Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 540
Filtrar
1.
BMB Rep ; 53(3): 154-159, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31964464

RESUMO

We investigated the effects of physalin A, B, D, and F on osteoclastogenesis induced by receptor activator of nuclear factor κB ligand (RANKL). The biological functions of different physalins were first predicted using an in silico bioinformatic tool (BATMAN-TCM). Afterwards, we tested cell viability and cell apoptosis rate to analyze the cytotoxicity of different physalins. We analyzed the inhibitory effects of physalins on RANKL-induced osteoclastogenesis from mouse bone-marrow macrophages (BMMs) using a tartrate-resistant acid phosphatase (TRAP) stain. We found that physalin D has the best selectivity index (SI) among all analyzed physalins. We then confirmed the inhibitory effects of physalin D on osteoclast maturation and function by immunostaining of F-actin and a pit-formation assay. On the molecular level, physalin D attenuated RANKLevoked intracellular calcium ([Ca(2+)](i)) oscillation by inhibiting phosphorylation of phospholipase Cγ2 (PLCγ2) and thus blocked the downstream activation of Ca2+/calmodulindependent protein kinases (CaMK)IV and cAMP-responsive element-binding protein (CREB). An animal study showed that physalin D treatment rescues bone microarchitecture, prevents bone loss, and restores bone strength in a model of rapid bone loss induced by soluble RANKL. Taken together, these results suggest that physalin D inhibits RANKL-induced osteoclastogenesis and bone loss via suppressing the PLCγ2-CaMK-CREB pathway. [BMB Reports 2020; 53(3): 154-159].


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Secoesteroides/farmacologia , Animais , Células da Medula Óssea/metabolismo , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Feminino , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Ligante RANK/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
2.
Arch Osteoporos ; 15(1): 10, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31897759

RESUMO

The mutual effects of drugs used in osteoporosis and cardiovascular diseases are a point of interest. A literature review and meta-analysis were conducted to address the impact of PTH analogs and anti-Rank ligand on cardiovascular events and overall mortality in individuals with idiopathic osteoporosis; these treatments do not appear to have any effect. INTRODUCTION: Two meta-analyses have been conducted to explore the cardiovascular effects of bisphosphonates. There is no review for other osteoporosis treatments. A literature review and meta-analysis were conducted to address the impact of PTH analogs and anti-Rank ligand on cardiovascular events and overall mortality in individuals with idiopathic osteoporosis. METHODS: A systematic review was conducted in December 2017 in the PubMed, Embase, and Cochrane databases and updated on PubMed in July 2019, selecting trials with a treatment and a control group. We also conducted a search for abstracts of the French Rheumatology Society, American College of Rheumatology, and European League Against Rheumatism's annual meetings over the past 4 years. The main endpoint was the occurrence of cardiovascular events; the secondary was mortality (all causes). RESULTS: Of the 2782 reports initially found, 16 articles were used for the meta-analysis (6 for the anti-Rank ligand and 10 for the PTH analog group). After meta-analysis, there was no significant difference between the placebo group and the anti-Rank ligand group for overall mortality (p = 0.13), the combined endpoint (overall mortality, coronary artery disease, and stroke; p 0.77), and the individual risk of coronary artery disease (p 0.53), arrhythmia (p 0.95), and stroke (p 0.62). After meta-analysis, there was no significant difference between the placebo group and the PTH analogs group for overall mortality (p 0.77), the combined endpoint (p = 0.95), and the individual risk of coronary artery disease (p = 0.74), arrhythmia (p = 0.28), and stroke (p = 0.61). CONCLUSIONS: The anti-Rank ligand and PTH analogs have no impact on cardiovascular risk and overall mortality in idiopathic osteoporosis. To better answer the question whether these treatments can reduce the long-term cardiovascular risk, further comparative studies with longer duration are required.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Osteoporose Pós-Menopausa/tratamento farmacológico , Hormônio Paratireóideo/análogos & derivados , Ligante RANK/antagonistas & inibidores , Arritmias Cardíacas/mortalidade , Arritmias Cardíacas/prevenção & controle , Conservadores da Densidade Óssea/uso terapêutico , Doenças Cardiovasculares/mortalidade , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/prevenção & controle , Denosumab/uso terapêutico , Difosfonatos/uso terapêutico , Feminino , Humanos , Fatores de Risco , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Teriparatida/uso terapêutico
4.
Int Immunol ; 32(2): 89-104, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31713625

RESUMO

Staphylococcus aureus is a main pathogen of osteomyelitis and protein A is a virulence factor with high affinity for IgG. In this study, we investigated whether S. aureus affects the differentiation and bone resorption of osteoclasts through the IgG-binding capacity of protein A. Staphylococcus aureus pre-treated with serum or IgG showed marked enhancement in osteoclastogenesis and bone resorption compared to non-treated S. aureus or a protein A-deficient mutant. Blocking of the Fc receptor and deletion of the Fcγ receptor gene in osteoclast precursor cells showed that enhanced osteoclastogenesis stimulated by S. aureus IgG immune complexes (ICs) was mediated by the Fc receptor on osteoclast precursor cells. In addition, osteoclastogenesis stimulated by S. aureus ICs but not the protein A-deficient mutant was markedly reduced in osteoclast precursor cells of Myd88-knockout mice. Moreover, NFATc1, Syk and NF-κB signals were necessary for osteoclastogenesis stimulated by S. aureus ICs. The results suggest the contribution of a of Toll-like receptor 2 (TLR2)-Myd88 signal to the activity of S. aureus ICs. We further examined the expression of pro-inflammatory cytokines that is known to be enhanced by FcγR-TLR cross-talk. Osteoclasts induced by S. aureus ICs showed higher expression of TNF-α and IL-1ß, and marked stimulation of proton secretion of osteoclasts activated by pro-inflammatory cytokines. Finally, injection of S. aureus, but not the protein A-deficient mutant, exacerbated bone loss in implantation and intra-peritoneal administration mouse models. Our results provide a novel mechanistic aspect of bone loss induced by S. aureus in which ICs and both Fc receptors and TLR pathways are involved.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Diferenciação Celular , Imunoglobulina G/imunologia , Receptores Fc/imunologia , Proteína Estafilocócica A/imunologia , Staphylococcus aureus/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/imunologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteogênese/efeitos dos fármacos , Ligante RANK/antagonistas & inibidores , Ligante RANK/farmacologia , Receptores Fc/deficiência , Receptores Fc/genética , Proteína Estafilocócica A/genética , Staphylococcus aureus/citologia , Ácidos Teicoicos/farmacologia
5.
J Immunol Res ; 2019: 8459281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828174

RESUMO

Objective: To investigate the transplantation effect of bone marrow mesenchymal stem cells (MSCs) on the expression of interlukin-22 (IL-22) and RANKL in collagen-induced arthritis (CIA) rats. Methods: 32 CIA models were established. 16 CIA rats were transplanted with MSCs, and others were used as nontreatment CIA controls. The concentrations of IL-22 and RANKL in serum were detected by ELISA and those in synovial tissue of rats' joints by immunohistochemical staining. In addition, the expression of RANKL mRNA was measured by RT-PCR in the fibroblast-like synoviocytes (FLSs), cultured with IL-22 in vitro, which were delivered from the joints of CIA rats treated with or without MSCs. Results: The transplantation of MSCs into CIA rats relieved the destruction of joints, measured by AI score, X-ray, and histopathology. MSCs also reduced the expression of IL-22 and RANKL in serum by ELISA (P < 0.001) and similarly in FLSs by immunohistochemical staining. In vitro, IL-22 induced significantly the expression of RANKL mRNA in cultured FLSs in a dose-dependent manner, whereas this induction was significantly reduced in FLSs derived from CIA rats transplanted with MSCs (normal controls: F = 79.33, P < 0.001; CIA controls: F = 712.72, P < 0.001; and CIA-MSC rats: F = 139.04, P < 0.001). Conclusion: Our results suggest that the transplantation of MSCs can reduce the expression of RANKL in vivo by downregulating the levels of IL-22, thereby ameliorating the degree of RA bone destruction. This study provides a theoretical basis for a potential therapy of RA with MSCs, and IL-22 and RANKL may become two new targets to treat RA.


Assuntos
Artrite Experimental/terapia , Interleucinas/antagonistas & inibidores , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Ligante RANK/antagonistas & inibidores , Animais , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/patologia , Regulação da Expressão Gênica , Interleucinas/genética , Interleucinas/imunologia , Interleucinas/farmacologia , Células-Tronco Mesenquimais/citologia , Cultura Primária de Células , Ligante RANK/genética , Ligante RANK/imunologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/imunologia , Sinoviócitos/patologia
6.
Trials ; 20(1): 753, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856909

RESUMO

BACKGROUND: Neoadjuvant immunotherapy targeting immune checkpoint programmed death-1 (PD-1) is under investigation in various tumour settings including non-small-cell lung cancer (NSCLC). Preclinical models demonstrate the superior power of the immunotherapy provided in a neoadjuvant (pre-operative) compared with an adjuvant (post-operative) setting to eradicate metastatic disease and induce long-lasting antigen-specific immunity. Novel effective immunotherapy combinations are widely sought in the oncology field, targeting non-redundant mechanisms of immune evasion. A promising combination partner with anti-PD1 in NSCLC is denosumab, a monoclonal antibody blocking receptor activator of NF-κB ligand (RANKL). In preclinical cancer models and in a large retrospective case series in NSCLC, anti-cancer activity has been reported for the combination of immune checkpoint inhibition (ICI) and denosumab. Furthermore, clinical trials of ICI and denosumab are underway in advanced melanoma and clear-cell renal cell carcinoma. However, the mechanism of action of combination anti-PD1 and anti-RANKL is poorly defined. METHODS: This open-label multicentre trial will randomise by minimisation 30 patients with resectable stage IA (primary > 2 cm) to IIIA NSCLC to a neoadjuvant treatment regime of either two doses of nivolumab (3 mg/kg every 2 weeks) or two doses of nivolumab (same regimen) plus denosumab (120 mg every 2 weeks, following nivolumab). Each treatment arm is of equal size and will be approximately balanced with respect to histology (squamous vs. non-squamous) and clinical stage (I-II vs. IIIA). All patients will receive surgery for their tumour 2 weeks after the final dose of neoadjuvant therapy. The primary outcome will be translational research to define the tumour-immune correlates of combination therapy compared with monotherapy. Key secondary outcomes will include a comparison of rates of the following between each arm: toxicity, response (pathological and radiological), and microscopically complete resection. DISCUSSION: The POPCORN study provides a unique platform for translational research to determine the mechanism of action of a novel proposed combination immunotherapy for cancer. TRIAL REGISTRATION: Prospectively registered on Australian New Zealand Clinical Trials Registry (ACTRN12618001121257) on 06/07/2018.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Terapia Neoadjuvante/métodos , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Denosumab/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Margens de Excisão , Estudos Multicêntricos como Assunto , Estadiamento de Neoplasias , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Pneumonectomia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Ligante RANK/antagonistas & inibidores
7.
Sci Rep ; 9(1): 19895, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882595

RESUMO

The anti-bone resorptive drugs denosumab, an anti-human-RANKL antibody, and zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, have recently been applied for treatment of pediatric patients with bone diseases, though details regarding their effects in growing children have yet to be fully elucidated. In the present study, we administered these anti-resorptive drugs to mice from the age of 1 week and continued once-weekly injections for a total of 7 times. Mice that received the anti-RANKL antibody displayed normal growth and tooth eruption, though osteopetrotic bone volume gain in long and alveolar bones was noted, while there were nearly no osteoclasts and a normal of number osteoblasts observed. In contrast, ZOL significantly delayed body growth, tooth root formation, and tooth eruption, with increased osteoclast and decreased osteoblast numbers. These findings suggest regulation of tooth eruption via osteoblast differentiation by some types of anti-resorptive drugs.


Assuntos
Anticorpos/farmacologia , Ligante RANK/antagonistas & inibidores , Erupção Dentária/efeitos dos fármacos , Ácido Zoledrônico/farmacologia , Animais , Animais Recém-Nascidos , Humanos , Camundongos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteopetrose/tratamento farmacológico , Osteopetrose/metabolismo , Ligante RANK/metabolismo , Ratos
8.
Bioorg Chem ; 92: 103292, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31561105

RESUMO

Seven new diterpenoids, euphorantones A-D (1, 3, 6, and 10), 8,12,13-epi-3,7,12-O-triacetyl-8-O-(2-methylbutanoyl)-ingol (9), 8,12,13-epi-3,12-O-diacetyl-7-O-benzoyl-8-methoxyingol (11), 2,3-epi-7,12-diacetate-8-benzoate-ingol (12), together with eighteen known compounds (2, 4-5, 7-8, and 13-25), were isolated from the aerial parts of Euphorbia antiquorum L.. The structures of new compounds 1, 3, 6, and 9-12 were elucidated by extensive spectroscopic analyses. The absolute configurations of new compounds were assigned using X-ray diffraction, Rh2(OCOCF3)4-induced CD spectrum, and confirmed through comparison of the calculated and experimental 13C NMR and electronic circular dichroism (ECD) data. Compounds 1-25 were evaluated for their inhibition of RANKL-induced osteoclastogenesis. Compound 1 showed the most potent inhibition of RANKL-induced osteoclastogenesis with IC50 value of 0.3 µM. It inhibited NFAT transcript activity and osteoclast related genes TRAcP, CTSK, and NFATc1 expression.


Assuntos
Diterpenos/farmacologia , Descoberta de Drogas , Euphorbia/química , Osteogênese/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ligante RANK/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cristalografia por Raios X , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Osteoclastos/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ligante RANK/metabolismo , Relação Estrutura-Atividade
9.
Rev. esp. cir. oral maxilofac ; 41(3): 145-148, jul.-sept. 2019. ilus
Artigo em Espanhol | IBECS | ID: ibc-191778

RESUMO

Las metástasis en hueso malar de tumores sólidos infraclaviculares son excepcionales. En aquellos de estirpe neuroendocrina, se debe considerar la expresión de receptores de somatostatina mediante diferentes técnicas de medicina nuclear para realizar terapias dirigidas. Se presenta un caso clínico de un varón de 66 años con neoplasia pulmonar con diferenciación oncocítica, cuyo debut es una metástasis malar de lenta evolución. Es tratado con lanreotido y ácido zolendrónico con enfermedad estable al año de seguimiento


Malar bone metastases of solid infraclavicular tumours are exceptional. Expression of somatostatin receptors should be considered in neuroendocrine strains, in order to carry out targeted therapies. We report a clinical case of a 66-year-old man with a tumour of the lung with oncocytic features, which debut is a malar metastasis of slow evolution. He is treated with Lanreotide and Zolendronic acid with stable disease at 1-year follow-up


Assuntos
Humanos , Masculino , Idoso , Zigoma/patologia , Neoplasias Orbitárias/secundário , Tumores Neuroendócrinos/patologia , Neoplasias Pulmonares/patologia , Metástase Neoplásica/patologia , Biomarcadores Tumorais/análise , Tumores Neuroendócrinos/tratamento farmacológico , Somatostatina/análise , Difosfonatos/uso terapêutico , Ligante RANK/antagonistas & inibidores
10.
Biochem Biophys Res Commun ; 517(3): 407-412, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31376931

RESUMO

Periprosthetic asepteic loosening, caused by wear debris, is one of the most severe complications, generally resulting in implant failure. Extensive osteoclast formation and activation are considered as the cause for periprosthetic osteolysis. However, few approaches have been approved to be used for preventing early-stage periprosthetic osteolysis. In this study, we investigated the preventive effects of CEP on titanium particles-induced osteolysis in a murine calvaria model. This inhibitory effect was confirmed to be realized by attenuating osteoclastogenesis in vivo. In addition, CEP markedly reduced wear particles-induced elevation of receptor activator of nuclear factor kappa B ligand (RANKL)/Osteoprotegerin (OPG) ratio in vivo. In conclusion, these data concluded that CEP demonstrated a preventive effect of CEP on titanium particles induced osteolysis, suggesting that CEP might be a novel therapeutic for periprosthesis loosening.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzilisoquinolinas/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteólise/prevenção & controle , Osteoprotegerina/genética , Ligante RANK/genética , Titânio/efeitos adversos , Animais , Prótese Ancorada no Osso , Interface Osso-Implante/cirurgia , Catepsina D/genética , Catepsina D/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Masculino , Camundongos , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese/genética , Osteólise/induzido quimicamente , Osteólise/genética , Osteólise/patologia , Osteoprotegerina/antagonistas & inibidores , Osteoprotegerina/metabolismo , Falha de Prótese/efeitos dos fármacos , Ligante RANK/antagonistas & inibidores , Ligante RANK/metabolismo , Crânio/efeitos dos fármacos , Crânio/cirurgia , Fosfatase Ácida Resistente a Tartarato/genética , Fosfatase Ácida Resistente a Tartarato/metabolismo
11.
J Bone Miner Res ; 34(12): 2171-2182, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31295366

RESUMO

Fibrous dysplasia of bone/McCune-Albright syndrome (Polyostotic FD/MAS; OMIM#174800) is a crippling skeletal disease caused by gain-of-function mutations of Gs α. Enhanced bone resorption is a recurrent histological feature of FD and a major cause of fragility of affected bones. Previous work suggests that increased bone resorption in FD is driven by RANKL and some studies have shown that the anti-RANKL monoclonal antibody, denosumab, reduces bone turnover and bone pain in FD patients. However, the effect of RANKL inhibition on the histopathology of FD and its impact on the natural history of the disease remain to be assessed. In this study, we treated the EF1α-Gs αR201C mice, which develop an FD-like phenotype, with an anti-mouse RANKL monoclonal antibody. We found that the treatment induced marked radiographic and microscopic changes at affected skeletal sites in 2-month-old mice. The involved skeletal segments became sclerotic due to the deposition of new, highly mineralized bone within developing FD lesions and showed a higher mechanical resistance compared to affected segments from untreated transgenic mice. Similar changes were also detected in older mice with a full-blown skeletal phenotype. The administration of anti-mouse RANKL antibody arrested the growth of established lesions and, in young mice, prevented the appearance of new ones. However, after drug withdrawal, the newly formed bone was remodelled into FD tissue and the disease progression resumed in young mice. Taken together, our results show that the anti-RANKL antibody significantly affected the bone pathology and natural history of FD in the mouse. Pending further work on the prevention and management of relapse after treatment discontinuation, our preclinical study suggests that RANKL inhibition may be an effective therapeutic option for FD patients. © 2019 American Society for Bone and Mineral Research.


Assuntos
Displasia Fibrosa Óssea/metabolismo , Ligante RANK/antagonistas & inibidores , Animais , Fenômenos Biomecânicos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Calcificação Fisiológica , Denosumab/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Displasia Fibrosa Óssea/complicações , Displasia Fibrosa Óssea/diagnóstico por imagem , Displasia Fibrosa Óssea/patologia , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Camundongos Transgênicos , Osteólise/sangue , Osteólise/complicações , Fator 1 de Elongação de Peptídeos/metabolismo , Fenótipo , Ligante RANK/metabolismo , Ratos
12.
Cancer Immunol Immunother ; 68(7): 1187-1194, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31187176

RESUMO

BACKGROUND: PD-1 inhibition (PD-1i) is the standard of care in melanoma and other malignancies. In patients with bone metastases of solid tumors, the monoclonal antibody denosumab directed against RANKL is approved for the prevention of skeletal-related events. However, RANKL is not only relevant in osteoclastogenesis, but also has immunological effects. Hence, we aimed at investigating, whether the combination of PD-1i and denosumab produces synergistic effects in metastatic melanoma treatment. METHODS: We retrospectively collected and analyzed clinical data of metastatic melanoma patients with bone metastases, who received PD-1i and denosumab therapy. RESULTS: 29 patients were identified with a median age of 60.7 years: 20 were male and 9 were female. 20 patients (69%) were in stage IV M1c and 9 (31%) in stage IV M1d; 52% had an increased serum LDH. 24 patients (83%) received PD-1i as first-line therapy and five patients (17%) as second- or third-line therapy. 13 patients received the triple combination nivolumab, ipilimumab and denosumab (N + I+D), 16 patients received PD-1i and denosumab (PD-1i + D). Within a median follow-up time of 19.8 months, 17 patients progressed with a median time to progression of 6 months. The objective response rate was 54% in the N + I + D group and 50% in the PD-1i + D group. Recalcification of bone metastases was radiologically observed in 18 (62%) patients. No unexpected treatment-related adverse events emerged. CONCLUSIONS: The combination therapy of metastatic melanoma with PD-1i and denosumab was feasible without unexpected safety issues and showed a promising efficacy signal. Further investigation in prospective studies is needed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Denosumab/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Denosumab/farmacologia , Feminino , Humanos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Ligante RANK/antagonistas & inibidores , Ligante RANK/imunologia , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia
13.
Hum Mol Genet ; 28(18): 3101-3112, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31179501

RESUMO

Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy which leads to progressive muscle degeneration and inflammation. The receptor activator of nuclear factor NF-κB ligand (RANKL) and its receptor (RANK), which are expressed in bone and skeletal and cardiac muscles, form a signaling network upstream from nuclear factor-kappa B (NF-κB). We thus hypothesized that prolonged silencing RANKL/RANK signaling would significantly improve DMD. We showed that RANK and RANKL protein levels were increased in the microenvironment of myofibers of 5-month-old utrophin haploinsufficient mdx (mdx/utrn+/-) mice and that a 4 mg/kg dose of anti-RANKL antibody every 3 d for 28 days is optimal and more effective than 1 mg/kg every 3 d for improving the ex vivo maximum specific force (sP0) of dystrophic EDL muscles from mdx/utrn+/- mice. This functional improvement was associated with a reduction in muscle edema, damage, and fibrosis and a marked reduction in serum CK levels. The anti-RANKL treatment inhibited the NF-κB pathway, increased the proportion of anti-inflammatory and non-cytotoxic M2 macrophages, and reduced the number of centrally-nucleated myofibers and the frequency of small myofibers, suggesting that anti-RANKL inhibits the cycle of degeneration/regeneration in dystrophic mice. A three-point bending test showed that a 28-d anti-RANKL treatment increases the mechanical properties of bone in mdx/utrn+/- dystrophic mice. In conclusion, the anti-RANKL treatment protected against skeletal muscle dysfunctions while enhancing bone mechanical properties, filling two needs with one deed in the context of muscular dystrophy.


Assuntos
Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Miosite/metabolismo , Ligante RANK/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais/farmacologia , Microambiente Celular , Modelos Animais de Doenças , Fibrose , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofias Musculares , Miosite/tratamento farmacológico , Miosite/etiologia , Miosite/patologia , NF-kappa B/metabolismo , Fenótipo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Biochem Biophys Res Commun ; 516(2): 350-356, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31208720

RESUMO

Receptor activator of NF-κB ligand (RANKL) is a member of the TNF superfamily. RANKL increases endothelial permeability and induces angiogenesis, suggesting its critical roles in the vasculature. Despite the evidence implicating RANKL in vascular pathology, its role in ischemic retinopathy has not been previously reported. In this study, neonatal mice were exposed to 75% oxygen from postnatal day (P)7 to P12 to induce vaso-obliteration, and then returned to room air from P12 to P17, causing the retina to become hypoxic and inducing vascular endothelial growth factor (VEGF) signaling, which produces pathological neovascularization. On P12, the mice received a single intravitreal injection of control IgG1 or RANK-Fc, and retinas were obtained at P17. On P17, RANKL was expressed strongly and selectively in the neovascular tufts (NVT) area. RANKL colocalized with αSMA or PDGFRß in NVT. However, co-immunostaining revealed that CD31-positive areas were not the same as RANKL, which indicates that RANKL might be produced by retinal pericytes, not endothelial cells. Consistent with this finding, chemical hypoxia upregulated RANKL expression in cultured human retinal pericytes but not in endothelial cells. Treatment with RANK-Fc markedly reduced the NVT area compared to that in mice administered the IgG1 injection. In contrast, the central avascular region of RANKL-Fc retina was comparable to the controls. In addition, we assessed retinal vascular permeability using FITC-labeled dextran. RANK-Fc treated mice displayed decreased vascular leakages compared to those injected with IgG1. Our work supports the use of an RANKL blockade as a potential therapeutic approach against ischemic retinopathies.


Assuntos
Isquemia/patologia , Neovascularização Patológica/patologia , Ligante RANK/antagonistas & inibidores , Doenças Retinianas/patologia , Animais , Animais Recém-Nascidos , Permeabilidade Capilar , Hipóxia Celular , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Isquemia/complicações , Camundongos Endogâmicos C57BL , Neovascularização Patológica/complicações , Pericitos/metabolismo , Ligante RANK/metabolismo , Doenças Retinianas/complicações , Células Ganglionares da Retina/metabolismo
16.
Cancer Immunol Res ; 7(6): 854-859, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160305

RESUMO

A major breakthrough in cancer treatment occurred with the development of strategies that overcome T-cell tolerance toward tumor cells. These approaches enhance antitumor immunity by overcoming mechanisms that are normally in place to prevent autoimmunity but simultaneously prevent rejection of tumor cells. Although tolerance mechanisms that restrict antitumor immunity take place both in the thymus and periphery, only immunotherapies that target peripheral tolerance mechanisms occurring outside of the thymus are currently available. We review here recent gains in our understanding of how thymic tolerance mediated by the autoimmune regulator (Aire) impedes antitumor immunity. It is now clear that transient depletion of Aire-expressing cells in the thymus can be achieved with RANKL blockade. Finally, we discuss key findings that support the repurposing of anti-RANKL as a cancer immunotherapy with a unique mechanism of action.


Assuntos
Tolerância Central/genética , Tolerância Central/imunologia , Neoplasias/etiologia , Neoplasias/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Autoimunidade/genética , Deleção Clonal/genética , Deleção Clonal/imunologia , Humanos , Imunomodulação , Imunoterapia , Terapia de Alvo Molecular , Neoplasias/patologia , Neoplasias/terapia , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Ligante RANK/antagonistas & inibidores , Ligante RANK/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Timo/imunologia , Timo/metabolismo
17.
BMC Musculoskelet Disord ; 20(1): 225, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101043

RESUMO

BACKGROUND: The expression of the receptor activator of nuclear factor kappa B (RANK) /RANK ligand (RANKL) /osteoprotegerin (OPG) system and its association with the progression of intervertebral disc (IVD) degeneration has recently been reported in a human IVD. However, the effect of the RANK/RANKL/OPG system on the matrix metabolism of human IVD cells, especially on the expression of catabolic factors relevant to IVD degeneration, remains unknown. The purpose of this study was to examine the expression of the RANK/RANKL/OPG system, and then to evaluate the effect of this system on the expression of catabolic factors by human IVD cells. METHODS: Annulus fibrosus (AF) and nucleus pulposus (NP) cells isolated by sequential enzyme digestion from human IVD tissues obtained during spine surgeries were monolayer cultured. The expression of the RANK/RANKL/OPG system was determined using immunohistochemical methods and real-time polymerase chain reaction (PCR). To evaluate the influence of interleukin-1 beta (IL-1ß) stimulation on the mRNA expression of RANK, RANKL, and OPG, recombinant human IL-1ß (rhIL-1ß) was administered in the culture media of IVD cells. To examine the influence of RANKL signaling on the expression of matrix metalloprotease-3 (MMP-3), MMP-13, and IL-1ß, the cells were cultured with exogenous recombinant human RANKL (rhRANKL), recombinant human OPG (rhOPG) or anti-human RANKL mouse monoclonal antibody (ahRANKL-mAB) with or without rhIL-1ß. RESULTS: Immunoreactivity to RANK/RANKL/OPG and the mRNA expression of the three genes were obviously identified in both AF and NP cells. rhIL-1ß stimulation significantly upregulated the mRNA expression level of RANK/RANKL/OPG. The mRNA expression of catabolic factors was significantly upregulated by stimulation of rhRANKL in the presence of rhIL-1ß. On the other hand, the administration of either rhOPG or ahRANKL-mAB significantly suppressed the mRNA expression of catabolic factors that had been upregulated by rhIL-1ß stimulation. The suppressive effect of ahRANKL-mAB against rhIL-1ß stimulation was also confirmed by the protein expression of MMP-3. CONCLUSIONS: The present study showed that the RANK/RANKL/OPG system may be involved in the progression of IVD degeneration. This study also suggested the potential use of anti-RANKL monoclonal antibody and OPG as therapeutic agents to suppress the progression of IVD degeneration.


Assuntos
Degeneração do Disco Intervertebral/patologia , Disco Intervertebral/patologia , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Células Cultivadas , Condrócitos , Progressão da Doença , Feminino , Fibroblastos , Humanos , Disco Intervertebral/citologia , Degeneração do Disco Intervertebral/cirurgia , Masculino , Camundongos , Pessoa de Meia-Idade , Cultura Primária de Células , Ligante RANK/antagonistas & inibidores , Proteínas Recombinantes/metabolismo
18.
J Clin Invest ; 129(8): 3214-3223, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31120440

RESUMO

Receptor activator of Nfkb ligand (RANKL) activates, while osteoprotegerin (OPG) inhibits, osteoclastogenesis. In turn a neutralizing Ab against RANKL, denosumab improves bone strength in osteoporosis. OPG also improves muscle strength in mouse models of Duchenne's muscular dystrophy (mdx) and denervation-induce atrophy, but its role and mechanisms of action on muscle weakness in other conditions remains to be investigated. We investigated the effects of RANKL inhibitors on muscle in osteoporotic women and mice that either overexpress RANKL (HuRANKL-Tg+), or lack Pparb and concomitantly develop sarcopenia (Pparb-/-). In women, denosumab over 3 years improved appendicular lean mass and handgrip strength compared to no treatment, whereas bisphosphonate did not. HuRANKL-Tg+ mice displayed lower limb force and maximal speed, while their leg muscle mass was diminished, with a lower number of type I and II fibers. Both OPG and denosumab increased limb force proportionally to the increase in muscle mass. They markedly improved muscle insulin sensitivity and glucose uptake, and decrease anti-myogenic and inflammatory gene expression in muscle, such as myostatin and protein tyrosine phosphatase receptor-γ. Similarly, in Pparb-/-, OPG increased muscle volume and force, while also normalizing their insulin signaling and higher expression of inflammatory genes in skeletal muscle. In conclusions, RANKL deteriorates, while its inhibitor improves, muscle strength and insulin sensitivity in osteoporotic mice and humans. Hence denosumab could represent a novel therapeutic approach for sarcopenia.


Assuntos
Osso e Ossos/metabolismo , Denosumab/farmacologia , Resistência à Insulina , Força Muscular , Ligante RANK/antagonistas & inibidores , Animais , Osso e Ossos/patologia , Linhagem Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/genética , Osteoporose/tratamento farmacológico , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , PPAR beta/genética , PPAR beta/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismo , Sarcopenia/tratamento farmacológico , Sarcopenia/genética , Sarcopenia/metabolismo , Sarcopenia/patologia
19.
Orthod Fr ; 90(1): 55-63, 2019 Mar.
Artigo em Francês | MEDLINE | ID: mdl-30994449

RESUMO

INTRODUCTION: Recent observations performed in the orthodontic department of La Pitié-Salpêtrière hospital in Paris reported an increase of non-familial eruption defects of permanent molars. Our recent data have evidenced the involvement of osteoclasts (OC) in both the eruption and the dental retention processes through the RANKL/RANK/OPG signaling pathway. These facts are at the origin of the hypothesis of the existence of an environmental etiology for those eruption defects that would correspond to the perturbation of cellular autocrine/paracrine signaling pathways as the RANKL/ RANK/OPG. MATERIALS AND METHODS: C57BL/6 mice were submitted to repeated injections with anti-RANKL neutralizing antibody during the nine days following birth. A phenotypic comparison with transgenic mice overexpressing RANK was performed for the functional characterization of the RANKL/RANK/OPG pathway. The dento-alveolar complex was analyzed using micro-CT for bone density and Masson's trichrome staining for histological examination. RESULTS: The RANKL transient invalidation of RANKL stopped the molar root development and tooth eruption contrary to transgenic mice overexpressing RANK. The recruitment and the OC activity were strongly impacted. DISCUSSION: This research is of direct clinical interest in understanding the pathology of eruption as indirect in establishing orthodontic treatment protocols for particular cases.


Assuntos
Anticorpos Monoclonais/farmacologia , Dente Molar/efeitos dos fármacos , Ligante RANK/imunologia , Erupção Dentária/efeitos dos fármacos , Raiz Dentária/efeitos dos fármacos , Animais , Anticorpos Monoclonais/administração & dosagem , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Dente Molar/diagnóstico por imagem , Dente Molar/crescimento & desenvolvimento , Ligante RANK/antagonistas & inibidores , Raiz Dentária/diagnóstico por imagem , Raiz Dentária/crescimento & desenvolvimento , Microtomografia por Raio-X
20.
FASEB J ; 33(6): 7261-7273, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30857415

RESUMO

Skeletal homeostasis is closely effectuated by the regulation of bone formation and bone resorption. Osteoclasts are multinuclear giant cells responsible for bone resorption. Overactivated osteoclasts and excessive bone resorption result in various lytic bone diseases, such as osteoporosis, osteoarthritis, periprosthetic infection, and inflammatory aseptic loosening of orthopedic implants. In consideration of the severe side effects caused by the currently available drugs, exploitation of novel drugs has gradually attracted attention. Because of its anti-inflammatory, antioxidant, and antitumor capacities, diallyl disulfide (DADS), a major oil-soluble organosulfur ingredient compound derived from garlic, has been widely researched. However, the effects of DADS on osteoclasts and lytic bone diseases are still unknown. In this study, we investigated the effects of DADS on receptor activator of NF-κB ligand (RANKL)- and LPS-mediated osteoclastogenesis, LPS-stimulated proinflammatory cytokines related to osteoclasts, and LPS-induced inflammatory osteolysis. The results showed that DADS significantly inhibited RANKL-mediated osteoclast formation, fusion, and bone resorption in a dose-dependent manner via inhibiting the NF-κB and signal transducer and activator of transcription 3 signaling and restraining the interaction of NF-κB p65 with nuclear factor of activated T cells cytoplasmic 1. Furthermore, DADS also markedly suppressed LPS-induced osteoclastogenesis and reduced the production of proinflammatory cytokines with LPS stimulation to indirectly mediate osteoclast formation. Consistent with the in vitro results, DADS prevented the LPS-induced severe bone loss by blocking the osteoclastogenesis. All of the results indicate that DADS may be a potential and exploitable drug used for preventing and impeding osteolytic lesions.-Yang, J., Tang, R., Yi, J., Chen, Y., Li, X., Yu, T., Fei, J. Diallyl disulfide alleviates inflammatory osteolysis by suppressing osteoclastogenesis via NF-κB-NFATc1 signal pathway.


Assuntos
Compostos Alílicos/farmacologia , Anti-Inflamatórios/farmacologia , Dissulfetos/farmacologia , NF-kappa B/fisiologia , Osteoclastos/efeitos dos fármacos , Osteólise/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Compostos Alílicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Dissulfetos/uso terapêutico , Endotoxemia/complicações , Feminino , Inflamação , Lipopolissacarídeos/toxicidade , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/patologia , Osteólise/etiologia , Ligante RANK/antagonistas & inibidores , Ligante RANK/farmacologia , Células RAW 264.7 , Distribuição Aleatória , Proteínas Recombinantes/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA