Asunto(s)
Caveolina 1/metabolismo , Diterpenos/farmacología , Factores de Transcripción NFATC/metabolismo , Osteogénesis/efectos de los fármacos , Osteoporosis/prevención & control , Administración Oral , Animales , Resorción Ósea/prevención & control , Calcio/metabolismo , Diferenciación Celular/efectos de los fármacos , Diterpenos/administración & dosificación , Femenino , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Osteoclastos/efectos de los fármacos , Osteoporosis/etiología , Ovariectomía/efectos adversos , Ligando RANK/metabolismo , Ligando RANK/farmacología , Transducción de Señal/efectos de los fármacos
12.
Int J Nanomedicine ; 15: 10029-10043, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33335393

RESUMEN

Purpose: Despite the significant advances in modeling of biomechanical aspects of cell microenvironment, it remains a major challenge to precisely mimic the physiological condition of the particular cell niche. Here, the metal-organic frameworks (MOFs) have been introduced as a feasible platform for multifactorial control of cell-substrate interaction, given the wide range of physical and mechanical properties of MOF materials and their structural flexibility. Results: In situ crystallization of zeolitic imidazolate framework-8 (ZIF-8) on the polydopamine (PDA)-modified membrane significantly raised surface energy, wettability, roughness, and stiffness of the substrate. This modulation led to an almost twofold increment in the primary attachment of dental pulp stem cells (DPSCs) compare to conventional plastic culture dishes. The findings indicate that polypropylene (PP) membrane modified by PDA/ZIF-8 coating effectively supports the growth and proliferation of DPSCs at a substantial rate. Further analysis also displayed the exaggerated multilineage differentiation of DPSCs with amplified level of autocrine cell fate determination signals, like BSP1, BMP2, PPARG, FABP4, ACAN, and COL2A. Notably, osteogenic markers were dramatically overexpressed (more than 100-folds rather than tissue culture plate) in response to biomechanical characteristics of the ZIF-8 layer. Conclusion: Hence, surface modification of cell culture platforms with MOF nanostructures proposed as a powerful nanomedical approach for selectively guiding stem cells for tissue regeneration. In particular, PP/PDA/ZIF-8 membrane presented ideal characteristics for using as a barrier membrane for guided bone regeneration (GBR) in periodontal tissue engineering.


Asunto(s)
Regeneración Ósea/efectos de los fármacos , Técnicas de Cultivo de Célula/métodos , Regeneración Tisular Dirigida/métodos , Membranas Artificiales , Polipropilenos/química , Polipropilenos/farmacología , Zeolitas/química , Diferenciación Celular/efectos de los fármacos , Indoles/química , Osteogénesis/efectos de los fármacos , Polímeros/química , Células Madre/citología , Células Madre/efectos de los fármacos
13.
Int J Nanomedicine ; 15: 8465-8478, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33149587

RESUMEN

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.


Asunto(s)
Ácido Aspártico/química , Materiales Biocompatibles/farmacología , Proteína Morfogenética Ósea 2/farmacología , Huesos/efectos de los fármacos , Cerámica/farmacología , Matriz Extracelular/metabolismo , Osteoblastos/efectos de los fármacos , Péptidos/farmacología , Factor de Crecimiento Transformador beta/farmacología , Animales , Regeneración Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Cinética , Masculino , Ratones , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Porosidad , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacología , Porcinos , Andamios del Tejido/química
14.
Nat Commun ; 11(1): 5596, 2020 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-33154378

RESUMEN

Age-related osteoporosis is characterized by the deterioration in bone volume and strength, partly due to the dysfunction of bone marrow mesenchymal stromal/stem cells (MSCs) during aging. Alpha-ketoglutarate (αKG) is an essential intermediate in the tricarboxylic acid (TCA) cycle. Studies have revealed that αKG extends the lifespan of worms and maintains the pluripotency of embryonic stem cells (ESCs). Here, we show that the administration of αKG increases the bone mass of aged mice, attenuates age-related bone loss, and accelerates bone regeneration of aged rodents. αKG ameliorates the senescence-associated (SA) phenotypes of bone marrow MSCs derived from aged mice, as well as promoting their proliferation, colony formation, migration, and osteogenic potential. Mechanistically, αKG decreases the accumulations of H3K9me3 and H3K27me3, and subsequently upregulates BMP signaling and Nanog expression. Collectively, our findings illuminate the role of αKG in rejuvenating MSCs and ameliorating age-related osteoporosis, with a promising therapeutic potential in age-related diseases.


Asunto(s)
Envejecimiento , Histonas/metabolismo , Ácidos Cetoglutáricos/uso terapéutico , Osteoporosis/tratamiento farmacológico , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Biomarcadores/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Regeneración Ósea/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Femenino , Ácidos Cetoglutáricos/sangre , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Metilación/efectos de los fármacos , Ratones , Osteogénesis/efectos de los fármacos , Osteoporosis/metabolismo , Osteoporosis/patología , Transducción de Señal/efectos de los fármacos
15.
Int J Nanomedicine ; 15: 7185-7198, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33061375

RESUMEN

Background: Next generation of coating materials on the surface of implants is designed with a paradigm shift from an inert material to an osteoimmunomodulatory material. Regulating immune response to biomedical implants through influencing the polarization of macrophage has been proven to be an effective strategy. Methods: Through anodization and hydrothermal treatment, magnesium ion incorporated TiO2 nanotube array (MgN) coating was fabricated on the surface of titanium and it is hypothesized that it has osteoimmunomodulatory properties. To verify this assumption, systematic studies were carried out by in vitro and in vivo experiments. Results: Mg ion release behavior results showed that MgN coating was successfully fabricated on the surface of titanium using anodization and hydrothermal technology. Scanning electron microscopy (SEM) images showed the morphology of the MgN coating on the titanium. The expression of inflammation-related genes (IL-6, IL-1ß, TNF-α) was downregulated in MgN group compared with TiO2 nanotube (NT) and blank Ti groups, but anti-inflammatory genes (IL-10 and IL-1ra) were remarkably upregulated in the MgN group. The in vitro and in vivo results demonstrated that MgN coating influenced macrophage polarization toward the M2 phenotype compared with NT and blank-Ti groups, which enhanced osteogenic differentiation of rat bone mesenchymal stem cells rBMSCs in conditioned media (CM) generated by macrophages. Conclusion: MgN coating on the titanium endowed the surface with immune-regulatory features and exerted an advantageous effect on osteogenesis, thereby providing excellent strategies for the surface modification of biomedical implants.


Asunto(s)
Inflamación/patología , Macrófagos/patología , Magnesio/farmacología , Nanoestructuras/química , Oseointegración/efectos de los fármacos , Titanio/farmacología , Animales , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Macrófagos/efectos de los fármacos , Ratones , Osteogénesis/efectos de los fármacos , Células RAW 264.7 , Ratas Wistar , Propiedades de Superficie
16.
Int J Nanomedicine ; 15: 7523-7551, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33116486

RESUMEN

During continuous innovation in the preparation, characterization and application of various bone repair materials for several decades, nanomaterials have exhibited many unique advantages. As a kind of representative two-dimensional nanomaterials, graphene and its derivatives (GDs) such as graphene oxide and reduced graphene oxide have shown promising potential for the application in bone repair based on their excellent mechanical properties, electrical conductivity, large specific surface area (SSA) and atomic structure stability. Herein, we reviewed the updated application of them in bone repair in order to present, as comprehensively, as possible, their specific advantages, challenges and current solutions. Firstly, how their advantages have been utilized in bone repair materials with improved bone formation ability was discussed. Especially, the effects of further functionalization or modification were emphasized. Then, the signaling pathways involved in GDs-induced osteogenic differentiation of stem cells and immunomodulatory mechanism of GDs-induced bone regeneration were discussed. On the other hand, their applications as contrast agents in the field of bone repair were summarized. In addition, we also reviewed the progress and related principles of the effects of GDs parameters on cytotoxicity and residues. At last, the future research was prospected.


Asunto(s)
Regeneración Ósea/efectos de los fármacos , Grafito/farmacología , Nanoestructuras/química , Osteogénesis/efectos de los fármacos , Animales , Materiales Biocompatibles/química , Huesos/citología , Diferenciación Celular/efectos de los fármacos , Conductividad Eléctrica , Grafito/química , Humanos , Osteogénesis/fisiología , Células Madre/citología , Ingeniería de Tejidos/métodos
17.
Int J Nanomedicine ; 15: 7889-7900, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33116507

RESUMEN

Purpose: In this study, a novel oxygenated nanocomposite thin film, TaON-Ag, was investigated in vitro and in vivo to evaluate its biocompatibility and antibacterial ability. Material and Methods: The antibacterial ability of TaON-Ag nanocomposite-coated titanium (Ti) was evaluated using the Kirby-Bauer disk diffusion susceptibility test. The effects of TaON-Ag nanocomposite-coated metal on osteogenesis were further evaluated in an in vitro osteogenic culture model with rat marrow-derived mesenchymal stem cells (rMSCs). Furthermore, titanium rods coated with TaON-Ag were implanted into a rat femur fracture model either with or without osteomyelitis to investigate the effects of TaON-Ag in osteogenesis. Results: The TaON-Ag-coated Ti exhibited an effective antibacterial effect against Staphylococcus aureus, coagulase-negative Staphylococcus, and the Gram-negative strains Escherichia coli and Pseudomonas aeruginosa. Using an osteogenic culture with rMSCs and a rat femoral fracture model, the TaON-Ag-coated Ti did not interfere with the ossification of rMSCs in vitro or during fracture healing in vivo. Field-emission scanning electron microscopy (FE-SEM) revealed that coating with TaON-Ag could inhibit pathogen adhesion and biofilm formation in both Staphylococcus aureus and Escherichia coli. Conclusion: Using the proposed novel oxygenation process, TaON-Ag nanocomposite-coated Ti yielded robust biocompatibility and antibacterial ability against common microorganisms in orthopedic infections, thereby demonstrating potential for use in clinical applications.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Nanocompuestos/química , Ortopedia , Plata/química , Titanio/química , Titanio/farmacología , Animales , Fracturas del Cuello Femoral/microbiología , Ensayo de Materiales , Osteogénesis/efectos de los fármacos , Osteomielitis/prevención & control , Prótesis e Implantes , Ratas
18.
Cell Prolif ; 53(10): e12882, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32871020

RESUMEN

OBJECTIVES: Intracellular reactive oxygen species (ROS) induced by receptor activator of NF-kB ligand (RANKL) has been proven to be a critical factor in the development of osteoclasts. This study aimed to prove that schisandrin A (Sch), a novel anti-oxidant compound, is able to suppress osteoclastogenesis and prevent bone loss in ovariectomized (OVX) mice by suppressing ROS via nuclear factor erythroid 2-related factor (Nrf2). MATERIAL AND METHODS: Micro-CT was used to detect bone formation. The effects of Sch on receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced reactive oxygen species (ROS) were measured by dihydroethidium (DHE) staining in vivo and 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining in vitro. Immunofluorescence staining was used to detect the expression of Nrf2 in vivo. siRNA was used to evaluate the effect of Nrf2 in osteoclastogenesis. RESULTS: Sch suppresses RANKL-induced ROS production by regulating nuclear factor erythroid 2-related factor (Nrf2) in vitro and vivo. Mechanistically, Sch enhances the expression of Nrf2 by regulating the degradation of Nrf2. Further, Sch suppresses phosphorylation of P65 and its nuclear translocation, as well as the degradation of IκBα. Collectively, our findings reveal that Sch protects against OVX-induced bone loss by suppressing ROS via Nrf2. CONCLUSIONS: Our results showed the potential of anti-oxidant compound schisandrin A in the treatment of osteoporosis, highlighting Nrf2 as a novel promising target in osteoclast-related disease.


Asunto(s)
Ciclooctanos/farmacología , Lignanos/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Osteogénesis/efectos de los fármacos , Compuestos Policíclicos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Femenino , Fémur/diagnóstico por imagen , Fémur/patología , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/genética , FN-kappa B/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Ligando RANK/farmacología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Células Madre/citología , Células Madre/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Regulación hacia Arriba/efectos de los fármacos
19.
Int J Nanomedicine ; 15: 6761-6777, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32982232

RESUMEN

Purpose: Guided bone regeneration (GBR) therapy, which is a widely used technique in clinical practice and is effective in improving the repair of alveolar bone defects or bone mass deficiency regeneration, requires the use of membrane materials with good biocompatibility, barrier function, rigidity matching the space maintenance ability, economic benefits and excellent clinical applicability. The aim of this study was to develop an electrospun attapulgite (ATT)-doped poly (lactic-co-glycolic acid) (PLGA) scaffold (PLGA/ATT scaffold) as a novel material for GBR applications. Methods and Results: Scanning electron microscopy (SEM) and X-ray diffraction (XRD) were used to determine the morphology and the crystalline structure of the PLGA/ATT scaffolds, respectively. Porosity and contact-angle measurements were also carried out to further characterize the physical properties of the PLGA/ATT scaffolds. The results of in vitro studies showed that bone marrow mesenchymal stem cells (BMSCs) attached more readily to and spread better over the PLGA/ATT scaffolds than the Bio-Gide membrane. Furthermore, in the in vitro osteoinductive experiments with BMSCs, the PLGA/ATT scaffolds were found to enhance the activity of alkaline phosphatase (ALP), promote the formation of mineralized bone nodules, and up-regulate the expression of several osteogenic markers-namely, runt-related transcription factor 2, alkaline phosphatase, osteopontin, and osteocalcin-which are similar to the effects of the Bio-Gide membrane. Further, in in vivo studies, the results of sequential fluorescent labeling, micro-computed tomography, and histological analysis suggest that using the PLGA/ATT scaffolds for repairing V-shaped buccal dehiscence on a dog's tooth root improved bone regeneration, which is not only similar to the result obtained using the Bio-Gide membrane but also much better than that obtained using PLGA scaffolds and the negative control. Conclusion: To achieve satisfactory therapeutic results and to lower the cost of GBR treatment, this study provided a promising alternative material of bio-degradable membrane in clinical treatment.


Asunto(s)
Pérdida de Hueso Alveolar/terapia , Regeneración Ósea/fisiología , Compuestos de Magnesio/farmacología , Compuestos de Silicona/farmacología , Andamios del Tejido/química , Animales , Regeneración Ósea/efectos de los fármacos , Calcificación Fisiológica , Colágeno , Perros , Expresión Génica , Encía/citología , Humanos , Compuestos de Magnesio/química , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Osteogénesis/fisiología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Porosidad , Ratas Sprague-Dawley , Compuestos de Silicona/química , Raíz del Diente/diagnóstico por imagen , Microtomografía por Rayos X
20.
Chem Biol Interact ; 331: 109235, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-32971123

RESUMEN

Ellagic acid (EA) is a naturally occurring polyphenolic compound that has been shown to exhibit diverse beneficial pharmacological activities including anti-osteoclastogenesis effect. However, the molecular mechanism by which EA inhibits osteoclastogenesis remains to be elucidated. The protein-protein interaction between receptor activator of nuclear factor (NF)-κB ligand (RANKL) and its receptor RANK contributes to osteoclast differentiation and activation in bone remodeling, and is regarded as an important therapeutic target for the treatment of osteoporosis. The current study is focused on investigating whether EA can directly bind to RANKL and/or RANK and block the interaction between RANKL and RANK, thereby inhibiting downstream signaling pathways. Interestingly, we found that EA had strong affinities to RANK and RANKL, with the estimated equilibrium dissociation constants (KD) of 2.485 × 10-11 and 1.688 × 10-9 M, respectively, and could disrupt the interaction between RANKL and RANK, thereby inhibiting RANKL-induced canonical RANK signaling pathways (p65, JNK, ERK, and p38) and expression of downstream master transcriptional factors (NFATc1 and c-Fos) and osteoclast-specific genes and proteins (TRAP, c-Src, and cathepsin K), which could ultimately suppress RANKL-induced osteoclast differentiation and F-actin ring formation. Taken together, our results revealed that EA could block RANKL-RANK interaction and suppress RANKL-induced osteoclastogenesis by inhibiting RANK signaling pathways in RAW 264.7 murine macrophages.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Ácido Elágico/farmacología , Osteogénesis/efectos de los fármacos , Ligando RANK/metabolismo , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Transducción de Señal/efectos de los fármacos , Actinas/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Cinética , Ratones , Factores de Transcripción NFATC/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ligando RANK/farmacología , Células RAW 264.7 , Fosfatasa Ácida Tartratorresistente/metabolismo
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