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1.
Acta Vet Scand ; 61(1): 47, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31601238

RESUMO

BACKGROUND: Among the most prominent health problems marring the global poultry industry for several decades are skeletal abnormalities. The aim of this study was to investigate a recent emergence of a novel form of skeletal deformity affecting cervical spine in broiler chickens. This work presents the natural history of this newly emerging skeletal anomaly along with long term observations of epidemiological trends in commercial broiler flocks, and clinical and pathological features. RESULTS: In distinction from other forms of skeletal deformities commonly reported in broiler chickens, this new form of cervical spine anomaly have been observed in newly hatched chicks and in fully developed embryos that died in the shell. On clinical and post mortem examination this condition presents characteristic features consistent with congenital cervical scoliosis and torticollis (CCST). The pathogenesis of CCST appears to be linked to pathological remodeling of the cervical vertebrae bone associated with excessive activity of osteoclasts. Long term observations indicate that the incidence of CCST showed increasing epidemiological trends over time. More recently CCST has been observed in newly hatched chicks with incidence ranging from 0.1 to > 1%, and in fully developed embryos that failed to hatch about 4 to 5%. CONCLUSIONS: The increasing trends in incidence of CCST in commercial broiler flocks are of concern from an economic perspective, and also represent a very specific and important aspect of animal welfare.


Assuntos
Vértebras Cervicais/anormalidades , Galinhas/anormalidades , Doenças das Aves Domésticas/epidemiologia , Doenças das Aves Domésticas/patologia , Escoliose/veterinária , Torcicolo/congênito , Criação de Animais Domésticos , Animais , Embrião não Mamífero , Osteoclastos/patologia , Escoliose/epidemiologia , Escoliose/patologia , Torcicolo/epidemiologia , Torcicolo/patologia , Torcicolo/veterinária
2.
Int J Nanomedicine ; 14: 7839-7849, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576127

RESUMO

Background: Nobiletin (NOB), a polymethoxy flavonoid, possesses anti-cancer and anti-inflammatory activities, has been reported that it played role in anti-osteoporosis treatment. However, previous research did not focus on practical use due to lack of hydrophilicity and cytotoxicity at high concentrations. The aim of this study was to develop a therapeutic formulation for osteoporosis based on the utilization of NOB. Methods: In this study, NOB-loaded poly(ethylene glycol)-block-poly(e-caprolactone) (NOB-PEG-PCL) was prepared by dialysis method. The effects on osteoclasts and anti-osteoporosis functions were investigated in a RANKL-induced cell model and ovariectomized (OVX) mice. Results: Dynamic light scattering and transmission electron microscopy examination results revealed that the NOB-PEG-PCL had a round shape, with a mean diameter around 124 nm. The encapsulation efficiency and drug loading were 76.34±3.25% and 7.60±0.48%, respectively. The in vitro release of NOB from NOB-PEG-PCL showed a remarkably sustained releasing characteristic and could be retained at least 48 hrs in pH 7.4 PBS. Anti-osteoclasts effects demonstrated that the NOB-PEG-PCL significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells stimulated by RANKL. Furthermore, the NOB-PEG-PCL did not produce cytotoxicity on bone marrow-derived macrophages (BMMs). The mRNA expressions of genetic markers of osteoclasts including TRAP and cathepsin K were significantly decreased in the presence of NOB-PEG-PCL. In addition, the NOB-PEG-PCL inhibited OC differentiation of BMMs through RANKL-induced MAPK signal pathway. After administration of the NOB-PEG-PCL, NOB-PEG-PCL prevented bone loss and improved bone density in OVX mice. These findings suggest that NOB-PEG-PCL might have great potential in the treatment of osteoporosis. Conclusion: The results suggested that NOB-PEG-PCL micelles could effectively prevent NOB fast release from micelles and extend circulation time. The NOB-PEG-PCL delivery system may be a promising way to prevent and treat osteoporosis.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Flavonas/uso terapêutico , Micelas , Osteoclastos/patologia , Osteogênese , Ovariectomia/efeitos adversos , Animais , Morte Celular/efeitos dos fármacos , Citocinas/metabolismo , Liberação Controlada de Fármacos , Feminino , Flavonas/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Poliésteres/química , Polietilenoglicóis/química , Transdução de Sinais/efeitos dos fármacos
3.
Int J Mol Sci ; 20(16)2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31405099

RESUMO

Bone metastasis is a common clinical complication in several cancer types, and it causes a severe reduction in quality of life as well as lowering survival time. Bone metastases proceed through a vicious self-reinforcing cycle that can be osteolytic or osteoblastic in nature. The vicious cycle is characterized by cancer cells residing in bone releasing signal molecules that promote the differentiation of osteoclasts and osteoblasts either directly or indirectly. The increased activity of osteoclasts and osteoblasts then increases bone turnover, which releases growth factors that benefit metastatic cancer cells. In order to improve the prognosis of patients with bone metastases this cycle must be broken. Radium-223 dichloride (radium-223), the first targeted alpha therapy (TAT) approved, is an osteomimetic radionuclide that is incorporated into bone metastases where its high-linear energy transfer alpha radiation disrupts both the activity of bone cells and cancer cells. Therefore, radium-223 treatment has been shown preclinically to directly affect cancer cells in both osteolytic breast cancer and osteoblastic prostate cancer bone metastases as well as to inhibit the differentiation of osteoblasts and osteoclasts. Clinical studies have demonstrated an increase in survival in patients with metastatic castration-resistant prostate cancer. Due to the effectiveness and low toxicity of radium-223, several novel combination treatment strategies are currently eliciting considerable research interest.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Rádio (Elemento)/uso terapêutico , Animais , Neoplasias Ósseas/diagnóstico , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Humanos , Terapia de Alvo Molecular , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Prognóstico , Radioisótopos/uso terapêutico
4.
BMC Cancer ; 19(1): 763, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375071

RESUMO

BACKGROUND: Bladder leiomyosarcoma is the most frequent mesenchymal neoplasm of the bladder. However, the rarity of the disease and some morphological aspects could give serious problems to differential diagnosis. CASE PRESENTATION: A 86-year-old male patient was referred to our institution to undergo endoscopic low-urinary-tract re-evaluation 2 months after the detection of a "low-grade urothelial neoplasia" in urinary cytology. A TURBT (transurethral resection of bladder tumor) was performed and revealed a tumor extending for 3.5 cm with thin stalk peduncle on the left lateral wall of the bladder, cephalad and lateral to the left ureteral orifice. The exophytic part of the tumor was resected with the underlying bladder wall. Histologically, the tumor showed a quite complex pattern, composed of spindle cells, with often invasion to the surrounding bladder muscular wall, and the presence of numerous multinucleated, osteoclast-like giant cells, scattered throughout the neoplasia. CONCLUSIONS: Here we report a unique case of urinary bladder leiomyosarcoma with osteoclast-like multinucleated giant cells (OGCs). These cells, confounding the morphological aspect, indeed showed an immunohistochemical phenotype of non-neoplastic origin (most likely a histiocyte/macrophage differentiation). We feel that the presence of the OGCs within this tumor is reactive. Nevertheless, more research is necessary to understand the role of OGCs in urinary bladder tumors and leiomyosarcoma, in paticular.


Assuntos
Cistectomia , Células Gigantes/patologia , Leiomiossarcoma/patologia , Leiomiossarcoma/cirurgia , Osteoclastos/patologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Idoso de 80 Anos ou mais , Cistoscopia , Seguimentos , Humanos , Leiomiossarcoma/diagnóstico por imagem , Masculino , Fenótipo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Neoplasias da Bexiga Urinária/diagnóstico por imagem
5.
Eur J Pharmacol ; 859: 172550, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31323222

RESUMO

Postmenopausal osteoporosis, mainly caused by osteoclast-induced bone resorption, has become a global public health burden. Natural compounds are emerging as potential therapeutics for postmenopausal osteoporosis. In vitro osteoclastogenesis assay was conducted to investigate the effect of Glycyrrhizic acid (Gly) on osteoclast differentiation without cytotoxity. We applied bone resorption pit assessment and F-actin immunofluoresence to explore the effect of Gly on osteoclasts function in vitro. RT-qPCR was used to evaluate the expression level of RANKL-induced osteoclast-specific gene. Western blotting was conducted for analyzing potential mechanisms of inhibitory influence of Gly on the formation and function of osteoclasts in vitro. Ovariectomized (OVX) mice model, micro-CT and histomorphometry was used to survey the potential effect of Gly on the resorption of bone in vivo. Gly inhibited osteoclast differentiation and function without significant cytotoxicity at a dose of no more than 8 mM in vitro. Gly attenuated mRNA expression of osteoclast-specific genes including NFATc1, c-fos, TRAP, CTR, cathepsin K, and V-ATPase d2 in vitro. Gly inhibited degradation of IκBα, phosphorylation of ERK and JNK without disturbing phosphorylation of p38 after treating osteoclasts in vitro. In OVX mice, Gly attenuates osteoclast formation and preserves bone mass and trabecular structure. Gly can effectively inhibit osteoclast maturation and bone resorption by suppressing NF-κB, ERK, and JNK pathway in vitro and exhibits an osteoprotective effect in OVX mice.


Assuntos
Diferenciação Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ácido Glicirrízico/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glicirrízico/uso terapêutico , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Osteoclastos/citologia , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/patologia , Ligante RANK/metabolismo , Células RAW 264.7
6.
Biomed Res Int ; 2019: 4934128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31317031

RESUMO

Introduction: With an increasing demand for orthodontic treatment for adult patients, orthodontic professionals are constantly seeking novel strategies and technologies that can accelerate tooth movement in order to shorten the treatment period. For instance, in recent years, the influences of different surgical techniques on orthodontic tooth movement in the ipsilateral side of surgery were intensively investigated. Here, we attempt to examine if corticotomy could also affect the rate of tooth movement in the contralateral side of the surgery by using a rodent model. Materials and Methods: 72 eight-week-old Sprague-Dawley rats were randomly divided into three groups as follows: the Control group (orthodontic treatment devices delivered only, no tooth movement), the orthodontic tooth movement (OTM) group (orthodontic treatment devices delivered and orthodontic treatment performed), and the Corticotomy + OTM group (remote corticotomy performed, orthodontic treatment devices delivered, followed by orthodontic treatment). The surgical procedure was conducted on the right side of the maxilla at the time of appliance placement and a force of 60 g was applied between the maxillary left first molar and maxillary incisors using nickel-titanium springs to stimulate OTM. The OTM distance and speed were tracked at 3, 7, 14, and 28 days post-surgery, followed by histological and immunohistochemical assessments. Results: In comparison with orthodontic treatment only, the contralateral corticotomy significantly accelerated OTM. Furthermore, animals undergoing corticotomy + OTM presented with a greater number of osteoclasts on the compression side, stronger staining of the osteogenic marker on the tension side, and higher expression of an inflammatory marker than the OTM group animals. Conclusion: Our current study demonstrates that remote corticotomy effectively accelerates alveolar bone remodeling and OTM. The study enriches our understanding of the regional acceleratory phenomenon (RAP) and offers an alternative strategy for accelerating OTM to shorten the orthodontic treatment period.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/cirurgia , Incisivo/cirurgia , Osteogênese/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Humanos , Incisivo/crescimento & desenvolvimento , Incisivo/patologia , Maxila/crescimento & desenvolvimento , Maxila/patologia , Maxila/cirurgia , Dente Molar/crescimento & desenvolvimento , Dente Molar/patologia , Dente Molar/cirurgia , Níquel/uso terapêutico , Fios Ortodônticos , Osteoclastos/metabolismo , Osteoclastos/patologia , Ratos , Titânio/uso terapêutico , Técnicas de Movimentação Dentária
7.
Phytomedicine ; 63: 153006, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31299594

RESUMO

BACKGROUND: Bone destructive diseases like rheumatoid arthritis (RA), osteoporosis and bone metastatic tumors are mainly mediated by over-activated osteoclasts. Asperosaponin VI (AVI), isolated from the rhizome of Dipsacus asper, belongs to triterpenoid saponins. It has multiple physiological activities but its effects on RA, especially on osteoclast differentiation and activation are still unclear. PURPOSE: Explore the protective role of AVI on collagen induced arthritis (CIA) in vivo and RANKL induced osteoclastogenesis in vitro. METHODS: The effects of AVI on cell viability and RANKL-induced osteoclastogenesis, actin ring formation, bone resorption activity as well as on osteoclast specific gene and protein expression were tested using bone marrow derived monocytes (BMMs). Paws from CIA mice were used for micro-CT, HE and TRAP staining, real-time PCR and western blot. Sera were used for cytokine analysis by ELISA. The signaling pathways were detected using western blot, real-time PCR and immunofluorescence assay. RESULTS: AVI significantly inhibited RANKL-induced osteoclast formation and bone resorption activity by suppressing the formation of actin ring. It also inhibited the expression of various osteoclatogenesis marker genes and signaling pathways. AVI protected arthritis in vivo by suppressing inflammation and bone loss. CONCLUSION: AVI exerts its anti-osteoclastogenic activity both in vitro and in vivo by inhibiting RANKL-induced osteoclast differentiation and function. Thus, our studies demonstrate a potential therapeutic role for AVI in preventing or inhibiting RANKL-mediated osteolytic bone diseases.


Assuntos
Artrite Experimental/tratamento farmacológico , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Saponinas/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Colágeno/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Osteoclastos/patologia , Osteogênese/fisiologia , Ligante RANK/metabolismo , Ligante RANK/toxicidade , Transdução de Sinais/efeitos dos fármacos
8.
Am J Orthod Dentofacial Orthop ; 156(1): 75-86, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31256844

RESUMO

INTRODUCTION: Maintaining tooth anchorage during orthodontic treatment has challenged orthodontists and threatening the success of some orthodontic therapy. The objective of this study was to evaluate the effect of local administration of simvastatin on orthodontic tooth movement. METHODS: Nickel-titanium coil springs were used to induce orthodontic tooth movement in 10 white New Zealand rabbits for 21 days. A split-mouth design was implemented where one mandibular quadrant received local administration of simvastatin and the corresponding mandibular quadrant received control vehicle solution on a weekly basis. Magnitudes of tooth movement were measured on 3-dimensional models of the experimental teeth. Animals were killed at the end of the experimental period to allow histomorphometric analysis of alveolar bone modeling. RESULTS: The total magnitude of tooth movement in the quadrant receiving simvastatin was significantly less than that in the quadrant receiving control vehicle solution. Local administration of simvastatin resulted in a significant percentage of inhibition of tooth movement of 39.8 ± 22.6%. Histomorphometric analysis revealed a significant reduction in the numbers of osteoclasts and areas of active bone-resorptive lacunae hindering bone resorption processes in the quadrant receiving simvastatin. CONCLUSIONS: Local administration of simvastatin can reduce the rate and magnitude of orthodontic tooth movement. Moreover, local administration of simvastatin diminishes bone resorption processes associated with orthodontic tooth movement reducing the number of osteoclasts and the subsequent area of active bone resorption.


Assuntos
Reabsorção Óssea/patologia , Osteoclastos/efeitos dos fármacos , Sinvastatina/administração & dosagem , Sinvastatina/antagonistas & inibidores , Técnicas de Movimentação Dentária/métodos , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/patologia , Animais , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/diagnóstico por imagem , Masculino , Mandíbula/irrigação sanguínea , Mandíbula/efeitos dos fármacos , Mandíbula/patologia , Modelos Animais , Níquel/química , Aparelhos Ortodônticos , Fios Ortodônticos , Osteoclastos/patologia , Coelhos , Titânio/química , Técnicas de Movimentação Dentária/instrumentação
9.
Eur J Pharmacol ; 859: 172558, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325437

RESUMO

Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) is related to inflammation. In this study, we investigated the function of PSTPIP2 in adjuvant-induced arthritis (AIA) by using adeno-associated virus (AAV) to overexpress PSTPIP2 in rat. AIA rats were developed by injecting Lewis rats with complete Freund's adjuvant (CFA) on day 0. AAV-empty or AAV-PSTPIP2, or PBS was administered intraarticularly into each knee joint on day 8 postinduction. All animals were killed at day 18 after adjuvant injection. WB was used to detect the expression of PSTPIP2 in rat synovial tissues. Fluorescence microscopy showed the transduction efficiency in synovial tissue. The morphology of arthritic joints was examined by HE, safranin O/fast green, or Toluidine blue staining. The bone destruction was examined via X-ray and micro-CT analysis. Immunohistochemical analysis or TRAP staining were used to investigate the role of PSTPIP2 in osteoclasts and the expression of PSTPIP2 in synovial tissue. RT-qPCR and ELISA were used to examine the expression of pro-inflammatory cytokines in synovial tissue or serum. AIA rats were found to have decreased PSTPIP2 expression and AIA-associated bone loss and inflammatory infiltration. We showed that administration of AAV-PSTPIP2 before arthritis onset significantly reduces the severity of AIA. PSTPIP2 was highly expressed in synovial cells. In addition, inflammatory responses and the number of osteoclasts were reduced with AAV-PSTPIP2 treatment. These findings demonstrate that PSTPIP2 may improve the severity of AIA by inhibiting the function of fibroblast-like synoviocytes, suppressing inflammation and reducing the number of osteoclasts.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Articulações/patologia , Animais , Contagem de Células , Articulações/metabolismo , Osteoclastos/patologia , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Ratos
10.
J Cancer Res Ther ; 15(3): 704-707, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169246

RESUMO

Anaplastic thyroid carcinoma (ATC) is a rare, highly malignant thyroid tumor with dismal prognosis. Osteoclastic giant cell variant of ATC is extremely rare and is characterized by the presence of a large number of multinucleated giant cells resembling osteoclasts. We report here this unusual variant in a 67-year-old female with a history of long-standing goiter of 13 years duration. Histologically, many multinucleated osteoclast-like giant cells were seen accompanying the malignant spindle cell component. Despite extensive sampling, no evidence of differentiated thyroid malignancy could be elucidated.


Assuntos
Osteoclastos/metabolismo , Osteoclastos/patologia , Carcinoma Anaplásico da Tireoide/diagnóstico , Carcinoma Anaplásico da Tireoide/metabolismo , Idoso , Biomarcadores , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Carcinoma Anaplásico da Tireoide/cirurgia , Tireoidectomia , Resultado do Tratamento , Ultrassonografia
11.
Nutrients ; 11(6)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234292

RESUMO

There is growing interest in bioactive substances from marine organisms for their potential use against diverse human diseases. Osteoporosis is a skeletal disorder associated with bone loss primarily occurring through enhanced osteoclast differentiation and resorption. Recently, we reported the anti-osteoclastogenic activity of fermented Pacific oyster (Crassostrea gigas) extract (FO) in vitro. The present study focused on investigating the anti-osteoporotic efficacy of FO in bone loss prevention in an experimental animal model of osteoporosis and elucidating the mechanism underlying its effects. Oral administration of FO significantly decreased ovariectomy-induced osteoclast formation and prevented bone loss, with reduced serum levels of bone turnover biomarkers including osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus (CTX). FO significantly suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced differentiation of bone marrow-derived macrophages (BMMs) into osteoclasts and attenuated the induction of osteoclast-specific genes required for osteoclastogenesis and bone resorption. Furthermore, FO inhibited RANKL-mediated IκBα and p65 phosphorylation in BMMs. Taken together, these results demonstrate that FO effectively suppresses osteoclastogenesis in vivo and in vitro, and that FO can be considered as a potential therapeutic option for the treatment of osteoporosis and osteoclast-mediated skeletal diseases.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Crassostrea/microbiologia , Fermentação , Lactobacillus brevis/fisiologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose Pós-Menopausa/prevenção & controle , Ovariectomia , Alimentos Marinhos/microbiologia , Tíbia/efeitos dos fármacos , Actinas/metabolismo , Animais , Conservadores da Densidade Óssea/isolamento & purificação , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/patologia , Osteoporose Pós-Menopausa/fisiopatologia , Transdução de Sinais , Tíbia/metabolismo , Tíbia/patologia , Tíbia/fisiopatologia
12.
Cells ; 8(6)2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234425

RESUMO

Osteoclast-mediated bone destruction is amplified in the hypoxic synovial microenvironment of rheumatoid arthritis (RA). This increased bone resorption is driven by the hypoxia-inducible transcription factor HIF. We identified hypoxic induction of the HIF-regulated adenosine A2B receptor in primary human osteoclasts (mRNA, 3.8-fold increase, p < 0.01) and sought to identify the role(s) of purinergic signaling via this receptor in the bone resorption process. Primary human osteoclasts were differentiated from CD14+ monocytes and exposed to hypoxia (2% O2) and A2B receptor inhibitors (MRS1754, PSB603). The hypoxic increase in bone resorption was prevented by the inhibition of the A2B receptor, at least partly by the attenuation of glycolytic and mitochondrial metabolism via inhibition of HIF. A2B receptor inhibition also reduced osteoclastogenesis in hypoxia by inhibiting early cell fusion (day 3-4, p < 0.05). The A2B receptor is only functional in hypoxic or inflammatory environments when the extracellular concentrations of adenosine (1.6-fold increase, p < 0.05) are sufficient to activate the receptor. Inhibition of the A2B receptor under normoxic conditions therefore did not affect any parameter tested. Reciprocal positive regulation of HIF and the A2B receptor in a hypoxic microenvironment thus enhances glycolytic and mitochondrial metabolism in osteoclasts to drive increased bone resorption. A2B receptor inhibition could potentially prevent the pathological osteolysis associated with hypoxic diseases such as rheumatoid arthritis.


Assuntos
Reabsorção Óssea/metabolismo , Microambiente Celular , Osteoclastos/metabolismo , Receptor A2B de Adenosina/metabolismo , Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia Celular/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia
13.
Int J Mol Sci ; 20(11)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185614

RESUMO

Gangliosides are widely expressed in almost all tissues and cells and are also considered to be essential in the development and maintenance of various organs and tissues. However, little is known about their roles in bone metabolism. In this study, we investigated the effects of genetic deletion of ganglioside D3 (GD3) synthase, which is responsible for the generation of all b-series gangliosides, on bone metabolism. Although b-series gangliosides were not expressed in osteoblasts, these gangliosides were expressed in pre-osteoclasts. However, the expression of these gangliosides was decreased after induction of osteoclastogenesis by receptor activator of nuclear factor kappa-B ligand (RANKL). Three-dimensional micro-computed tomography (3D-µCT) analysis revealed that femoral cancellous bone mass in GD3 synthase-knockout (GD3S KO) mice was higher than that in wild type (WT) mice at the age of 40 weeks, although there were no differences in that between GD3S KO and WT mice at 15 weeks old. Whereas bone formation parameters (osteoblast numbers/bone surface and osteoblast surface/bone surface) in GD3S KO mice did not differ from WT mice, bone resorption parameters (osteoclast numbers/bone surface and osteoclast surface/bone surface) in GD3S KO mice became significantly lower than those in WT mice at 40 weeks of age. Collectively, this study demonstrates that deletion of GD3 synthase attenuates bone loss that emerges with aging.


Assuntos
Envelhecimento/patologia , Reabsorção Óssea/genética , Sialiltransferases/genética , Animais , Células Cultivadas , Gangliosídeos/metabolismo , Camundongos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese , Ligante RANK/metabolismo , Células RAW 264.7 , Sialiltransferases/deficiência
14.
Biomed Pharmacother ; 115: 108916, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054506

RESUMO

Lipopolysaccharide (LPS) can induce bone loss by stimulating osteoclast formation. Colony-stimulating factor 1 receptor (CSF 1R) inhibitors have great potential for the treatment of rheumatoid arthritis and tumor-related bone erosion. However, its role in LPS-induced bone loss is still not clarified. In this study, we observed the effects of CSF 1R inhibitor, PLX3397, on LPS-induced bone damage in an animal model. The models were established by LPS administration in male Sprague-Dawley rats. PLX3397 (30 mg/kg body weight) was given by oral gavage. MicroCT analysis, biomechanical properties, biomarker assay, histological examination, and mRNA expression of osteoclast differentiation-related genes (Traf6, Fra1, c-fos and NFATc1) were performed on the 8th week. LPS induced bone loss was shown as the decrease in bone volume fraction and trabecular number and increase in trabecular separation (p < 0.05). LPS exposure also markedly decreased the bone biomechanical properties. PLX3397 significantly abolished the LPS-induced bone microstructure damage (p < 0.05) and loss of biomechanical properties. PLX3397 also inhibited the increases of serum tartrate-resistant acid phosphatase 5b level enhanced by LPS (p < 0.05). PLX3397 attenuated the high expression of Traf6, Fra1, c-fos and NFATc1 stimulated by LPS. Our data demonstrated that PLX3397, a type of CSF 1R inhibitor, can suppress LPS-induced bone loss via the inhibition osteoclast formation.


Assuntos
Aminopiridinas/farmacologia , Reabsorção Óssea/prevenção & controle , Osteoclastos/efeitos dos fármacos , Osteoporose/prevenção & controle , Pirróis/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Fenômenos Biomecânicos , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/metabolismo , Osso Esponjoso/patologia , Modelos Animais de Doenças , Lipopolissacarídeos/farmacologia , Masculino , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteoporose/induzido quimicamente , Osteoporose/metabolismo , Osteoporose/patologia , Ratos Sprague-Dawley , Tíbia/efeitos dos fármacos , Tíbia/metabolismo , Tíbia/patologia
15.
Biomed Res Int ; 2019: 8650846, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058194

RESUMO

Prostate cancer is a serious disease that can invade bone tissues. These bone metastases can greatly decrease a patient's quality of life, pose a financial burden, and even result in death. In recent years, tumor cell-secreted microvesicles have been identified and proposed to be a key factor in cell interaction. However, the impact of cancer-derived exosomes on bone cells remains unclear. Herein, we isolated exosomes from prostate cancer cell line PC-3 and investigated their effects on human osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) staining. The potential mechanism was evaluated by qRT-PCR, western blotting, and microRNA transfection experiments. The results showed that PC-3-derived exosomes dramatically inhibited osteoclast differentiation. Marker genes of mature osteoclasts, including CTSK, NFATc1, ACP5, and miR-214, were all downregulated in the presence of PC-3 exosomes. Furthermore, transfection experiments showed that miR-214 downregulation severely impaired osteoclast differentiation, whereas overexpression of miR-214 promoted differentiation. Furthermore, we demonstrated that PC-3-derived exosomes block the NF-κB signaling pathway. Our study suggested that PC-3-derived exosomes inhibit osteoclast differentiation by downregulating miR-214 and blocking the NF-κB signaling pathway. Therefore, elevating miR-214 levels in the bone metastatic site may attenuate the invasion of prostate cancer.


Assuntos
Neoplasias Ósseas/genética , MicroRNAs/genética , Osteogênese/genética , Neoplasias da Próstata/genética , Animais , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Catepsina K/genética , Diferenciação Celular/genética , Exossomos/metabolismo , Exossomos/patologia , Regulação Neoplásica da Expressão Gênica/genética , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Fatores de Transcrição NFATC/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Osteoclastos/patologia , Células PC-3 , Neoplasias da Próstata/patologia , Transdução de Sinais/genética , Fosfatase Ácida Resistente a Tartarato/química , Fosfatase Ácida Resistente a Tartarato/genética
16.
J Vasc Res ; 56(3): 139-151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31064000

RESUMO

BACKGROUND: It has been reported that smoking is one of the strongest positive risk factors for abdominal aortic aneurysms (AAAs). Although many studies have been directed to decipher the effect of smoking on AAA, its effect on macrophage activation has not yet been explored. OBJECTIVES: We have reported the importance of osteoclastogenesis (OCG) in aneurysm formation. Therefore, we examined the effect of cigarette smoking on OCG and arterial aneurysmal formation by using cigarette smoke extract (CSE) in this study. METHODS: Macrophage cell lines were stimulated with CSE, and their activation and differentiation were examined in vitro. Since macrophages activated through the OCG pathway are identified by tartrate-resistant acid phosphatase (TRAP) expression, these cells are referred to as TRAP-positive macrophages (TPMs) in this study. We also applied CSE-contained PBS in the calcium chloride-induced mouse carotid aneurysm model in vivo. RESULTS: Macrophages stimulated with CSE expressed significantly higher levels of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), TRAP, cathepsin K, matrix metalloproteinase-9 and membrane-type metalloproteinase (MT1-MMP). CSE-treated mouse aneurysms showed increased aneurysm size with increased TPM infiltration and protease expression compared to non-CSE-treated mouse aneurysms. CONCLUSIONS: These results suggest that CSE intensifies OCG in macrophages and promotes arterial aneurysmal progression.


Assuntos
Aneurisma/induzido quimicamente , Doenças das Artérias Carótidas/induzido quimicamente , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Fumaça/efeitos adversos , Fosfatase Ácida Resistente a Tartarato/metabolismo , Produtos do Tabaco/efeitos adversos , Aneurisma/enzimologia , Aneurisma/patologia , Animais , Cloreto de Cálcio , Doenças das Artérias Carótidas/enzimologia , Doenças das Artérias Carótidas/patologia , Catepsina K/metabolismo , Modelos Animais de Doenças , Macrófagos/enzimologia , Macrófagos/patologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/enzimologia , Osteoclastos/patologia , Células RAW 264.7 , Transdução de Sinais
17.
Cell Biol Int ; 43(6): 658-668, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30958621

RESUMO

Periprosthetic osteolysis caused by wear particles is the main factor that affects the long-term efficacy of artificial joint replacement, and macrophages play a vital role in the pathogenesis of periprosthetic osteolysis, while the potential mechanism underlying this is still unclear. To investigate the underlying role of miR-377 in wear particle-induced osteolysis (PIO), blood samples from patients undergoing arthroplasty were collected for analyzing the correlation between miR-377 expression and the clinicopathological parameters of PIO. Peripheral blood macrophages were obtained to compare the miR-377 and receptor activator of NF-κB ligand (RANKL) expressions. Bone marrow macrophages (BMMs) following titanium (Ti) particle treatment and/or miR-377 mimic transfection were used. The expressions of RANKL, pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) and the osteoclast-related molecules tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CTSK) were determined using real-time polymerase chain reaction or western blotting or enzyme-linked immunosorbent assay or TRAP staining, when appropriate. The interaction between miR-377 and RANKL was assessed by luciferase reporter assay. The in vivo role of miR-377 in PIO was evaluated using a mouse calvarial osteolysis model. There were significant differences in downregulated miR-377 expression between the different numbers of particles in the joint prostheses. The Ti particle treatment increased pro-inflammatory cytokine levels, downregulated RANKL and increased osteoclast activity in BMMs, while miR-377 overexpression led to the opposite effect. Taken together, miR-377 downregulated the target gene RANKL, resulting in PIO inhibition. MiR-377 relieved PIO by negatively regulating RANKL.


Assuntos
MicroRNAs/metabolismo , Osteólise/metabolismo , Ligante RANK/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular/fisiologia , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Interleucina-6/metabolismo , Macrófagos/metabolismo , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteólise/genética , Osteólise/patologia , Ligante RANK/genética , Transdução de Sinais/efeitos dos fármacos , Titânio/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
18.
In Vitro Cell Dev Biol Anim ; 55(5): 376-386, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31025251

RESUMO

Osteoporosis results from the imbalance between osteogenesis and bone resorption mediated by osteoblasts and osteoclasts. During the disease process of osteoporosis, the alteration of gene expression occurs, which lead to the disease progression. MicroRNAs (miRNAs) have been previously demonstrated to be modulators for bone metabolism via regulation of osteoblast and osteoclast differentiation. In the present study, we detected the expression levels of five osteoporosis-related miRNAs in bone and serum samples of patient with or without osteoporosis. The downstream molecular mechanism of miR-363-3p was analyzed and detected by using bioinformatics analysis and mechanism experiment. The upstream transcription factor of miR-363-3p was analyzed by applying bioinformatics analysis and ChIP assay and luciferase reporter assay. The role of this pathway in osteoclastogenesis was demonstrated by functional assays. MiR-363-3p was significantly highly expressed in osteoporotic samples. Mechanistically, miR-363-3p promotes osteoclastogenesis and inhibits osteogenic differentiation by targeting PTEN and therefore activating PI3K/AKT signaling pathway. MiR-363-3p was activated by its upstream transcription activator MYB. This study revealed that MYB-induced upregulation of miR-363-3p regulates osteoporosis pathogenesis via PTEN/PI3K/AKT signaling pathway.


Assuntos
Reabsorção Óssea/genética , MicroRNAs/genética , Osteoporose/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-myb/genética , Reabsorção Óssea/sangue , Reabsorção Óssea/patologia , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Diferenciação Celular/genética , Biologia Computacional , Regulação da Expressão Gênica/genética , Humanos , MicroRNAs/sangue , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese/genética , Osteoporose/sangue , Osteoporose/patologia , Pacientes , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética
19.
Int J Mol Med ; 43(6): 2329-2340, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017256

RESUMO

Ameloblastoma is a common odontogenic benign tumor located in the jaws and is characterized by severe local bone destruction. The current study aimed to investigate the effect of interactions between tumor cells and bone marrow stromal cells (BMSCs) on osteoclast formation in ameloblastoma. The impact of ameloblastoma/BMSC interactions on cytokine production, gene expression and osteoclastogenesis was examined using an immortalized ameloblastoma cell line that the authors' previously established. The results demonstrated that interactions between ameloblastoma cells and BMSCs increased interleukin (IL)­8 and activin A secretion by BMSCs. IL­8 expression in BMSCs was modulated by tumor­derived tumor necrosis factor­α and IL­8 contributed to osteoclast formation not only directly but also by stimulating receptor activator of NF­κB ligand (RANKL) expression in BMSCs. Activin A secretion in BMSCs was stimulated by ameloblastoma cells via cell­to­cell­mediated activation of c­Jun N­terminal kinase activation, acting as a cofactor of RANKL to induce osteoclast formation and function. The present study highlights the critical role of communication between BMSCs and ameloblastoma cells in bone resorption in ameloblastoma.


Assuntos
Ativinas/genética , Ameloblastoma/genética , Interleucina-8/genética , Neoplasias Maxilomandibulares/genética , Osteoclastos/patologia , Osteólise/genética , Regulação para Cima , Adulto , Ameloblastoma/complicações , Ameloblastoma/patologia , Células Cultivadas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Maxilomandibulares/complicações , Neoplasias Maxilomandibulares/patologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Osteoclastos/metabolismo , Osteólise/complicações , Osteólise/patologia , Células Tumorais Cultivadas , Adulto Jovem
20.
Cell Prolif ; 52(3): e12613, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30968984

RESUMO

OBJECTIVES: Fluorine, an organic trace element, has been shown to unfavourably effect osteoclasts function at a low dose. Use of hydroxyapatite (HA) has been effective in exploring its roles in promoting bone repair. In this study, we used HA modified with fluorine to investigate whether it could influence osteoclastic activity in vitro and ovariectomy-induced osteoclasts hyperfunction in vivo. MATERIALS AND METHODS: Fluorohydroxyapatite (FHA) was obtained and characterized by scanning electron microscope (SEM). Osteoclasts proliferation and apoptosis treated with FHA were assessed by MTT and TUNEL assay. SEM, F-actin, TRAP activity and bone resorption experiment were performed to determine the influence of FHA on osteoclasts differentiation and function. Moreover, HA and FHA were implanted into ovariectomized osteoporotic and sham surgery rats. Histology and Micro-CT were examined for further verification. RESULTS: Fluorine released from FHA slowly and sustainably. FHA hampered osteoclasts proliferation, promoted osteoclasts apoptosis, suppressed osteoclasts differentiation and function. Experiments in vivo validated that FHA participation brought about an inhibitory effect on osteoclasts hyperfunction and less bone absorption. CONCLUSION: The results indicated that FHA served as an efficient regulator to attenuate osteoclasts formation and function and was proposed as a candidature for bone tissue engineering applications.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/tratamento farmacológico , Hidroxiapatitas/farmacologia , Osteoclastos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Conservadores da Densidade Óssea/química , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Hidroxiapatitas/química , Camundongos , Osteoclastos/metabolismo , Osteoclastos/patologia , Ovariectomia , Células RAW 264.7 , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fosfatase Ácida Resistente a Tartarato/metabolismo
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