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1.
Adv Exp Med Biol ; 1155: 61-70, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468386

RESUMO

Taurine is an abundant sulfur-containing amino acid in myeloid cells. It undergoes halogenation in activated phagocytes and is converted to taurine chloramine (TauCl) and taurine bromamine. Bone homeostasis is mediated by the balance between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoclasts are bone-resorbing multinucleated cells differentiated from monocyte/macrophage precursor cells in response to receptor activator of NF-κB ligand (RANKL). In this study, we investigated the effect of TauCl on RANKL-induced osteoclastogenesis from RAW 264.7 macrophages. TauCl inhibited the formation of multi-nucleated osteoclast and the activity of tartrate-resistant acid phosphatase (TRAP). TauCl decreased the mRNA expression of osteoclast markers, such as TRAP, cathepsin K, and calcitonin receptor. TauCl also inhibited expression of the transcription factors, c-Fos and nuclear factor of activated T cells, which are important for osteoclast differentiation. These results suggest that TauCl might be used as a therapeutic agent to treat bone diseases associated with excessive bone resorption.


Assuntos
Diferenciação Celular , Osteoclastos/efeitos dos fármacos , Taurina/análogos & derivados , Animais , Camundongos , Ligante RANK/fisiologia , Células RAW 264.7 , Transdução de Sinais , Fosfatase Ácida Resistente a Tartarato/fisiologia , Taurina/farmacologia , Fatores de Transcrição/fisiologia
2.
Food Chem Toxicol ; 129: 344-353, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31055000

RESUMO

Porphyromonas gingivalis (P. gingivalis) is one of the major periodontal pathogens leading to inflammation and alveolar bone resorption. Bone resorption is induced by osteoclasts, which are multinucleated giant cells. Osteoclastic bone resorption is mediated by enhanced receptor activator of nuclear factor-kappa B ligand (RANKL) signaling. Therefore, the down-regulation of RANKL downstream signals is regarded as an effective therapeutic target in the treatment of bone loss-associated disorders. The aim of this study was to evaluate whether purified bee venom (BV) could attenuate P. gingivalis-induced inflammatory periodontitis and RANKL-induced osteoclast differentiation. Inflammatory periodontitis induced by P. gingivalis increased alveolar bone resorption and increased expression of TNF-α and IL-1ß, while BV treatment resulted in decreased bone loss and pro-inflammatory cytokines. Similarly, RANKL-induced multinucleated osteoclast differentiation and osteoclast-specific gene expression, such as nuclear factor of activated T cells 1 (NFATc1), cathepsin K, tartrate-resistant acid phosphatase (TRAP), and integrin αvß3 were significantly suppressed by treatment with BV. We show that BV reduces P. gingivalis-induced inflammatory bone loss-related periodontitis in vivo and RANKL-induced osteoclast differentiation, activation, and function in vitro. These results suggest that BV exerts positive effects on inflammatory periodontitis associated osteoclastogenesis.


Assuntos
Venenos de Abelha/toxicidade , Reabsorção Óssea , Diferenciação Celular/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Porphyromonas gingivalis/efeitos dos fármacos , Ligante RANK/fisiologia , Animais , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Osteoclastos/citologia , Porphyromonas gingivalis/fisiologia , Células RAW 264.7
3.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 33(4): 511-515, 2019 Apr 15.
Artigo em Chinês | MEDLINE | ID: mdl-30983204

RESUMO

Objective: To summarize the research progress on the calcitonin gene-related peptide (CGRP) and receptor activator of nuclear factor κB (RANK)/receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) system during bone reconstruction to provide theoretical basis for further research on the prevention and treatment of bone-related diseases. Methods: The relevant research results at home and abroad in recent years were analyzed and summarized. Results: CGRP and RANK/RANKL/OPG system play important regulatory roles in the bone reconstruction. Conclusion: At present, the research on the mechanism of CGRP and RANK/RANKL/OPG system in bone reconstruction is insufficient. Therefore, it is necessary to study further on the process and interrelation of CGRP and RANK/RANKL/OPG system in bone reconstruction to confirm their mechanism, which will bring new ideas and methods for the treatment of bone related diseases in clinic.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Osteoprotegerina , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Remodelação Óssea/fisiologia , Calcitonina , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Proteínas de Transporte , Glicoproteínas , Glicoproteínas de Membrana , NF-kappa B/fisiologia , Osteoprotegerina/fisiologia , Ligante RANK/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/fisiologia , Receptores Citoplasmáticos e Nucleares
4.
J Endod ; 45(2): 123-128, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30580840

RESUMO

INTRODUCTION: The exact mechanisms of periapical bone resorption have not been fully elucidated. This study aimed to analyze the expression of Notch signaling molecules (Notch2, Jagged1, and Hey1) and proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin [IL]-1ß, and IL-6) in human apical periodontitis lesions with different receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratios and determine their potential correlation. METHODS: The study group consisted of 50 periapical lesions collected in conjunction with apicoectomy. The relative gene expression of the investigated molecules (Notch2, Jagged1, Hey1, RANKL, OPG, TNF-α, IL-1ß, and IL-6) in all tissue samples was analyzed using reverse transcriptase real-time polymerase chain reaction. The Student t test, Mann-Whitney U test, and Spearman correlation were used for statistical analysis. RESULTS: Based on the RANKL/OPG ratio, periapical lesions were either RANKL predominant (RANKL > OPG, n = 33) or OPG predominant (RANKL < OPG, n = 17). Symptomatic lesions occurred more frequently in RANKL-predominant compared with OPG-predominant lesions (24 vs 7, P = .029). Notch2, Jagged1, Hey1, and TNF-α were significantly overexpressed in lesions with predominant RANKL compared with lesions with predominant OPG (P = .001, P = .001, P = .027, and P = .016, respectively). Significant correlations were observed between the investigated genes in periapical lesions. CONCLUSIONS: Notch signaling appeared to be activated in periapical inflammation. An increase in Notch2, Jagged1, Hey1, and TNF-α expression in RANKL-predominant periapical lesions corroborates their joined involvement in extensive periapical bone resorption.


Assuntos
Reabsorção Óssea/genética , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Periodontite Periapical/genética , Periodontite Periapical/fisiopatologia , Receptor Notch2/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Adolescente , Adulto , Idoso , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Osteoprotegerina/genética , Osteoprotegerina/fisiologia , Ligante RANK/genética , Ligante RANK/fisiologia , Receptor Notch2/genética , Adulto Jovem
5.
Cancer Prev Res (Phila) ; 11(12): 789-796, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30352839

RESUMO

The receptor activator of nuclear factor-κB (RANK) pathway plays essential roles in breast development. Mammographic density is a strong risk factor for breast cancer, especially in premenopausal women. We, therefore, investigated the associations of circulating RANK and soluble RANK ligand (sRANKL) with mammographic density in premenopausal women. Mammographic density was measured as volumetric percent density in 365 cancer-free premenopausal women (mean age, 47.5 years) attending screening mammogram at the Washington University School of Medicine (St. Louis, MO). We used linear regression models adjusted for confounders, to compare the least-square means of volumetric percent density across tertiles of circulating RANK and sRANKL. Furthermore, because RANKL levels in mammary tissue are modulated by progesterone, we stratified analyses by progesterone levels. The mean volumetric percent density increased across tertiles of circulating RANK from 8.6% in tertile 1, to 8.8% in tertile 2, and 9.5% in tertile 3 (P trend = 0.02). For sRANKL, the mean volumetric percent density was 8.5% in tertile 1, 9.4% in tertile 2, and 9.0% in tertile 3 (P trend = 0.30). However, when restricted to women with higher progesterone levels, the mean volumetric percent density increased from 9.1% in sRANKL tertile 1 to 9.5% in tertile 2, and 10.1% in tertile 3 (P trend = 0.01). Circulating RANK was positively associated with volumetric percent density, while circulating sRANKL was positively associated with volumetric percent density among women with higher progesterone levels. These findings support the inhibition of RANKL signaling as a pathway to reduce mammographic density and possibly breast cancer incidence in high-risk women with dense breasts.


Assuntos
Densidade da Mama/fisiologia , Neoplasias da Mama/diagnóstico por imagem , Mama/diagnóstico por imagem , Ligante RANK/sangue , Receptor Ativador de Fator Nuclear kappa-B/sangue , Adulto , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Humanos , Mamografia/estatística & dados numéricos , Pessoa de Meia-Idade , Pré-Menopausa/fisiologia , Progesterona/sangue , Progesterona/fisiologia , Ligante RANK/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/fisiologia
6.
Int J Med Sci ; 15(10): 969-977, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30013437

RESUMO

The receptor activator of nuclear factor-κB ligand (RANKL) modulates energy metabolism. However, how RANKL regulates energy homeostasis is still not clear. This study aims to investigate the central mechanisms by which central administration of RANKL inhibits food intake and causes weight loss in mice. We carried out a systematic and in-depth analysis of the neuronal pathways by which RANKL mediates catabolic effects. After intracerebroventricle (i.c.v.) injection of RANKL, the expression of neuropeptide Y (NPY) mRNA in the Arc was significantly decreased, while the CART mRNA expression dramatically increased in the Arc and DMH. However, the agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) mRNA had no significant changes compared with control groups. Together, the results suggest that central administration of RANKL reduces food intake and causes weight loss via modulating the hypothalamic NPY/CART pathways.


Assuntos
Peso Corporal , Ingestão de Alimentos , Ligante RANK/fisiologia , Animais , Hipotálamo/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeo Y/metabolismo
7.
Food Chem Toxicol ; 120: 418-429, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30048646

RESUMO

Thymol was identified as one of key compounds contributing to the aroma of thyme leaves. We investigated the effects of thymol on receptor activator NF-κB ligand (RANKL)-induced osteoclastogenesis in murine macrophage RAW264.7 cells and bone marrow derived macrophage (BMMs) cells and lipopolysaccharide (LPS)-induced bone loss in vivo. Thymol markedly reduced RANKL-stimulated osteoclast formation and differentiation in RAW264.7 cells and BMMs cells without any cytotoxic effects. The in vitro and in vivo osteoclastogenesis inhibitory effect of thymol was assessed by calculating the quantity of TRAP (+) multinucleated cells and its inhibitory effects on the resorbing capacity were examined on calcium phosphate-coated plates. Moreover, the inhibitory effects of thymol resulted in a reduction of RANK, cathepsin K, matrix metalloproteinase-9 (MMP-9), dendritic cell-specific transmembrane protein (DC-STAMP), c-terminal myc kinase (C-MYC), C-terminal Src kinase (C-SRC), GRB2-associated-binding protein 2 (GAB2), microphthalmia-associated transcription factor (MITF), and carbonic anhydrase II genes. Similarly, activities of ERK, JNK and AKT and protein expressions of NFATc1, C-FOS, MMP-9 and cathepsin K were downregulated by thymol. More importantly, the application of thymol significantly reduced LPS-induced inflammatory bone loss in mice. In conclusion, these findings identified that thymol could be a useful therapeutic agent for the prevention of bone destructive diseases.


Assuntos
Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoporose/prevenção & controle , Ligante RANK/antagonistas & inibidores , Timol/farmacologia , Animais , Reabsorção Óssea/prevenção & controle , Diferenciação Celular/efeitos dos fármacos , Ativação Enzimática , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ligante RANK/fisiologia , Células RAW 264.7
8.
J Leukoc Biol ; 104(6): 1133-1145, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30059166

RESUMO

Increased intake of vitamin A (retinoids) is associated with decreased bone mass and increased fracture risk in humans. Mechanistic studies in rodents have shown that hypervitaminosis A results in decreased bone mass caused by an increase in periosteal osteoclasts while simultaneously decreasing endocortic osteoclasts. In vivo and ex vivo bone organ cultures have demonstrated that excess retinoids increase osteoclast formation due to increased receptor activator of nuclear factor kappa B-ligand (RANKL) expression. In vitro, studies using murine bone marrow macrophages (BMM) have shown that retinoids inhibit osteoclast formation induced by recombinant RANKL. These opposing in vivo/ex vivo versus in vitro effects may elucidate why excess retinoids affect periosteal and endocortic osteoclast formation differently. In addition, it has been reported that retinoids can inhibit osteoclast formation under inflammatory conditions such as experimentally induced arthritis in mice. In the present study, we have compared the effect of all-trans-retinoic acid (ATRA) on physiologically and inflammatory induced osteoclastogenesis. ATRA inhibited physiologically induced (RANKL) osteoclast formation of human peripheral blood monocytes and mouse BMM as well as human monocytes stimulated with the pro-inflammatory compounds, TNF-α and LPS. The inhibition was due to impeded differentiation, rather than fusion, of mononucleated progenitor cells. ATRA disrupted differentiation by interfering with osteoclastogenic intracellular signaling. In line with this view, overexpression of Tnfrsf11a (encodes for RANK) in BMM could not overcome the inhibition of osteoclastogenesis by ATRA. The data suggest that ATRA inhibits both physiologic and inflammatory osteoclast differentiation of progenitors from the bone marrow and peripheral blood.


Assuntos
Inflamação/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Tretinoína/farmacologia , Animais , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/patologia , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/antagonistas & inibidores , Osteoclastos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Ligante RANK/farmacologia , Ligante RANK/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/biossíntese , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/antagonistas & inibidores , Receptores do Ácido Retinoico/fisiologia , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia
9.
Biomed Res Int ; 2018: 3936257, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29977911

RESUMO

FNDC4 acts as an anti-inflammatory factor on macrophages and improves mouse model of induced colitis. Considering osteoclast formation is characterized by the activation of inflammation-related pathways, we thus speculated that FNDC4 may play a pivotal role in this process. RT-qPCR analysis was performed to confirm the expression of osteoclast formation related genes in primary murine bone marrow macrophages (BMMs). RANKL-treated BMMs were cultured with FNDC4 to evaluate the effect of FNDC4 on osteoclast differentiation. TRAP staining and bone resorption pits assay were used to assess osteoclast formation and bone resorption, respectively. Luciferase assay and western blotting analysis were conducted to determine whether FNDC4 inhibited osteoclast formation via NF-κB signaling in RAW 264.7 cells. Furthermore, to identify gene signatures in FNDC4-treated BMMs and to use these to elucidate the underlying molecular mechanisms during osteoclast formation, we adopted a bioinformatics approach by downloading the GSE76172 gene expression profiling dataset from the Gene Expression Omnibus (GEO) database. FNDC4 inhibited RANKL-induced osteoclastogenesis and mature osteoclast resorptive function in a dose-dependent manner. Results of NF-κB luciferase assay suggested that FNDC4 could significantly suppress the RANKL-induced NF-κB transcriptional activity. Based on the protein-protein interaction network, CXCL10 was identified as the differentially expressed gene with the highest connectivity degree (degree = 23); it was drastically downregulated in the presence of FNDC4, but supplementation of CXCL10 (10 ng/mL) partially ameliorated the FNDC4-induced inhibition of osteoclast formation. Taken together, we speculated that FNDC4 could suppress osteoclast formation via NF-κB pathway and downregulation of CXCL10.


Assuntos
Quimiocina CXCL10/metabolismo , Proteínas de Membrana/fisiologia , NF-kappa B/metabolismo , Osteoclastos/fisiologia , Animais , Reabsorção Óssea , Diferenciação Celular , China , Macrófagos , Camundongos , Fatores de Transcrição NFATC , Ligante RANK/fisiologia , Coelhos
10.
Artigo em Inglês | MEDLINE | ID: mdl-29886255

RESUMO

This study aimed to investigate the precise data of gene expression, functions, and chronological relationships amongst communication molecules involved in the bone remodeling process with an in vivo model using autologous transplanted scales of goldfish. Autotransplantation of methanol-fixed cell-free scales triggers scale resorption and regeneration, as well as helps elucidate the process of bone remodeling. We investigated osteoclastic markers, osteoblastic markers, and gene expressions of communicating molecules (RANKL, ephrinB2, EphB4, EphA4, Wnt10b) by qPCR, in situ hybridization for Wnt10b, and immunohistochemistry for EphrinB2 and EphA4 proteins to elucidate the bone remodeling process. Furthermore, functional inhibition experiments for the signaling of ephrinB2/Eph, ephrin/EphA4, and Wnt10b using specific antibodies, revealed that these proteins are involved in key signaling pathways promoting normal bone remodeling. Our data suggests that the remodeling process comprises of two successive phases. In the first absorption phase, differentiation of osteoclast progenitors by RANKL is followed by the bone absorption by mature, active osteoclasts, with the simultaneous induction of osteoblast progenitors by multinucleated osteoclast-derived Wnt10b, and proliferation of osteoblast precursors by ehprinB2/EphB4 signaling. Subsequently, during the second formation phase, termination of bone resorption by synergistic cooperation occurs, with downregulation of RANKL expression in activated osteoblasts and Ephrin/EphA4-mediated mutual inhibition between neighboring multinucleated osteoclasts, along with simultaneous activation of osteoblasts via forward and reverse EphrinB2/EphB4 signaling between neighboring osteoblasts. In addition, the present study shows that autologous transplantation of methanol-fixed cell-free scale is an ideal in vivo model to study bone remodeling.


Assuntos
Escamas de Animais/transplante , Remodelação Óssea/fisiologia , Comunicação Celular/fisiologia , Efrinas/fisiologia , Proteínas de Peixes/fisiologia , Ligante RANK/fisiologia , Proteínas Wnt/fisiologia , Animais , Western Blotting , Carpa Dourada , Osteoblastos/citologia , Osteoclastos/citologia
11.
Mol Cells ; 41(5): 476-485, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29764006

RESUMO

Although tectorigenin (TG), a major compound in the rhizome of Belamcanda chinensis, is conventionally used for the treatment of inflammatory diseases, its effects on osteogenesis and osteoclastogenesis have not been reported. The objective of this study was to investigate the effects and possible underlying mechanism of TG on in vitro osteoblastic differentiation and in vivo bone formation, as well as in vitro osteoclast differentiation and in vivo bone resorption. TG promoted the osteogenic differentiation of primary osteoblasts and periodontal ligament cells. Moreover, TG upregulated the expression of the BMP2, BMP4, and Smad-4 genes, and enhanced the expression of Runx2 and Osterix. In vivo studies involving mouse calvarial bone defects with µCT and histologic analysis revealed that TG significantly increased new bone formation. Furthermore, TG treatment inhibited osteoclast differentiation and the mRNA levels of osteoclast markers. In vivo studies of mice demonstrated that TG caused the marked attenuation of bone resorption. These results collectively demonstrated that TG stimulated osteogenic differentiation in vitro, increased in vivo bone regeneration, inhibited osteoclast differentiation in vitro, and suppressed inflammatory bone loss in vivo. These novel findings suggest that TG may be useful for bone regeneration and treatment of bone diseases.


Assuntos
Reabsorção Óssea/prevenção & controle , Consolidação da Fratura/efeitos dos fármacos , Isoflavonas/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Transformada , Células Cultivadas , Feminino , Humanos , Isoflavonas/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Ligamento Periodontal/citologia , Cultura Primária de Células , Ligante RANK/fisiologia , Células RAW 264.7 , Crânio/efeitos dos fármacos , Crânio/lesões , Crânio/cirurgia , Fatores de Transcrição/metabolismo
12.
J Pharmacol Sci ; 137(1): 76-85, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29703642

RESUMO

Postmenopausal osteoporosis (POP) is quite prevalent and many new drugs are under development to obtain better therapeutic outcomes. Oleanolic acid (OA) has been reported to prevent bone loss in ovariectomized (OVX) rats by stimulating osteoblastogenesis. One previous study has demonstrated that acetate of OA suppressed lipopolysaccharides (LPS)-induced bone loss in mice. However, the role of OA in the receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis is still not elucidated. Here we show that OA dose-dependently inhibits RANKL-mediated osteoclastogenesis and the formation of functional osteoclasts without impairing the viability and osteoclastic potential in bone marrow macrophages (BMMs). Moreover, OA administration attenuates bone loss in OVX mice by inhibiting osteoclast's densities. Mechanistically, OA does not affect RANKL-induced activation of the NF-кB, JNK, p38, ERK and Akt pathways, but inhibits the expression of the nuclear factor of activated T-cells c1(NFATc1) and c-Fos. Moreover, OA significantly suppresses the expression of RANKL-activated osteoclast genes encoding matrix metalloproteinase 9 (MMP9), Cathepsin K(Ctsk), tartrate-resistant acid phosphatase (TRAP) and carbonic anhydrase II (Car2). This work has elucidated the molecular mechanism of OA in RANKL-mediated osteoclastogenesis and revealed the promising potential of OA to be further developed as a new drug to prevent and treat POP.


Assuntos
Ácido Oleanólico/farmacologia , Osteogênese/efeitos dos fármacos , Osteoporose Pós-Menopausa/prevenção & controle , Ovariectomia , Animais , Catepsina K/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Osteogênese/genética , Osteoporose Pós-Menopausa/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ligante RANK/fisiologia , Fosfatase Ácida Resistente a Tartarato/metabolismo
13.
Biomed Pharmacother ; 100: 142-146, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29428661

RESUMO

Gentiopicroside, a main active component from the traditional Chinese herb medicine Gentiana manshurica Kitag, has been shown to possess anti-arthritis effect. However, the molecular mechanism of gentiopicroside on the osteoclast formation remains unclear. The present study was designed to investigate the effects and mechanisms of gentiopicroside on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. The results showed that pre-treatment with gentiopicroside significantly inhibited RANKL-induced osteoclast formation from mouse bone marrow macrophages (BMMs). In addition, we observed that gentiopicroside efficiently suppressed osteoclastogenesis-related marker genes expression in RANKL-stimulated BMMs. Mechanistically, gentiopicroside suppressed RANKL-induced the activation of JNK and NF-κB signaling pathways in BMMs. Taken together, the present study demonstrated that gentiopicroside inhibits RANKL-induced osteoclastogenesis through the inactivation of JNK and NF-κB signaling pathways. Thus, gentiopicroside may be a promising agent for the treatment of osteoporosis.


Assuntos
Glucosídeos Iridoides/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ligante RANK/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismo , Ligante RANK/fisiologia , Proteínas Recombinantes
14.
Neuromolecular Med ; 20(1): 37-53, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29429076

RESUMO

The high prevalence of osteoporosis, observed in multiple sclerosis (MS) patients, has been attributed to reduced mobility and or the use of disease-modifying drugs. However, MS-impaired cardiovascular autonomic nervous system (ANS) function has the potential of reducing bone mass density (BMD) by altering the expression and/or function of the neuronal, systemic, and local mediators of bone remodeling. This review describes the complex regulation of bone homeostasis with a focus on MS, providing evidence that ANS dysfunction and low BMD are intertwined with MS inflammatory and neurodegenerative processes, and with other MS-related morbidities, including depression, fatigue, and migraine. Strategies for improving ANS function could reduce the prevalence of MS osteoporosis and slow the rate of MS progression, with a significant positive impact on patients' quality of life.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Remodelação Óssea/fisiologia , Sistema Cardiovascular/fisiopatologia , Esclerose Múltipla/complicações , Degeneração Neural/etiologia , Osteoporose/etiologia , Adiponectina/metabolismo , Densidade Óssea/fisiologia , Encéfalo/metabolismo , Depressão/etiologia , Depressão/fisiopatologia , Endocanabinoides/metabolismo , Fadiga/etiologia , Fadiga/fisiopatologia , Humanos , Inflamação , Leptina/fisiologia , Transtornos de Enxaqueca/etiologia , Transtornos de Enxaqueca/fisiopatologia , Esclerose Múltipla/metabolismo , Degeneração Neural/metabolismo , Neuropeptídeo Y/metabolismo , Osteocalcina/fisiologia , Osteopontina/fisiologia , Osteoporose/metabolismo , Osteoprotegerina/fisiologia , Hormônio Paratireóideo/metabolismo , Ligante RANK/fisiologia , Serotonina/metabolismo , Vitamina D/metabolismo
15.
Ann Clin Biochem ; 55(3): 308-327, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29368538

RESUMO

The bone remodelling cycle replaces old and damaged bone and is a highly regulated, lifelong process essential for preserving bone integrity and maintaining mineral homeostasis. During the bone remodelling cycle, osteoclastic resorption is tightly coupled to osteoblastic bone formation. The remodelling cycle occurs within the basic multicellular unit and comprises five co-ordinated steps; activation, resorption, reversal, formation and termination. These steps occur simultaneously but asynchronously at multiple different locations within the skeleton. Study of rare human bone disease and animal models have helped to elucidate the cellular and molecular mechanisms that regulate the bone remodelling cycle. The key signalling pathways controlling osteoclastic bone resorption and osteoblastic bone formation are receptor activator of nuclear factor-κB (RANK)/RANK ligand/osteoprotegerin and canonical Wnt signalling. Cytokines, growth factors and prostaglandins act as paracrine regulators of the cycle, whereas endocrine regulators include parathyroid hormone, vitamin D, calcitonin, growth hormone, glucocorticoids, sex hormones, and thyroid hormone. Disruption of the bone remodelling cycle and any resulting imbalance between bone resorption and formation leads to metabolic bone disease, most commonly osteoporosis. The advances in understanding the cellular and molecular mechanisms underlying bone remodelling have also provided targets for pharmacological interventions which include antiresorptive and anabolic therapies. This review will describe the remodelling process and its regulation, discuss osteoporosis and summarize the commonest pharmacological interventions used in its management.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea , Osteoporose/fisiopatologia , Animais , Reabsorção Óssea/metabolismo , Homeostase , Humanos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoprotegerina/metabolismo , Ligante RANK/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Via de Sinalização Wnt
16.
J Orthop Res ; 36(5): 1425-1434, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29068483

RESUMO

We aimed to develop an in vitro model for bone implant loosening, allowing analysis of biophysical and biological parameters contributing to mechanical instability-induced osteoclast differentiation and peri-implant bone loss. MLO-Y4-osteocytes were mechanically stimulated for 1 h by fluid shear stress using regimes simulating: (i) supraphysiological loading in the peri-prosthetic interface (2.9 ± 2.9 Pa, 1 Hz, square wave); (ii) physiologic loading in the cortical bone (0.7 ± 0.7 Pa, 5 Hz, sinusoidal wave); and (iii) stress shielding. Cellular morphological parameters, membrane-bound RANKL expression, gene expression influencing osteoclast differentiation, nitric oxide release and caspase 3/7-activity were determined. Either Mouse bone marrow cells were cultured on top of loaded osteocytes or osteocyte-conditioned medium was added to bone marrow cells. Osteoclast differentiation was assessed after 6 days. We found that osteocytes subjected to supraphysiological loading showed similar morphology and caspase 3/7-activity compared to simulated physiological loading or stress shielding. Supraphysiological stimulation of osteocytes enhanced osteoclast differentiation by 1.9-fold compared to physiological loading when cell-to-cell contact was permitted. In addition, it enhanced the number of osteoclasts using conditioned medium by 1.7-fold, membrane-bound RANKL by 3.3-fold, and nitric oxide production by 3.2-fold. The stimulatory effect of supraphysiological loading on membrane-bound RANKL and nitric oxide production was higher than that achieved by stress shielding. In conclusion, the in vitro model developed recapitulated the catabolic biological situation in the peri-prosthetic interface during instability that is associated with osteoclast differentiation and enhanced RANKL expression. The model thus provides a platform for pre-clinical testing of pharmacological interventions with potential to stop instability-induced bone implant loosening. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1425-1434, 2018.


Assuntos
Osteoclastos/fisiologia , Osteócitos/fisiologia , Osteogênese/fisiologia , Próteses e Implantes , Falha de Prótese , Animais , Apoptose , Comunicação Celular , Diferenciação Celular , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/citologia , Osteoprotegerina/fisiologia , Ligante RANK/fisiologia , Estresse Mecânico
17.
Mol Psychiatry ; 23(7): 1626-1631, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28555075

RESUMO

Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation-the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)-play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. The OPG-RANK-RANKL system plays the principal role in determining the balance between bone resorption and bone formation. RANKL is the osteoclast differentiating factor and diminishes BMD. OPG is a decoy receptor for RANKL, thereby increasing BMD. OPN is the bone glue that acts as a scaffold between bone tissues matrix composition to bind them together and is an important component of bone strength and fracture resistance. Twenty-eight medication-free inpatients with treatment-resistant MDD and 16 healthy controls (HCs) participated in the study. Peripheral bone marker levels and their responses to IV ketamine infusion in MDD patients and HCs were measured at four time points: at baseline, and post-infusion at 230 min, Day 1, and Day 3. Patients with MDD had significant decreases in baseline OPG/RANKL ratio and in plasma OPN levels. Ketamine significantly increased both the OPG/RANKL ratio and plasma OPN levels, and significantly decreased RANKL levels. Bone marker levels in HCs remained unaltered. We conclude that the OPG-RANK-RANKL system and the OPN system play important roles in the serious bone abnormalities associated with MDD. These data suggest that, in addition to its antidepressant effects, ketamine also has a salutary effect on a major medical complication of depressive illness.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Adulto , Biomarcadores , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/anormalidades , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteopontina/fisiologia , Osteoprotegerina/fisiologia , Ligante RANK/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/fisiologia
18.
Anat Sci Int ; 93(1): 23-34, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29098649

RESUMO

Microfold cells (M cells), which are located in the follicle-associated epithelium (FAE) covering mucosal lymphoid follicles, are specialized epithelial cells that initiate mucosal immune responses. These cells take luminal antigens and transport them via transcytosis across the FAE to the antigen-presenting cells underneath. Several intestinal pathogens exploit M cells as their portal for entry to invade the host and cause disease conditions. Recent studies have revealed that the uptake of antigens by M cells is essential for efficient antigen-specific IgA production and that this process likely maintains the homeostasis of mucosal tissues. The present article reviews recent advances in understanding the molecular mechanism of M-cell differentiation and describes the molecules expressed by M cells that are associated with antigen uptake and/or the transcytosis process. Current efforts to augment M-cell-mediated uptake for use in the development of effective mucosal vaccines are also discussed.


Assuntos
Diferenciação Celular , Células Epiteliais/citologia , Células Epiteliais/imunologia , Imunidade nas Mucosas , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Mucosa Nasal/citologia , Mucosa Nasal/imunologia , Transcitose/imunologia , Transcitose/fisiologia , Animais , Antígenos/imunologia , Diferenciação Celular/genética , Humanos , Imunidade nas Mucosas/genética , Imunoglobulina A , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , NF-kappa B/fisiologia , Ligante RANK/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Transcitose/genética
19.
J Steroid Biochem Mol Biol ; 177: 70-76, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29146302

RESUMO

Active forms of vitamin D enhance osteoclastogenesis in vitro and in vivo through the vitamin D receptor (VDR) in osteoblast-lineage cells consisting of osteoblasts and osteocytes. This pro-resorptive activity was evident basically with higher concentrations of active vitamin D than those expected in physiological conditions. Nevertheless, vitamin D compounds have been used in Japan for treating osteoporosis to increase bone mineral density (BMD). Of note, the increase in BMD by long-term treatment with pharmacological (=near-physiological) doses of vitamin D compounds was caused by the suppression of bone resorption. Therefore, whether vitamin D expresses pro-resorptive or anti-resorptive properties seems to be dependent on the treatment protocols. We established osteoblast lineage-specific and osteoclast-specific VDR conditional knockout (cKO) mice using Osterix-Cre transgenic mice and Cathepsin K-Cre knock-in mice, respectively. According to our observation using these cKO mouse lines, neither VDR in osteoblast-lineage cells nor that in osteoclasts played important roles for osteoclastogenesis and bone resorption at homeostasis. However, using our cKO lines, we observed that VDR in osteoblast-lineage cells, but not osteoclasts, was involved in the anti-resorptive properties of pharmacological doses of vitamin D compounds in vivo. Two different osteoblast-lineage VDR cKO mouse lines were reported. One is a VDR cKO mouse line using alpha 1, type I collagen (Col1a1)-Cre transgenic mice (here we call Col1a1-VDR-cKO mice) and the other is that using dentin matrix protein 1 (Dmp1)-Cre transgenic mice (Dmp1-VDR-cKO mice). Col1a1-VDR-cKO mice exhibited slightly increased bone mass due to lowered bone resorption. In contrast, Dmp1-VDR-cKO mice exhibited no difference in BMD in agreement with our results regarding Ob-VDR-cKO mice. Here we discuss contradictory results and multiple modes of actions of vitamin D in bone resorption in detail. (279 words).


Assuntos
Reabsorção Óssea/metabolismo , Osteogênese/efeitos dos fármacos , Vitamina D/farmacologia , Vitaminas/farmacologia , Animais , Reabsorção Óssea/tratamento farmacológico , Humanos , Osteoprotegerina/fisiologia , Ligante RANK/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/fisiologia , Receptores de Calcitriol/fisiologia , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico
20.
Nihon Rinsho Meneki Gakkai Kaishi ; 40(5): 367-376, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-29238019

RESUMO

  Osteoclasts are differentiated from precursors of the monocyte/macrophage lineage originated from bone marrow hematopoietic stem cells and are the sole bone-resorbing cells in the body. Osteoclast differentiation is thought to require M-CSF (macrophage colony-stimulating factor) and RANKL (receptor activator of nuclear factor kappa-B ligand) signaling. However, it has recently been proposed that under chronic inflammatory conditions, such as systemic autoimmune diseases (e.g., rheumatoid arthritis), an increase in inflammatory cytokine levels within joints induces pathological osteoclast differentiation, causing excessive bone resorption. In addition, the authors have reported that stimulating mouse bone marrow monocytes and human CD14+ monocytes with combination of TNFα and IL-6 can induce differentiation of osteoclast-like cells, which are cells with bone resorption activity. In the present article, we discuss the mechanism of osteoclast differentiation of RANKL-independent bone-resorbing cells, using both data from the aforementioned report as well as the latest findings. Understanding the mechanisms underlying RANKL-independent, cytokine-mediated osteoclast differentiation could facilitate the development of novel therapies for inflammatory joint diseases.


Assuntos
Diferenciação Celular/genética , Inflamação/etiologia , Inflamação/patologia , Osteoclastos/citologia , Osteoclastos/fisiologia , Animais , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Reabsorção Óssea/etiologia , Citocinas/fisiologia , Descoberta de Drogas , Humanos , Mediadores da Inflamação/fisiologia , Interleucina-6/fisiologia , Fator Estimulador de Colônias de Macrófagos , Camundongos , Terapia de Alvo Molecular , Osteoclastos/patologia , Ligante RANK/fisiologia , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/fisiologia
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