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1.
Adv Exp Med Biol ; 1182: 263-269, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31777023

RESUMO

The anti-osteoporosis effect of Ganoderma lucidum (G. lucidum, Lingzhi) is closely associated with inhibition of osteoclastogenesis in the charge of osteoclasts. This article reviewed the anti-osteoporosis effect of Ganoderma and its active components, including a kind of triterpenoids, a polysaccharide and a protein named Ling Zhi-8 (LZ-8). Triterpenoids are a kind of active compounds as candidates for the treatment of osteoporosis. Among these, ganoderic acids are currently considered as the most important and potential components, and their structure-activity relationship highlights the essential group to hamper osteoclast differentiation. The data confirmed that the active compounds isolated from triterpenoids and meroterpenoids could suppress bone resorption of osteoclast via RANKL/RANK pathway and/or its downstream signaling transduction related to ERK, JNK and p38 MAPKs, contributing to inhibition of the level of c-Fos and NFATc1, two key target genes of osteoclast for osteoclastogenesis. However, the comprehensive mechanism remains to be elucidated in the future.


Assuntos
Produtos Biológicos/farmacologia , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Reishi/química , Diferenciação Celular , Humanos , Osteoclastos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
2.
BMC Complement Altern Med ; 19(1): 319, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31747910

RESUMO

BACKGROUND: ChondroT is a complex herbal medicine consisting of water extracts of Ostericum koreanum (Maxim.) Kitag., Lonicera japonica Thunb., Angelica gigas Nakai, Clematis manshurica Rupr., and Phellodendron amurense Rupr. (6:4:4:4:3). Previous studies have reported that ChondroT possesses chondroprotective and anti-inflammatory, anti-osteoarthritic, and anti-hyperuricemic activities. The study is aim to demonstrate the effects of ChondroT and its five constituent herbs on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and the underlying mechanisms. METHODS: Osteoclastogenesis was identified in bone marrow-derived macrophages (BMDMs) by tartrate-resistant acid phosphatase (TRAP) staining assay, actin ring formation assay and the bone resorption assay. For the molecular mechanisms, activation of RANKL-induced NF-κB and MAPK signaling pathways and the expression levels of osteoclast-specific proteins were investigated by Western blotting. Cell viability was assessed by MTT assay. Actin ring formation and NF-κB translocation were evaluated by immunostaining. RESULTS: ChondroT and each of its constituent herbs significantly suppressed osteoclast differentiation dose dependently, and decreased actin ring formation as well as bone-resorbing capacity. Mechanistically, ChondroT and its constituent herbs downregulated the expressional levels of osteoclast-specific proteins such as NFATc1, c-Fos, Cathepsin K, and matrix metalloproteinase 9 (MMP9) by suppressing NF-κB translocation to nucleus and MAPKs phosphorylation at different levels. Compared to its five constituent herbs, ChondroT exhibited the best inhibitory efficiency against osteoclastogenesis. CONCLUSIONS: Taken together, ChondroT has anti-osteoclastogenesis properties by inhibiting NF-κB and MAPKs pathways. It could be considered as a potential therapeutic candidate for the treatment of osteoclast-related bone diseases.


Assuntos
Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Preparações de Plantas/farmacologia , Ligante RANK/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
3.
BMC Complement Altern Med ; 19(1): 269, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615565

RESUMO

BACKGROUND: Puerarin exerts therapeutic effect on osteoporosis due to its inhibitory effect on the formation of osteoclasts. Puerarin is also widely established as an autophagy inhibitor. The study aimed to investigate the significance of autophagy in Puerarin-treated osteoclast formation. METHODS: Osteoclast precursors (OCPs) derived from bone marrow-derived macrophages (BMMs) were treated with Puerarin along with RANKL or without RANKL, and then the autophagic parameters of OCPs (including autophagic proteins, LC3 transformation, autophagosome or LC3-puncta) were observed through Western Blotting, Transmission Electron Microscopy and Immunofluorescence assays. Next, after using overexpression vectors of autophagic genes (Atg7, Atg5 and BECN1) to alter autophagy activity, OCP proliferation was measured by Ethynyl deoxyuridine (EdU) assays and Cell Counting Kit-8 (CCK-8) kit, and osteoclast differentiation was assessed by Tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: The results showed that Puerarin could directly inhibit the autophagy and proliferation of OCPs. Importantly, overexpression of autophagic genes Atg5, Atg7 and BECN1 reversed Puerarin-inhibited OCP autophagy and proliferation. What's more, RANKL could promote the autography of OCPs, which was recovered by Puerarin treatment. Interestingly, different from single-Puerarin treatment, we found that in the presence of RANKL, only BECN1 overexpression significantly reversed Puerarin-inhibited osteoclast differentiation and OCP autophagy. CONCLUSION: In conclusion, Puerarin could inhibit the OCP autophagy in the presence or absence of RANKL, which blocked the OCP proliferation and osteoclast differentiation respectively. Moreover, BECN1 plays an essential role in Puerarin-inhibited osteoclastogenesis. Our study provides potential clue to further complete the intrinsic mechanism of Puerarin in treating osteoporosis.


Assuntos
Autofagia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Isoflavonas/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Animais , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Células Cultivadas , Feminino , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/citologia , Osteoclastos/metabolismo , Pueraria/química , Transdução de Sinais/efeitos dos fármacos
4.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(9): 1045-1051, 2019 Sep 30.
Artigo em Chinês | MEDLINE | ID: mdl-31640962

RESUMO

OBJECTIVE: To investigate the effects of continuous pumping of teriparatide (TPTD) on bone metabolism in ovariectomized and normal mice and provide experimental evidence for the selection of animal models for studying the effects of TPTD and its related peptides on osteoclasts. METHODS: Twenty-four female C57BL mice (6-weeks old) were subjected to ovariectomy (OVX) or sham operation followed 7 days later by continuous pumping of TPTD or the solvent vehicle (VEH) via a micropump (SHAM-VEH, SHAM-TPTD, OVX-VEH, and OVX-TPTD groups; n=6). Two weeks later, the tibial and femoral bones were harvested for micro-CT scanning to measure the parameters of the tibia and the femoral cortical bone. Histopathological examinations of the tibial tissue were conducted using HE staining and TRAP staining and the number of osteoclasts and the growth plate thickness were determined. The serum Ca2 + levels of the mice were measured. The primary osteoblasts from the cranial bone were treated with estradiol (E2) and TPTD for 48 h, and the expressions of ß-catenin and RANKL protein in the cells were analyzed. RESULTS: The trabecular bone mass of OVX mice was significantly lower than that of sham-operated mice (P < 0.05). Continuous TPTD pumping significantly reduced tibial cancellous bone mass and femoral cortical bone area in the sham-operated mice, while in the castrated mice, TPTD pumping increased the cancellous bone mass without changing the cortical bone area. TRAP staining showed that cancellous osteoblasts in the tibia increased significantly in the castrated mice as compared with the sham-operated mice, and TPTD pumping significantly increased the number of cancellous osteoblasts in the sham-operated mice (P < 0.05). In the primary cultured osteoblasts, treatment with both E2 and TPTD obviously lowered the expression of ß-catenin and increased the expression of RANKL as compared with TPTD treatment alone. CONCLUSIONS: Continuous pumping of TPTD promotes bone resorption in normal mice but does not produce obvious bone resorption effect in the ovariectomized mice, suggesting that castrated mice are not suitable models for studying the effect of TPTD and the related peptides on the osteoclasts.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Densidade Óssea , Osso e Ossos/metabolismo , Osteoclastos/efeitos dos fármacos , Ovariectomia , Teriparatida/administração & dosagem , Animais , Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/tratamento farmacológico , Osso e Ossos/efeitos dos fármacos , Feminino , Lâmina de Crescimento/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ligante RANK/metabolismo , Teriparatida/farmacologia , beta Catenina/metabolismo
5.
Chem Pharm Bull (Tokyo) ; 67(10): 1023-1029, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582623

RESUMO

The combinatorial synthesis and biological evaluation of destruxins are described herein. First, the total synthesis of destruxin E was achieved, and its absolute configuration was successfully determined to be (S). In addition, the preparation of a combinatorial library based on the structure of destruxins was carried out by the split-and-pool method. Biological evaluation of the resulting analogs against osteoclast-like multinuclear cells (OCLs) revealed that the N-methyl-alanine residue was crucial to inducing morphological changes in OCLs. In particular, functionalization at the ß-position of the proline (Pro) residue was found to be tolerant of the desired biological activity of destruxin E, suggesting that the ß-position of the Pro residue should be a promising site for the introduction of a chemical tag toward the preparation of a molecular probe.


Assuntos
Depsipeptídeos/farmacologia , Proteínas Fúngicas/farmacologia , Osteoclastos/efeitos dos fármacos , Técnicas de Química Combinatória , Depsipeptídeos/síntese química , Depsipeptídeos/química , Proteínas Fúngicas/síntese química , Proteínas Fúngicas/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
6.
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
7.
Int J Nanomedicine ; 14: 6019-6033, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534334

RESUMO

Objective: Icariin (IC) promotes osteogenic differentiation, and it may be a potential small molecule drug for local application in bone regeneration. Icariin-loaded hydroxyapatite/alginate (IC/HAA) porous composite scaffolds were designed in this study for the potential application of the sustainable release of icariin and subsequent bone regeneration. Methods: An icariin-loaded hydroxyapatite/alginate porous composite scaffold was prepared and characterized by SEM and HPLC for morphology and release behavior, respectively. The mechanical properties, degradation in PBS and cytotoxicity on BMSCs were also evaluated by MTT assay, compression strength and calculation of weight remaining ratio, respectively. Rabbit BMSCs were cocultured with IC/HAA scaffolds, and ALP activity and Alizarin Red staining were performed to evaluate osteogenic differentiation induction. The mRNA and protein expression level of an osteogenic gene was detected by RT-PCR and Western blotting, respectively. In vivo animal models of critical bone defects in the radius of rabbit were used. Four and 12 weeks after the implantation of IC/HAA scaffolds in the bone defect, radiographic images of the radius were obtained and scored by using the Lane and Sandhu X-ray scoring system. Tissue samples were also evaluated using H&E and Masson staining, and an osteogenic gene and Wnt signaling pathway genes were detected. Results: A hydroxyapatite/alginate (HAA) porous composite scaffold-loaded icariin was fabricated using a freeze-drying method. Our data indicated that the icariin was loaded in alginate scaffold without compromising the macro/microstructure or mechanical properties of the scaffold. Notably, the IC/HAA promoted the proliferation of rBMSCs without exerting cytotoxicity on rBMSCs. In vivo, rabbit radius bone defect experiments demonstrated that the IC/HAA scaffold exhibited better capacity for bone regeneration than HAA, and IC/HAA upregulated the relative expression levels of an osteogenic gene and the Wnt signaling pathway genes. Most notably, the IC/HAA scaffold also inhibited osteoclast activity in vivo. Conclusion: Our data suggests a promising application for the use of HAA scaffolds to load icariin and promote bone regeneration in situ through mediation of the coupling processes of osteogenesis induction and osteoclast activity inhibition.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Flavonoides/farmacologia , Osteoclastos/metabolismo , Osteogênese , Tecidos Suporte/química , Alginatos/farmacologia , Animais , Materiais Biocompatíveis/farmacologia , Biomarcadores/metabolismo , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Durapatita/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Porosidade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Coelhos , Rádio (Anatomia)/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
8.
Mater Sci Eng C Mater Biol Appl ; 104: 109933, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499966

RESUMO

Osteoporotic bone represents - particularly in case of fractures - difficult conditions for its regeneration. In the present study, the focus was put on a degradable bone substitute material of gelatin-modified calcium and strontium phosphates facing the special demands of osteoporotic bone. The release of strontium ions from the material ought to stimulate osteoblastogenesis either direct by ion release or indirect after material resorption by increased presence and activity of osteoclasts, which subsequently stimulate osteoblasts. A new porous material was produced from calcium phosphate, strontium phosphate and a mixed phase of calcium/strontium phosphate precipitated in presence of gelatin. Initially, ion release was analyzed in standard­calcium containing (2.0 mM) and low-calcium (0.4 mM) minimum essential medium. The cultivation of human peripheral blood mononuclear cells next to the material led to formation of osteoclast-like cells, able to migrate, fuse, and differentiate. Especially, the mixed gelatin-modified calcium/strontium phosphate allowed osteoclastogenesis as proven morphologically and by real-time quantitative polymerase chain reaction (RT-qPCR). It was precisely this material that led to the best osteoblastic reaction of human bone marrow stromal cells cultured on the material. The investigations of the bone substitute material indicate active involvement in the balance of cells of the bone morphogenetic unit.


Assuntos
Materiais Biocompatíveis/farmacologia , Fosfatos de Cálcio/farmacologia , Gelatina/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Fosfatos/farmacologia , Estrôncio/farmacologia , Animais , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Minerais/metabolismo , Monócitos/citologia , Monócitos/efeitos dos fármacos , Osteoblastos/citologia , Osteoclastos/citologia , Osteogênese/efeitos dos fármacos , Suínos
9.
Arch Oral Biol ; 108: 104538, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31476521

RESUMO

AIM: To investigate the effect of different alcohol concentrations on the development of apical periodontitis (AP) in rats. METHODS: Forty Wistar rats were arranged into five groups: (C) - control rats receiving sterile water as the only liquid; (G5) - animals receiving an alcohol solution at 5%, (G10) - alcohol solution at 10%, (G15) - alcohol solution at 15%, and (G20) - alcohol solution at 20%. The alcoholic solution or water was given to the groups as the sole source of hydration throughout the 30 days of the experiment. AP was induced in the mandibular molars on the first day. In the end, the animals were euthanized for histopathological and IL-1b, RANKL, OPG, and TRAP analyses. The Kruskal-Wallis test was used for nonparametric data, and ANOVA followed by the Tukey test were performed for parametric data, p < 0.05. RESULTS: G15 and G20 had a greater chronic inflammatory infiltrate (Score 3) and AP size bigger (1.59 ±â€¯0.41 and 1.83 ±â€¯0.38, respectively) than the C, G5 and G10 (p < 0.05). No significant difference was found in the IL-1b analyses. The G15 and G20 showed the highest immunolabeling pattern for RANKL and the lowest for OPG. The G20 had greater TRAP cells per mm (4.70 ±â€¯0.99) compared to the C, G5, and G10 (p < 0.05). Furthermore, G15 presented 3.92 ±â€¯0.64 TRAP cells/mm, higher than C (p < 0.05). CONCLUSIONS: G5 and G10 did not exert a protective or aggravating effect on the AP development. However, G15 and G20 had a significant effect on the AP severity, exacerbating the inflammation and osteoclast markers.


Assuntos
Etanol , Periodontite Periapical , Solventes , Animais , Etanol/farmacologia , Inflamação , Osteoclastos/efeitos dos fármacos , Ratos , Ratos Wistar , Solventes/farmacologia
10.
Phytother Res ; 33(11): 2948-2959, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31478281

RESUMO

The balance between the osteoblasts and the osteoclasts is important for the maintenance of the skeleton of the human body. The osteoclasts absorb bone after differentiated into polymorphonuclear cells by the fusion of monocytes/macrophages. We have found that 6,7,4'-Trihydroxyflavone (THF), a compound from the heartwood of Dalbergia Odorifera inhibits receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation, actin ring formation, and bone resorption in RAW 264.7 cells and bone marrow macrophage. THF significantly inhibited the c-Jun-N-terminal kinase signaling pathway without affecting extracellular signal-regulated kinase, p38, and AKT signaling. Moreover, THF inhibited the expression of c-Fos, nuclear factor-activated T cells cytoplasm 1, cathepsin K, and c-src by RANKL. We used a lipopolysaccharide (LPS)-induced bone loss model in mice. Consequently, bone volume per tissue volume, trabecular number's reduction was recovered in THF-treated mice, and trabecular separation's augmentation was also attenuated by THF administration. In summary, THF inhibits RANKL-induced osteoclast differentiation by MAPK signaling pathway and inhibits bone resorption by destroying the actin ring in mature osteoclasts. THF also prevented LPS-induced bone loss in a mice model. Thus, THF may be useful in the treatment of bone diseases associated with excessive osteoclast differentiation and bone resorption.


Assuntos
Reabsorção Óssea/prevenção & controle , Diferenciação Celular/efeitos dos fármacos , Isoflavonas/farmacologia , Osteoclastos/efeitos dos fármacos , Animais , Células Cultivadas , Dalbergia/química , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
11.
Pan Afr Med J ; 33: 37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31384352

RESUMO

Introduction: Osteoporosis is characterized by low bone mass and density, as well as change in microarchitecture of bone tissue leading to decreased bone strength. In vitro research shows nicotine can increase osteoblast activity and proliferation, also suppress osteoclast activity. Therefore we explore nicotine anti-resorptive property by in vivo true experimental and randomized posttest only controlled group research that was conducted in 18-20 weeks old Rattus norvegicus. Methods: Twenty-five female rats were divided into five groups, with 5 rats per group. The first group represented normal rats (Sham), while the second to fifth group underwent bilateral ovariectomy. The second group serves as positive control group (ovariectomy-only/OVX). The third to fifth group serve as dose 1 (P1-0.25mg/kg), dose 2 (P2-0.5 mg/kg), and Dose 3 (P3-0.75 mg/kg) treatment group receiving daily per-oral nicotine for 28 days, started 3 weeks post- ovariectomy. After 28 days treatment, the serum was checked. Results: Nicotine has dose-dependent manner on serum osteocalcin and serum DPD level. Level of osteocalcin in P2 group was significantly lower (Mann-Whitney, p = 0.008) compared to OVX group (59.4% lower). Level of DPD in all group was not significantly different (ANOVA, p < 0.05) but shows lowest level in P2 group. For serum calcitonin level, there's no significant different between groups. Conclusion: Nicotine at right low-dose might be able to inhibit osteoclast activity, thus open a possibility of anti-resorptive property of nicotine.


Assuntos
Densidade Óssea/efeitos dos fármacos , Nicotina/farmacologia , Osteoclastos/efeitos dos fármacos , Osteoporose/prevenção & controle , Aminoácidos/sangue , Animais , Biomarcadores/metabolismo , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Nicotina/administração & dosagem , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteocalcina/sangue , Osteoclastos/metabolismo , Osteoporose/patologia , Ovariectomia , Ratos , Ratos Wistar
12.
BMC Complement Altern Med ; 19(1): 207, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399090

RESUMO

BACKGROUND: Cnidii Rhizoma is the dried root stem of Cnidium officinale Makino. Cnidii Rhizoma (CR) has been used to treat menstrual irregularity, menstrual pain, and menopause in Korea. However, the effects and mechanisms of CR on RANKL-induced osteoclastogenesis pathway remain to be elucidated. In this study, we investigated the effects of CR on the inhibition of bone resorption of osteoclast and its mechanism RANK signaling pathway. METHODS: The anti-osteoclastogenesis of water extract of CR was measured using RAW 264.7 cell. Tartrate-resistant acid phosphatase (TRAP) assay, pit assay, reverse transcription polymerase chain reaction (RT-PCR) and western blot were performed. Moreover, the effects of CR were determined with an in vivo model using ovariectomized (OVX) rats. RESULTS: CR extract suppressed osteoclastogenesis, its activity and bone resorption activity through decreasing gene of osteoclast-related such as nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), c-Fos, etc. Moreover, CR extract prevented the bone loss in OVX rats. CONCLUSION: These results show that CR has a positive effect on menopausal osteoporosis by suppressing osteoclastogenesis.


Assuntos
Doenças Ósseas Metabólicas/prevenção & controle , Cnidium/química , Fatores de Transcrição NFATC/metabolismo , Osteogênese/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ligante RANK/metabolismo , Animais , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/fisiopatologia , Feminino , Humanos , Camundongos , Fatores de Transcrição NFATC/genética , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Ovariectomia , Proteínas Proto-Oncogênicas c-fos/genética , Ligante RANK/genética , Células RAW 264.7 , Ratos , República da Coreia , Rizoma/química , Transdução de Sinais/efeitos dos fármacos
13.
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
14.
Int J Mol Sci ; 20(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430857

RESUMO

Osteoporosis is a common disorder of bone remodeling, caused by the imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Recently, we reported that matrix metalloproteinase-9 (MMP-9)-dependent histone H3 proteolysis is a key event for proficient osteoclast formation. Although it has been reported that several MMP-9 inhibitors, such as tetracycline and its derivatives, show an inhibitory effect on osteoclastogenesis, the molecular mechanisms for this are not fully understood. Here we show that tetracycline analogs, especially tigecycline and minocycline, inhibit osteoclast formation by blocking MMP-9-mediated histone H3 tail cleavage. Our molecular docking approach found that tigecycline and minocycline are the most potent inhibitors of MMP-9. We also observed that both inhibitors significantly inhibited H3 tail cleavage by MMP-9 in vitro. These compounds inhibited receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast formation by blocking the NFATc1 signaling pathway. Furthermore, MMP-9-mediated H3 tail cleavage during osteoclast differentiation was selectively blocked by these compounds. Treatment with both tigecycline and minocycline rescued the osteoporotic phenotype induced by prednisolone in a zebrafish osteoporosis model. Our findings demonstrate that the tetracycline analogs suppress osteoclastogenesis via MMP-9-mediated H3 tail cleavage, and suggest that MMP-9 inhibition could offer a new strategy for the treatment of glucocorticoid-induced osteoporosis.


Assuntos
Histonas/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Minociclina/farmacologia , Osteogênese/efeitos dos fármacos , Tigeciclina/farmacologia , Animais , Células Cultivadas , Feminino , Humanos , Masculino , Modelos Moleculares , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Peixe-Zebra
15.
Fitoterapia ; 138: 104280, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376421

RESUMO

Osteoclastogenesis-related bone diseases including osteoporosis, rheumatoid arthritis, Paget's disease and periodontitis are worldwide occurred and cause severe health problems including bone fracture and bone cancer. However, A few studies have shown that Daemonorops draco (Willd.) Blume may decrease bone destruction and relieve bone cancer pain. In this research, we isolated and purified four known and two novel compounds from D. draco and investigated their anti-osteoclastogenesis activity using RAW264.7 cells. Among them, com.1 exhibited the most effective inhibitory activity on osteoclastogenesis with 78% inhibition at 10 µM and identified to be a novel natural flavan; and com.2 displayed a bit slighter inhibition (50% at 10 µM), indicating that the methylation of 7-hydroxyl group increased the anti-osteoclastogenesis activity. Moreover, nineteen commercial flavonoids were also performed in this study to investigate their inhibitory activity on osteoclastogenesis, and furtherly develop the SAR profile in flavonoid skeleton combined with the information of isolated compounds. Interestingly, the absence of substituents in B-ring and (3R)-hydroxyl group seems to play a crucial role in increasing anti-osteoclastogenesis activity.


Assuntos
Arecaceae/química , Flavonoides/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Animais , Flavonoides/química , Indonésia , Camundongos , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Células RAW 264.7 , Relação Estrutura-Atividade
16.
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
17.
Molecules ; 24(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443447

RESUMO

In traditional oriental medicine, Drynaria roosii Nakaike is widely used in treating bone diseases. Postmenopausal women are strongly associated with osteoporosis and obesity. This study aimed to investigate the effects of the water extract of D. roosii (WDR) on bone loss and obesity in ovariectomized (OVX) mice fed a high-fat diet (HFD). Body weight, gonadal fat weight, histological findings, and morphometric parameters in trabecular bone were evaluated after OVX mice were treated with WDR and HFD for four weeks. The receptor activator of nuclear κ-B ligand (RANKL)-induced osteoclast differentiation in bone marrow-derived macrophages (BMMs) was examined. Phytochemical identification of WDR using ultrahigh-performance liquid chromatography-tandem mass spectrometry was performed. WDR reversed the changes in body weight gain, gonadal fat mass, and trabecular bone parameters by ovariectomy. However, ovariectomy-induced uterine atrophy was not affected by WDR. WDR decreased adipocyte size and pro-inflammatory cytokines (interleukin (IL)-1ß and IL-6) in gonadal fats and lipid accumulation in the bone marrow, which were induced by ovariectomy. WDR significantly decreased RANKL-induced osteoclast differentiation in BMMs. Fifteen phytochemicals were identified in WDR: Seven and nine with anti-osteoporotic and anti-adipogenic activities, respectively. Our findings suggest that WDR may have beneficial effects on postmenopausal osteoporosis and obesity.


Assuntos
Adipogenia/efeitos dos fármacos , Dieta Hiperlipídica , Ovariectomia , Extratos Vegetais/farmacologia , Polypodiaceae/química , Animais , Biomarcadores , Diferenciação Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Citocinas/metabolismo , Feminino , Camundongos , Estrutura Molecular , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoporose/diagnóstico por imagem , Osteoporose/tratamento farmacológico , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Espectrometria de Massas em Tandem , Microtomografia por Raio-X
18.
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
19.
J Immunol Res ; 2019: 9716758, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341915

RESUMO

Osteocytes are abundant cells in bone, which contribute to bone maintenance. Osteocytes express receptor activator of nuclear factor kappa-B ligand (RANKL) and regulate osteoclast formation. Orthodontic tooth movement (OTM) occurs by osteoclast resorption of alveolar bone. Osteocyte-derived RANKL is critical in bone resorption during OTM. Additionally, tumor necrosis factor-α (TNF-α) is important in osteoclastogenesis during OTM. Sclerostin has been reported to enhance RANKL expression in the MLO-Y4 osteocyte-like cell line. This study investigated the effect of TNF-α on sclerostin expression in osteocytes during OTM. In vitro analysis of primary osteocytes, which were isolated from DMP1-Topaz mice by sorting the Topaz variant of GFP-positive cells, revealed that SOST mRNA expression was increased when osteocytes were cultured with TNF-α and that RANKL mRNA expression was increased when osteocytes were cultured with sclerostin. Moreover, the number of TRAP-positive cells was increased in osteocytes and osteoclast precursors cocultured with sclerostin. In vivo analysis of mouse calvariae that had been subcutaneously injected with phosphate-buffered saline (PBS) or TNF-α revealed that the number of TRAP-positive cells and the percentage of sclerostin-positive osteocytes were higher in the TNF-α group than in the PBS group. Furthermore, the level of SOST mRNA was increased by TNF-α. As an OTM model, a Ni-Ti closed-coil spring connecting the upper incisors and upper-left first molar was placed to move the first molar to the mesial direction in wild-type (WT) mice and TNF receptor 1- and 2-deficient (TNFRsKO) mice. After 6 days of OTM, the percentage of sclerostin-positive osteocytes on the compression side of the first molar in TNFRsKO mice was lower than that in WT mice. In this study, TNF-α increased sclerostin expression in osteocytes, and sclerostin enhanced RANKL expression in osteocytes. Thus, TNF-α may play an important role in sclerostin expression in osteocytes and enhance osteoclast formation during OTM.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Osteócitos/metabolismo , Osteogênese , Ligante RANK/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Linhagem Celular , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteócitos/citologia , Osteócitos/imunologia , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Técnicas de Movimentação Dentária
20.
Artif Cells Nanomed Biotechnol ; 47(1): 3087-3093, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31343277

RESUMO

Cnidium lactone is effective in the maintenance of bone mass in various osteoporosis models; however, the precise molecular mechanisms are not understood. In this study, we investigated the effects and underlying mechanisms of action of cnidium lactone on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. Cnidium lactone dose-dependently inhibited osteoclast differentiation and formation, decreased the bone-resorbing activity of osteoclasts, and downregulated the expression of osteoclast differentiation marker genes. Cnidium lactone treatment considerably reduced RANKL-induced p38 MAPK and PI3K-Akt signal activity in RAW264.7 cells. The cnidium lactone-induced osteoclastogenesis was significantly attenuated by inhibition of p38 and PI3K through pretreatment with SB203580 and LY294002, respectively. Furthermore, cnidium lactone inhibited the expression of c-Fos and NFATc-1 with dose-dependently and enhanced by SB203580 and LY294002. In conclusion, cnidium lactone inhibits osteoclast differentiation through p38 MAPK and PI3K-Akt signalling pathway/c-Fos/NFATc1 signalling pathway.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Cnidium/química , Lactonas/farmacologia , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Animais , Reabsorção Óssea/tratamento farmacológico , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Lactonas/uso terapêutico , Camundongos , Fatores de Transcrição NFATC/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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