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1.
Phytomedicine ; 80: 153397, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33130475

RESUMO

BACKGROUND: The fruit of Zanthoxylum piperitum (ZP) is an herbal medicine as well as a spice agent in Asia to treat carminative, stomachic, anthelmintic and degenerative diseases. Z. piperitum was reported to have anti-oxidant, anti-inflammatory, anti-osteoarthritic and osteosarcoma proliferation-control effects. PURPOSE AND STUDY DESIGN: This study was conducted to determine the anti-osteoporotic effects and mechanisms of action of ZP. METHODS: Female ICR mice underwent ovariectomies (OVX) and were orally administered ZP at 1, 10 and 100 mg/kg for 6 weeks. The femoral and tibial bones were assessed by dual-energy X-ray absorptiometry and histology to analyze the bone mineral density (BMD) and the number of osteoclasts. Raw 264.7 cells were stimulated by 100 ng/ml receptor activator of nuclear factor-κB ligand (RANKL) for 7 days in the presence of ZP. RANKL-induced signaling molecules were analyzed in osteoclasts. RESULTS: The levels of femoral and tibial BMD were significantly increased by ZP administration. Serum biomarkers such as osteocalcin, calcium, alkaline phosphatase and bone-specific alkaline phosphatase concentrations were markedly recovered to normal levels in ZP-treated osteoporotic mice. In addition, the number of osteoclasts in the head, trochanter and body of the femur was obviously decreased in the ZP treatment groups. Moreover, ZP treated-cells showed a reduction in the number of TRAP-positive multinuclear cells in RANKL-stimulated Raw 264.7 cells. ZP decreased the RANKL-activated NFATc1 and c-fos, transcription factors of osteoclast formation. The nuclear translocation of NF-κB and phosphorylation of ERK42/44 were inhibited by the ZP treatment in RANKL-induced osteoclasts. CONCLUSION: Collectively, ZP exerts its inhibitory effect against bone resorption by regulating RANKL-mediated c-fos/NFATc1/NF-κB in osteoclast. ZP may prove to be a therapeutic agent for osteoporosis.


Assuntos
Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Extratos Vegetais/farmacologia , Zanthoxylum/química , Animais , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Osteoporose/etiologia , Osteoporose/metabolismo , Ovariectomia/efeitos adversos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ligante RANK/metabolismo , Células RAW 264.7
2.
Phytomedicine ; 79: 153327, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32920290

RESUMO

BACKGROUND: The genus Uncaria (Rubiaceae) has several biological properties significant to human health. However, the mechanisms underlying the protective effect of this plant on bone diseases are uncertain. PURPOSE: The present study investigated the role of Uncaria tomentosa extract (UTE) on alveolar bone loss in rats and on osteoclastogenesis in vitro. MATERIALS: UTE was characterized by an Acquity UPLC (Waters) system, coupled to an Electrospray Ionization (ESI) interface and Quadrupole/Flight Time (QTOF, Waters) Mass Spectrometry system (MS). The effect of UTE treatment for 11 days on the ligature-induced bone loss was assessed focusing on several aspects: macroscopic and histological analysis of bone loss, neutrophil and osteoclast infiltration, and anabolic effect. The effect of UTE on bone marrow cell differentiation to osteoclasts was assessed in vitro. RESULTS: The analysis of UTE by UPLC-ESI-QTOF-MS/MS identified 24 compounds, among pentacyclic or tetracyclic oxindole alkaloids and phenols. The administration of UTE for 11 days on ligature-induced rat attenuated the periodontal attachment loss and alveolar bone resorption. It also diminished neutrophil migration to the gingiva tissue, demonstrated by a lower level of MPO. UTE treatment also decreased the level of RANKL/OPG ratio, the main osteoclast differentiation-related genes, followed by reduced TRAP-positive cell number lining the alveolar bone. Additionally, the level of bone-specific alkaline phosphatase, an anabolic bone marker, was elevated in the plasma of UTE treated rats. Next, we determined a possible direct effect of UTE on osteoclast differentiation in vitro. The incubation of primary osteoclast with UTE decreased RANKL-induced osteoclast differentiation without affecting cell viability. This effect was supported by downregulation of the nuclear factor activated T-cells, cytoplasmic 1 expression, a master regulator of osteoclast differentiation, and other osteoclast-specific activity markers, such as cathepsin K and TRAP. CONCLUSION: UTE exhibited an effective anti-resorptive and anabolic effects, which highlight it as a potential natural product for the treatment of certain osteolytic diseases, such as periodontitis.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/tratamento farmacológico , Unha-de-Gato/química , Extratos Vegetais/farmacologia , Perda do Osso Alveolar/tratamento farmacológico , Animais , Conservadores da Densidade Óssea/química , Células da Medula Óssea/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Regulação para Baixo/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoprotegerina/metabolismo , Periodontite/tratamento farmacológico , Periodontite/etiologia , Extratos Vegetais/química , Ligante RANK/metabolismo , Ratos Wistar , Espectrometria de Massas em Tandem
3.
BMC Complement Med Ther ; 20(1): 105, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245457

RESUMO

BACKGROUND: Cissus quadrangularis Linn. (CQ) has been used in Indian and Thai traditional medicine for healing bone fractures because of numerous active ingredients in CQ. It is still unclear which compounds are the active ingredients for bone formation. METHODS: The molecular docking technique, the ethanolic extraction along with hexane fractionation, and an in vitro experiment with a human osteoblast cell line (MG-63) were used to narrow down the active compounds, to prepare the CQ extract, and to test biological activities, respectively. RESULTS: The molecular docking technique revealed that quercetin and ß-sitosterol had highest and lowest potential to bind to estrogen receptors, respectively. Compared to the crude ethanol extract (P1), the ethanolic fraction (P2) was enriched with rutin and quercetin at 65.36 ± 0.75 and 1.06 ± 0.12 mg/g, respectively. Alkaline phosphatase (ALP) activity was significantly enhanced in osteoblasts exposed to the P2 in both tested concentrations. The amount of hydroxyproline was slightly increased in the P1 treatment, while osteocalcin was inhibited. Moreover, the P2 significantly activated osteoprotegerin (OPG) and inhibited receptor activator of nuclear factor κ ligand (RANKL) expression. CONCLUSIONS: Taken together, the enriched rutin and quercetin fraction of CQ triggered the molecules involved in bone formation and the molecules inhibiting bone resorption.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Cissus/química , Osteogênese/efeitos dos fármacos , Extratos Vegetais/farmacologia , Quercetina/farmacologia , Rutina/farmacologia , Sitosteroides/farmacologia , Linhagem Celular , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Extratos Vegetais/química , Quercetina/química , Rutina/química , Sitosteroides/química
4.
Phytomedicine ; 69: 153195, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32200293

RESUMO

BACKGROUND: Areca nut has anti-inflammatory, antiparasitic, antihypertensive, and antidepressant properties. The pathological hallmarks of inflammatory joint diseases are an increased number of osteoclasts and impaired differentiation of osteoblasts, which may disrupt the bone remodeling balance and eventually lead to bone loss. PURPOSE: The present study assessed the effects of arecoline, the main alkaloid found in areca nut, on osteoclast and osteoblast differentiation and function. METHOD: M-CSF/RANKL-stimulated murine bone marrow-derived macrophages (BMMs) were incubated with several concentrations of arecoline, and TRAP staining and pit formation were assessed to monitor osteoclast formation. Quantitative real-time RT-PCR and western blot analyses were used to analyze the expression of osteoclast-associated genes and signaling pathways. The effects of arecoline on bone were investigated in an in vivo mouse model of lipopolysaccharide (LPS)-induced trabecular bone loss after oral administration of arecoline. Alizarin red S staining and assays to measure ALP activity and the transcription level of osteoblast-related genes were used to evaluate the effects of arecoline on osteoblast differentiation and bone mineralization. RESULTS: In a dose-dependent manner, arecoline at concentrations of 50-100 µM reduced both the development of TRAP-positive multinucleated osteoclasts and the formation of resorption pits in M-CSF/RANKL-stimulated BMMs. In M-CSF/RANKL-stimulated BMMs, arecoline also suppressed the expression and translocation of c-Fos and NFATcl, and osteoclast differentiated-related genes via interference with the AKT, MAPK, and NF-kB activation pathways. Femur bone loss and microcomputed tomography parameters were recovered by oral administration of arecoline in the mouse LPS-induced bone loss model. Lastly, arecoline increased ALP activity, bone mineralization, and the expression of osteoblast differentiation-related genes, such as ALP and Runx2, in MC3T3-E1 cells. CONCLUSION: Our data suggest that arecoline may attenuate or prevent bone loss by suppressing osteoclastogenesis and promoting osteoblastogenesis. These findings provide evidence supporting arecoline's use as a potential therapeutic agent in bone-loss disorders and diseases.


Assuntos
Arecolina/farmacologia , Reabsorção Óssea/tratamento farmacológico , Osteoclastos/efeitos dos fármacos , Animais , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos DBA , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoclastos/citologia , Osteoclastos/fisiologia , Osteogênese/efeitos dos fármacos , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Ligante RANK/metabolismo , Ligante RANK/farmacologia , Microtomografia por Raio-X
5.
Sci Rep ; 10(1): 2277, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32042021

RESUMO

Megakaryocytes (MKs) play key roles in regulating bone metabolism. To test the roles of MK-secreted factors, we investigated whether MK and promegakaryocyte (pro-MK) conditioned media (CM) may affect bone formation and resorption. K562 cell lines were differentiated into mature MKs. Mouse bone marrow macrophages were differentiated into mature osteoclasts, and MC3T3-E1 cells were used for osteoblastic experiments. Bone formation was determined by a calvaria bone formation assay in vivo. Micro-CT analyses were performed in the femurs of ovariectomized female C57B/L6 and Balb/c nude mice after intravenous injections of MK or pro-MK CM. MK CM significantly reduced in vitro bone resorption, largely due to suppressed osteoclastic resorption activity. Compared with pro-MK CM, MK CM suppressed osteoblastic differentiation, but stimulated its proliferation, resulting in stimulation of calvaria bone formation. In ovariectomized mice, treatment with MK CM for 4 weeks significantly increased trabecular bone mass parameters, such as bone volume fraction and trabecular thickness, in nude mice, but not in C57B/L6 mice. In conclusion, MKs may secrete anti-resorptive and anabolic factors that affect bone tissue, providing a novel insight linking MKs and bone cells in a paracrine manner. New therapeutic agents against metabolic bone diseases may be developed from MK-secreted factors.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Megacariócitos/metabolismo , Osteogênese/efeitos dos fármacos , Comunicação Parácrina , Animais , Reabsorção Óssea/diagnóstico por imagem , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Diferenciação Celular/fisiologia , Meios de Cultivo Condicionados/metabolismo , Modelos Animais de Doenças , Feminino , Fêmur/diagnóstico por imagem , Fêmur/fisiologia , Humanos , Injeções Intravenosas , Células K562 , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Células Progenitoras de Megacariócitos/metabolismo , Camundongos , Osteoclastos/fisiologia , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/etiologia , Ovariectomia , Crânio/efeitos dos fármacos , Crânio/fisiologia , Microtomografia por Raio-X
6.
Int J Mol Sci ; 21(3)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033440

RESUMO

Balanced osteoclast and osteoblast activity is necessary for skeletal health, whereas unbalanced osteoclast activity causes bone loss in many skeletal conditions. A better understanding of pathways that regulate osteoclast differentiation and activity is necessary for the development of new therapies to better manage bone resorption. The roles of Protein Kinase D (PKD) family of serine/threonine kinases in osteoclasts have not been well characterized. In this study we use immunofluorescence analysis to reveal that PKD2 and PKD3, the isoforms expressed in osteoclasts, are found in the nucleus and cytoplasm, the mitotic spindle and midbody, and in association with the actin belt. We show that PKD inhibitors CRT0066101 and CID755673 inhibit several distinct aspects of osteoclast formation. Treating bone marrow macrophages with lower doses of the PKD inhibitors had little effect on M-CSF + RANKL-dependent induction into committed osteoclast precursors, but inhibited their motility and subsequent differentiation into multinucleated mature osteoclasts, whereas higher doses of the PKD inhibitors induced apoptosis of the preosteoclasts. Treating post-fusion multinucleated osteoclasts with the inhibitors disrupted the osteoclast actin belts and impaired their resorptive activity. In conclusion, these data implicate PKD kinases as positive regulators of osteoclasts, which are essential for multiple distinct processes throughout their formation and function.


Assuntos
Diferenciação Celular/fisiologia , Osteoclastos/metabolismo , Osteoclastos/fisiologia , Proteína Quinase C/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Azepinas/farmacologia , Benzofuranos/farmacologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo
7.
Int J Mol Sci ; 21(3)2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32046264

RESUMO

Interleukin (IL)-33 is a member of the IL-1 family, which acts as an alarmin. Several studies suggested that IL-33 inhibited osteoclastogenesis and bone resorption. Tumor necrosis factor-α (TNF-α) is considered a direct inducer of osteoclastogenesis. However, there has been no report regarding the effect of IL-33 on TNF-α-induced osteoclastogenesis and bone resorption. The objective of this study is to investigate the role of IL-33 on TNF-α-induced osteoclastogenesis and bone resorption. In an in vitro analysis of osteoclastogenesis, osteoclast precursors, which were derived from bone marrow cells, were treated with or without IL-33 in the presence of TNF-α. Tartrate-resistant acid phosphatase (TRAP) staining solution was used to assess osteoclast formation. In an in vivo analysis of mouse calvariae, TNF-α with or without IL-33 was subcutaneously administrated into the supracalvarial region of mice daily for 5 days. Histological sections were stained for TRAP, and osteoclast numbers were determined. Using micro-CT reconstruction images, the ratio of bone destruction area on the calvariae was evaluated. The number of TRAP-positive cells induced by TNF-α was significantly decreased with IL-33 in vitro and in vivo. Bone resorption was also reduced. IL-33 inhibited IκB phosphorylation and NF-κB nuclear translocation. These results suggest that IL-33 inhibited TNF-α-induced osteoclastogenesis and bone resorption.


Assuntos
Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/tratamento farmacológico , Interleucina-33/farmacologia , Interleucina-33/uso terapêutico , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Animais , Imunofluorescência , Immunoblotting , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Fosforilação/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Sci Rep ; 10(1): 2513, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054921

RESUMO

Excessive bone loss occurs in inflammatory disorders such as periodontitis and osteoporosis. The underlying mechanism is related to the differentiation of macrophages into multinucleated giant osteoclasts and their bone resorptive activity. C-Phycocyanin (C-PC) is a phycobiliprotein extracted from the blue-green algae, which has been shown to have various pharmacological effects. The role of C-PC on bone metabolism needs revelation. In this study, we determined the effectiveness of C-PC as an inhibitor of osteoclast differentiation, activity, and survival in vitro. We found that C-PC strongly inhibited the differentiation of macrophages to TRAP-positive osteoclasts, distinctive osteoclast specific podosomal organization, and dentine matrix resorption without any cytotoxicity. Also, it suppressed the expression of osteoclast specific markers, such as cathepsin K and integrin ß3 at mRNA and protein levels. RANKL mediated signaling utilizes reactive oxygen species (ROS) for the differentiation of osteoclasts. C-PC attenuated RANKL stimulated ROS. Mechanistic studies indicate that C-PC has the potential to reduce osteoclast formation via blocking the degradation of cytosolic IκB-α and hence, the activation of downstream markers such as c-Fos and NFATc1. However, it does not have any effect on osteoblast-mediated bone formation in vitro. Collectively, our data suggest that C-PC may be utilized as a therapeutic agent that can target bone loss mediated by excessive osteoclastic bone resorption without affecting osteoblastic activity in bone.


Assuntos
Reabsorção Óssea/tratamento farmacológico , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteogênese/efeitos dos fármacos , Ficocianina/farmacologia , Ligante RANK/metabolismo , Animais , Reabsorção Óssea/metabolismo , Morte Celular/efeitos dos fármacos , Camundongos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
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
10.
Exp Cell Res ; 388(2): 111857, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31972221

RESUMO

Bone resorption, caused by osteoclasts (OCs), is important to bone homeostasis. The abnormalities of bone resorption may induce a series of diseases, including osteoarthritis, osteoporosis and aseptic peri-implant loosening. The latest research developed,a novel tyrosine and phosphoinositide kinase dual inhibitor, named PP121, inhibited Src in anaplastic thyroid carcinoma cell. However, the therapeutic function of PP121 on abnormal bone resorption is still uncertain. In the present study, we showed that PP121 could potently suppress osteoclast differentiation, osteoclast-specific gene expression and bone resorption via suppressing Src/MAPK (ERK and p38)/Akt-mediated NFATc1 induction in vitro. \It was found that PP121 could suppress the formation of osteoclasts from bone marrow macrophages (BMMs) without causing cytotoxicity, inhibit bone resorption and downregulate the mRNA level of osteoclast-specific markers, including calcitonin receptor (CTR), tartrate resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloproteinase 3 (MMP3), Cellular oncogene fos (C-Fos) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Consistent with in vitro observation, we found that PP121 greatly ameliorated LPS-induced bone resorption. Our results provide promising evidence of the therapeutic potential of PP121 for osteolytic diseases related to excessive osteoclast-mediated bone resorption.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular , Lipopolissacarídeos/toxicidade , Osteoclastos/efeitos dos fármacos , Osteogênese , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ligante RANK/metabolismo , Animais , Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismo , Ligante RANK/genética
11.
Int J Mol Sci ; 21(3)2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31979046

RESUMO

Osteoporosis is a common skeletal disorder, occurring as a result of an imbalance between bone resorption and bone formation, with bone breakdown exceeding bone building. Bone resorption inhibitors, e.g., bisphosphonates, have been designed to treat osteoporosis, while anabolic agents such as teriparatide stimulate bone formation and correct the characteristic changes in the trabecular microarchitecture. However, all of these drugs are associated with significant side effects. It is therefore crucial that we continue to research the pathogenesis of osteoporosis and seek novel modes of therapy. This editorial summarizes and discusses the themes of the fifteen articles published in the Special Issue, Osteoporosis: From Molecular Mechanisms to Therapies 2019, as part of the global picture of the current understanding of osteoporosis.


Assuntos
Osteoporose/tratamento farmacológico , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Osso e Ossos/efeitos dos fármacos , Humanos , Osteogênese/efeitos dos fármacos
12.
J Cell Physiol ; 235(1): 599-610, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271661

RESUMO

Nutritional factors influence bone development. Previous studies demonstrated that bone mass significantly increased with suppressed bone resorption in early life of rats fed with AIN-93G semi-purified diets supplemented with 10% whole blueberry (BB) powder for 2 weeks. However, the effects of increased phenolic acids in animal serum due to this diet on bone and bone resorption were unclear. This in vitro and in ex vivo study examined the effects of phenolic hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA) on osteoclastic cell differentiation and bone resorption. We cultured murine osteoclast (macrophage) cell line, RAW 264.7 cells, and hematopoietic osteoclast progenitor cells (isolated from 4-week-old C57BL6/J mice) with 50 ng/ml of receptor activator of nuclear factor κ-Β ligand (RANKL). Morphologic studies showed decreased osteoclast number with treatment of 2.5% mouse serum from BB diet-fed animals compared with those treated with serum from standard casein diet-fed mice in both RAW 264.7 cell and primary cell cultures. HA and 3-3-PPA, but not 3-4-PPA, had dose-dependent suppressive effects on osteoclastogenesis and osteoclast resorptive activity in Corning osteo-assay plates. Signaling pathway analysis showed that after pretreatment with HA or 3-3-PPA, RANKL-stimulated increase of osteoclastogenic markers, such as nuclear factor of activated T-cells, cytoplasmic 1 and matrix metallopeptidase 9 gene/protein expression were blunted. Inhibitory effects of HA and 3-3-PPA on osteoclastogenesis utilized RANKL/RANK independent mediators. The study revealed that HA and 3-3-PPA significantly inhibited osteoclastogenesis and bone osteoclastic resorptive activity.


Assuntos
Hipuratos/farmacologia , Osteogênese/efeitos dos fármacos , Fenóis/farmacologia , Propionatos/farmacologia , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Animais , Células da Medula Óssea/citologia , Reabsorção Óssea/tratamento farmacológico , Linhagem Celular , AMP Cíclico/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/citologia , Osteogênese/fisiologia , Células RAW 264.7 , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
J Bone Miner Metab ; 38(1): 27-37, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31493249

RESUMO

The development of postmenopausal osteoporosis is thought to be closely related to oxidative stress. Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a novel superoxide dismutase (SOD) mimetic, could protect osteoblasts from cytotoxicity and dysfunction caused by oxidative stress. However, it is still unclear whether MnTBAP has effect on the development of postmenopausal osteoporosis. Here, we demonstrated that MnTBAP can inhibit bone mass loss and bone microarchitecture alteration, and increase the number of osteoblasts while reducing osteoclasts number, as well as improve the BMP-2 expression level in ovariectomized rat model. Additionally, MnTBAP can also prevent oxidative stress status up-regulation induced by ovariotomy and hydrogen peroxide (H2O2). Furthermore, MnTBAP reduced the effect of oxidative stress on osteoblasts differentiation and increased BMP-2 expression levels with a dose-dependent manner, via reducing the levels of mitochondrial oxidative stress in osteoblasts. Taken together, our findings provide new insights that MnTBAP inhibits bone loss in ovariectomized rats by reducing mitochondrial oxidative stress in osteoblasts, and maybe a potential drug in postmenopausal osteoporosis therapy.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/prevenção & controle , Metaloporfirinas/uso terapêutico , Mitocôndrias/metabolismo , Osteoblastos/metabolismo , Ovariectomia , Estresse Oxidativo , Animais , Proteína Morfogenética Óssea 2/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Peróxido de Hidrogênio/toxicidade , Metaloporfirinas/farmacologia , Mitocôndrias/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
14.
Endocr J ; 67(1): 31-35, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31527321

RESUMO

We report a case of a 47-year-old woman with hypercalcemia 6 months after discontinuation of denosumab. She underwent right mastectomy for breast cancer and had received aromatase inhibitor and denosumab therapy for 5 years. Thirst, appetite loss, and bilateral ankle pain began few months after cessation of denosumab. She was admitted to the hospital for hypercalcemia and hyperthyroidism 6 months after the last dose of denosumab. Laboratory investigations revealed hypercalcemia, normophosphatemia, normal renal function, and elevated levels of fibroblast growth factor 23 (FGF-23). Serum tartrate-resistant acid phosphatase 5b and urine N-terminal cross-linked telopeptide of type I collagen were both elevated, and bone scintigraphy revealed increase of whole bone uptake. Radiological examinations showed no recurrence of breast cancer or tumors that secrete intact PTH or FGF-23. Hypercalcemia, which lasted for 1 month, was refractory to discontinuation of the aromatase inhibitor, normalization of thyroid hormone levels, saline hydration, and calcitonin administration, but was effectively treated with zoledronic acid. Abnormal uptake on bone scintigraphy and ankle pain both resolved a few months after treatment, and hypercalcemia has not recurred in the ensuing 2 years. In conclusion, we found elevated levels of circulating FGF-23 with hypercalcemia following the discontinuation of denosumab. FGF-23 might be a surrogate marker for massive bone resorption triggered by discontinuation of long-term denosumab treatment.


Assuntos
Inibidores da Aromatase/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/prevenção & controle , Reabsorção Óssea/sangue , Neoplasias da Mama/tratamento farmacológico , Denosumab/uso terapêutico , Desprescrições , Hipercalcemia/sangue , Tornozelo , Anorexia/etiologia , Anorexia/fisiopatologia , Antitireóideos/uso terapêutico , Artralgia/etiologia , Artralgia/fisiopatologia , Neoplasias Ósseas/secundário , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Reabsorção Óssea/fisiopatologia , Colágeno Tipo I/urina , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Doença de Graves/diagnóstico , Doença de Graves/tratamento farmacológico , Humanos , Hipercalcemia/tratamento farmacológico , Hipercalcemia/etiologia , Hipercalcemia/fisiopatologia , Metimazol/uso terapêutico , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Peptídeos/urina , Iodeto de Potássio/uso terapêutico , Cintilografia , Fosfatase Ácida Resistente a Tartarato/sangue , Sede , Ácido Zoledrônico/uso terapêutico
15.
Mod Rheumatol ; 30(1): 85-92, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30486712

RESUMO

Objectives: To investigate the role of non-receptor tyrosine kinases (NRTKs) in inflammation-induced osteoclastogenesis.Methods: Microarray analyses of global mRNA expression during receptor activator of NF-κB ligand (RANKL) and RANKL plus tumor necrosis factor (TNF)-α-induced osteoclast differentiation were performed. The inhibitory effect on TNF-α-induced osteoclast differentiation of A-419259, a potent inhibitor of hematopoietic cell kinase (Hck), was examined. The in vivo therapeutic effect of A-419259 treatment on lipopolysaccharide (LPS)-induced inflammatory bone destruction was evaluated.Results: We confirmed that Hck expression was selectively increased among the NRTKs during the osteoclast differentiation induced by RANKL and TNF-α, but not by RANKL alone. RANKL and TNF-α-induced osteoclast differentiation and they were dose-dependently inhibited by A-419259 treatment through inhibition of the expression of key regulators of osteoclastogenesis, including Prdm1 and Nfatc1. Notably, LPS-induced inflammatory bone loss in murine calvarial bones was ameliorated by the administration of A-419259.Conclusions: Our results demonstrate that the administration of A-419259 is effective for the inhibition of osteoclast differentiation induced by TNF-α in the presence of RANKL. Therefore, an inhibitor of Hck may be useful as a potent anti-osteoclastogenic agent for the treatment of inflammatory bone destruction.


Assuntos
Reabsorção Óssea/genética , Regulação da Expressão Gênica , Inflamação/genética , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-hck/genética , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Western Blotting , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Diferenciação Celular , Células Cultivadas , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Proteínas Proto-Oncogênicas c-hck/biossíntese , RNA/genética , Quinases da Família src
16.
Biol Trace Elem Res ; 194(1): 221-227, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31187394

RESUMO

Bone wasting occurs during the progression of breast cancer and contributes to breast cancer mortality. We evaluated the effect of methylseleninic acid (MSeA), an anti-carcinogenic form of selenium, on bone microstructural changes in the presence of mammary tumors in a male breast cancer model of mouse mammary tumor virus-polyomavirus middle T-antigen (MMTV-PyMT). In this study, we performed microcomputed tomographic analysis of femurs and vertebrae collected from a study showing that dietary supplementation with MSeA reduces mammary tumorigenesis in male mice. Compared to age-matched, non-tumor-bearing mice (MMTV-PyMT negative), the presence of mammary tumors significantly reduced the bone volume fraction, trabecular thickness, and bone mineral density while it increased the structure model index in femurs, but not in vertebrae. Moreover, mammary tumorigenesis decreased plasma concentrations of osteocalcin. Supplementation with MSeA did not affect these changes in MMTV-PyMT mice. In conclusion, mammary tumorigenesis caused bone loss in MMTV-PyMT mice. However, dietary supplementation with MSeA did not attenuate mammary tumor-associated bone loss in this model of male breast cancer.


Assuntos
Antioxidantes/farmacologia , Reabsorção Óssea/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias Mamárias Animais/patologia , Selênio/farmacologia , Animais , Antioxidantes/administração & dosagem , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Selênio/administração & dosagem
17.
Support Care Cancer ; 28(3): 1151-1162, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31203509

RESUMO

BACKGROUND: Patients with cancer can experience bone metastases and/or cancer treatment-induced bone loss (CTIBL), and the resulting bone complications place burdens on patients and healthcare provision. Management of bone complications is becoming increasingly important as cancer survival rates improve. Advances in specialist oncology nursing practice benefit patients through better management of their bone health, which may improve quality of life and survival. METHODS: An anonymised online quantitative survey asked specialist oncology nurses about factors affecting their provision of support in the management of bone metastases and CTIBL. RESULTS: Of 283 participants, most stated that they worked in Europe, and 69.3% had at least 8 years of experience in oncology. The most common areas of specialisation were medical oncology, breast cancer and/or palliative care (20.8-50.9%). Awareness of bone loss prevention measures varied (from 34.3% for alcohol intake to 77.4% for adequate calcium intake), and awareness of hip fracture risk factors varied (from 28.6% for rheumatoid arthritis to 74.6% for age > 65 years). Approximately one-third reported a high level of confidence in managing bone metastases (39.9%) and CTIBL (33.2%). International or institution guidelines were used by approximately 50% of participants. Common barriers to better specialist care and treatment were reported to be lack of training, funding, knowledge or professional development. CONCLUSION: This work is the first quantitative analysis of reports from specialist oncology nurses about the management of bone metastases and CTIBL. It indicates the need for new nursing education initiatives with a focus on bone health management.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Neoplasias Ósseas/secundário , Reabsorção Óssea/tratamento farmacológico , Neoplasias da Mama/patologia , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Reabsorção Óssea/induzido quimicamente , Neoplasias da Mama/tratamento farmacológico , Denosumab/uso terapêutico , Difosfonatos/uso terapêutico , Europa (Continente) , Feminino , Humanos , Masculino , Enfermagem Oncológica , Cuidados Paliativos , Qualidade de Vida/psicologia , Inquéritos e Questionários
18.
Mol Cell Endocrinol ; 500: 110637, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678610

RESUMO

BACKGROUND/PURPOSE: It remains unclear what role curcumin plays in the autophagy of osteoclast precursors (OCPs) during osteoclastogenesis, since some researchers found that curcumin has the ability to inhibit osteoclastogenesis. While others have considered it as an autophagy activator. This study aimed to determine the effect of curcumin-regulated autophagy on osteoclastogenesis. RESULTS: The results revealed that direct administration of curcumin enhanced the OCP autophagy response in bone marrow-derived macrophages (BMMs). Curcumin could also abate RANKL's stimulatory effect on OCP autophagy and osteoclastogenesis. Autophagic suppression related to pharmacological inhibitors or gene silencing could further enhance the inhibitory effect of curcumin on osteoclastogenesis. As expected, curcumin ameliorated ovariectomy (OVX)-induced bone loss and its effect could be promoted by an autophagy inhibitor (chloroquine). CONCLUSIONS: In conclusion, curcumin can directly enhance the autophagic activity of OCPs, which inhibits its anti-osteoclastogeneic effects. Autophagy inhibition-based drugs are expected to enhance curcumin's efficacy in treating osteoporosis.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Curcumina/farmacologia , Macrófagos/citologia , Osteogênese/efeitos dos fármacos , Ovariectomia/efeitos adversos , Animais , Autofagia , Reabsorção Óssea/etiologia , Células Cultivadas , Cloroquina/farmacologia , Modelos Animais de Doenças , Feminino , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Ligante RANK/farmacologia
19.
J Periodontol ; 91(6): 809-818, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31675438

RESUMO

BACKGROUND: Periodontitis is an inflammatory disease of the tissues surrounding teeth that causes destruction of connective tissues. During the progress of periodontitis, osteoclasts are solely accountable for the resorption of alveolar bones that leads to the loss of teeth if not properly treated. Thus, the development of effective anti-resorptive therapies will greatly benefit the treatment of periodontitis patients. In the present study, we suggest an inhibitory effect of 6-shogaol, an ingredient of ginger, on osteoclast differentiation and bone resorption. METHODS: Mouse bone marrow cells were cultured in the presence of macrophage-colony stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL) to investigate the effect of 6-shogaol on osteoclast differentiation and intracellular signaling pathways. 6-shogaol significantly reduced osteoclast differentiation, actin ring formation, and resorption. In the presence of 6-shogaol, osteoclast signaling including the RANKL-induced activation of mitogen-activated protein kinases, Ca2+ oscillation, generation of reactive oxygen species, and nuclear factor of activated T-cells, cytoplasmic 1 nuclear translocation was significantly inhibited in vitro. Furthermore, a ligature-induced periodontitis model in mice was used to determine the role of 6-shogaol in vivo. RESULTS: The administration of 6-shogaol prevented osteoclastogenesis and alveolar bone resorption induced by ligature. Furthermore, the ligature-induced number of macrophages and neutrophils as well as the expression of interleukin-1ß and tumor necrosis factor-α were considerably lower in the periodontal tissues following shogaol injection. CONCLUSION: These results confirm the anti-osteoclastogenic effect of 6-shogaol and suggest the possibility of application as an anti-resorptive strategy in periodontitis.


Assuntos
Reabsorção Óssea , Gengibre , Periodontite , Animais , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/prevenção & controle , Catecóis , Diferenciação Celular , Humanos , Camundongos , Osteoclastos , Osteogênese , Periodontite/complicações , Periodontite/tratamento farmacológico , Ligante RANK
20.
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
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