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1.
Int J Nanomedicine ; 16: 7233-7247, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34737562

RESUMO

Purpose: To evaluate the effects of anatase and rutile TiO2 nanoparticles (NPs) on the growth and development of bones in young rats and explore their possible mechanisms. Methods: Three-week-old male rats were orally administered anatase TiO2 NPs and rutile TiO2 NPs for 28 days. The indicators of rat growth and development, liver function, bone metabolism, and insulin-like growth factor-1 (IGF-1) levels were evaluated. Micro-computed tomography (micro-CT) and immunohistochemistry were used to evaluate the tibia. Results: No significant differences were observed among growth and development indicators in young rats. Significant differences were found in IGF-1 levels, phosphorus levels, and liver function. Micro-CT revealed osteoporosis in the bones. The micro-CT data supported the same result. Bone immunohistochemistry results showed that the expression of osteoprotegerin (OPG) was decreased and the expression of receptor activator of nuclear factor-κB ligand (RANKL) and cathepsin K (CTSK) was increased. Conclusion: This study demonstrated that TiO2 NPs can damage bones via the IGF-1/OPG/RANKL/CTSK pathway in young rats. Furthermore, rutile TiO2 NPs damaged the bones more seriously than anatase TiO2 NPs.


Assuntos
Fator de Crescimento Insulin-Like I , Nanopartículas , Animais , Masculino , Ligante RANK , Ratos , Transdução de Sinais , Titânio , Microtomografia por Raio-X
2.
BMC Oral Health ; 21(1): 523, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645448

RESUMO

OBJECTIVE: MicroRNA-146a (miR-146a) is a regulator of inflammatory response. Periodontitis is a disease with immune pathophysiology of the periodontium in which the inflammation results in the destruction of the soft tissues and alveolar bone. Therefore, the aim of this study was to investigate the expressions of miR-146a, OPG, and RANKL in diseased and healthy periodontal tissues to understand whether miR-146a expression level may associate with OPG and RANKL mRNA levels and OPG/RANKL ratio after non-surgical periodontal treatment. METHODS: The levels of miR-146a, RANKL, and OPG in gingival tissues from patients with generalized periodontitis stages II and III and grades A and B (n = 15, group A), patients with generalized periodontitis stages III and IV and grade C (n = 15, group B), and healthy individuals (n = 10) were determined by real-time PCR. The associations of miR-146a expression with OPG and RANKL levels were evaluated. RESULTS: The levels of miR-146a in two subgroups within periodontitis patients were significantly higher than healthy subjects (P < 0.0001). MiR-146a showed the increased level in group A of patients compared with group B (P < 0.05). Clinical parameters such as probing depth (PD) and clinical attachment loss (CAL) were significantly higher in patients than control group (P < 0.05). The levels of OPG and RANKL were increased in patients compared with healthy subjects, although the elevated levels were not statistically significant. MiR-146a was not associated with OPG and RANKL levels and OPG/RANKL ratio. CONCLUSIONS: The results of this study failed to show the associations of miR-146a level with OPG and RANKL levels and OPG/RANKL ratio in periodontitis after non-surgical periodontal treatment.


Assuntos
MicroRNAs , Osteoprotegerina/genética , Periodontite , Ligante RANK/genética , Gengiva , Humanos , Inflamação , MicroRNAs/genética , Periodontite/genética , Periodontite/terapia
3.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638884

RESUMO

Osteoclasts are large, multinucleated cells that are responsible for the resorption of bone. Bone degenerative diseases, such as osteoporosis, are characterized by overactive osteoclasts. Receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) binding to its receptor on osteoclast precursors will trigger osteoclast formation and resorption. The production of reactive oxygen species (ROS) is known to play a crucial role in RANKL-induced osteoclast formation and resorption. G-protein coupled receptor 120 (GPR120) signalling has been shown to affect osteoclast formation, but the exact mechanisms of action require further investigation. RAW264.7 murine macrophages were seeded into culture plates and exposed to the GPR120 agonist, TUG-891, at varying concentrations (20-100 µM) and RANKL to induce osteoclast formation. TUG-891 was shown to inhibit osteoclast formation and resorption without affecting cell viability in RAW264.7 macrophages. TUG-891 further decreased ROS production when compared to RANKL only cells. Antioxidant proteins, Nrf2, HO-1 and NQO1 were shown to be upregulated while the ROS inducing protein, Nox1, was downregulated by TUG-891. Gene silencing revealed that TUG-891 exerted its effects specifically through GPR120. This study reveals that GPR120 signalling may inhibit osteoclast formation and resorption through inhibition on ROS production.


Assuntos
Compostos de Bifenilo/farmacologia , Reabsorção Óssea/prevenção & controle , Macrófagos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Fenilpropionatos/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Receptores Acoplados a Proteínas G/agonistas , Animais , Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/metabolismo , Heme Oxigenase-1/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Ligante RANK , Células RAW 264.7 , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Arch Oral Biol ; 132: 105280, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34678605

RESUMO

Periodontitis is a chronic disease clinically defined by loss of alveolar bone and connective tissue degeneration. Although Moringa oleifera Lam. (MO), a tree belonging to the Moringacea family, is widely used as an anti-inflammatory agent, its effect on periodontitis is still unclear. In this work, the phenol compounds in MO leaf extract (MOL) were identified by UPLC-ESI-MS/MS, and the anti-periodontitis effects and mechanism of MOL were predicted using network pharmacology and molecular docking. Moreover, the cytotoxic, antioxidant, and anti-periodontitis properties of MOL were confirmed in vivo and in vitro. In total, 88 phenolic compounds and 234 potential MOL periodontitis targets were screened, involving 2916 biological processes (BP). The p38α MAPK (MAPK14) pathway and OPG/RANKL complex were predicted to be involved in the process of molecular docking. Furthermore, experimental validation suggested that MOL significantly ameliorated inflammation and reduced alveolar bone resorption. The OPG/RANKL ratio was regulated through the inhibition of MAPK14, and the anti-periodontitis effect was realized by the antioxidant properties of MOL. Hematoxylin and eosin (H&E) staining of rat vital organs and the survival rate of RAW 264.7 cells confirmed the safety of MOL. The present study provides valuable insights into how MOL reduces inflammation and alveolar bone resorption associated with periodontitis. In conclusion, MOL safely inhibits chronic periodontitis highly likely by regulating the expression of p38α/MAPK14-OPG/RANKL. Network pharmacology coupled with experimental validation is an effective way to find new drugs in the future. DATA AVAILABILITY STATEMENT: The original data presented in the study are included in the article. Further inquiries can be directed to the corresponding authors.


Assuntos
Perda do Osso Alveolar , Proteína Quinase 14 Ativada por Mitógeno , Moringa oleifera , Periodontite , Perda do Osso Alveolar/prevenção & controle , Animais , Simulação de Acoplamento Molecular , Osteoprotegerina , Periodontite/tratamento farmacológico , Periodontite/prevenção & controle , Extratos Vegetais/farmacologia , Ligante RANK , Ratos , Espectrometria de Massas em Tandem
5.
J Agric Food Chem ; 69(44): 12994-13005, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34694780

RESUMO

As part of our continuous program to identify new potential candidates for controlling osteolytic bone diseases from natural products, the alkaloid fraction of barley (Hordeum vulgare var. hexastichon) grass (HVA) significantly inhibited RANKL-induced osteoclast formation and protected mice from LPS-induced bone loss. A phytochemical investigation of HVA afforded nine indole alkaloids, including one new compound [hordeumin A (1)] and eight known analogues (2-9). Of them, four (1, 2, 4, and 5) were anti-osteoclastogenic compounds. Of these four, compound 5 significantly suppressed RANKL-induced osteoclast formation, actin ring formation, and bone resorption in a concentration-dependent manner. It also suppressed the RANKL-induced NF-κB and MAPK signaling pathways and the activation of c-Fos and NFATc1. Compound 5 also reduced the expression levels of osteoclast-specific marker genes, including TRAP, CtsK, DC-STAMP, OSCAR, and MMP9. Our findings suggest that HVA and its alkaloid constituents could be valuable candidates for the prevention and treatment of osteolytic bone diseases.


Assuntos
Reabsorção Óssea , Hordeum , Animais , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular , Alcaloides Indólicos , Camundongos , NF-kappa B , Fatores de Transcrição NFATC , Osteoclastos , Osteogênese , Poaceae , Ligante RANK/genética
6.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34638736

RESUMO

In rheumatoid arthritis (RA), inflammatory cytokines play a pivotal role in triggering abnormal osteoclastogenesis leading to articular destruction. Recent studies have demonstrated enhanced levels of interleukin-9 (IL-9) in the serum and synovial fluid of patients with RA. In RA, strong correlation has been observed between tissue inflammation and IL-9 expression in synovial tissue. Therefore, we investigated whether IL-9 influences osteoclastogenesis in patients with RA. We conducted the study in active RA patients. For inducing osteoclast differentiation, mononuclear cells were stimulated with soluble receptor activator of NF-kB ligand (sRANKL) and macrophage-colony-stimulating factor (M-CSF) in the presence or absence of recombinant (r) IL-9. IL-9 stimulation significantly enhanced M-CSF/sRANKL-mediated osteoclast formation and function. Transcriptome analysis revealed differential gene expression induced with IL-9 stimulation in the process of osteoclast differentiation. IL-9 mainly modulates the expression of genes, which are involved in the metabolic pathway. Moreover, we observed that IL-9 modulates the expression of matrix metalloproteinases (MMPs), which are critical players in bone degradation. Our results indicate that IL-9 has the potential to influence the structural damage in the RA by promoting osteoclastogenesis and modulating the expression of MMPs. Thus, blocking IL-9 pathways might be an attractive immunotherapeutic target for preventing bone degradation in RA.


Assuntos
Artrite Reumatoide/metabolismo , Regulação da Expressão Gênica , Interleucina-9/biossíntese , Osteoclastos/metabolismo , Membrana Sinovial/metabolismo , Adulto , Artrite Reumatoide/patologia , Colagenases/biossíntese , Feminino , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Osteoclastos/patologia , Ligante RANK/metabolismo , Membrana Sinovial/patologia
7.
Arch Osteoporos ; 16(1): 146, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34606009

RESUMO

RANKL and OPG are cytokines involved in bone remodeling that makes them potential bone biomarkers. The reference interval for these cytokines, their ratio, and bone turnover markers CTX and PINP were established in Indian women, which may serve in diagnosis and management of osteoporosis. PURPOSE: The aim of the study was to establish reference interval for RANKL, OPG, RANKL/OPG, and bone turnover markers CTX and PINP in healthy Indian women. METHODS: This was a cross-sectional study on 374 healthy Indian women in the age group of 20-65 years. Serum levels of total RANKL, OPG, CTX, PINP, and estradiol were determined by commercial ELISA kits. The reference intervals for these cytokines and bone turnover markers were based on the 95% centrally distributed data. RESULTS: Median RANKL (245.6 pmol/L vs. 149 pmol/L) and RANKL/OPG (38.7 vs. 20.4) were higher, while sCTX (380 ng/L vs. 551 ng/L) and OPG levels (6.1 pmol/L vs. 7.4 pmol/L) were lower in premenopausal women than those in postmenopausal women. PINP levels were comparable in both groups. Women were classified into 5 groups according to decades of age and the reference intervals for RANKL, OPG, RANKL/OPG ratio, and CTX and PINP in each group were reported. CONCLUSION: We reported menopausal status-based and age-related reference intervals for serum RANKL, OPG, RANKL/OPG ratio, and CTX and PINP in healthy Indian women.


Assuntos
Osteoporose , Ligante RANK , Adulto , Idoso , Biomarcadores , Densidade Óssea , Remodelação Óssea , Estudos Transversais , Estradiol , Feminino , Humanos , Pessoa de Meia-Idade , Valores de Referência , Adulto Jovem
8.
PLoS One ; 16(10): e0258254, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34610044

RESUMO

Epidemiology and pathogenesis of cardiovascular diseases (CVD) and osteoporosis are strikingly overlapping. This study presents matrix metalloproteinase-9 (MMP-9), as a simple molecular link more consistently associated with the pathophysiology of both osteoporosis and CVD risk factors. 40 adult female rats were randomly distributed into 4 groups [control sham-operated, untreated osteoporosis, carvedilol-treated osteoporosis and alendronate-treated osteoporosis]. After 8 weeks, blood samples were collected to estimate Lipid profile (Total cholesterol, HDL, Triglycerides), inflammatory markers (IL-6, TNF alpha, CRP and NO), and Bone turnover markers (BTM) (Alkaline phosphatase, osteocalcin and pyridinoline). The tibias were dissected to estimate MMP-9 and NF-kB gene expression, OPG, RANKL levels and for histological examination. Induction of osteoporosis resulted in a significant elevation in BTM, inflammatory markers and dyslipidemia. MMP-9 was significantly elevated and positively correlated with BTM, inflammation and dyslipidemia markers. Carvedilol and alendronate exerted a bone preservative role and attenuated dyslipidaemia and inflammation in accordance with their respective effect on MMP-9.


Assuntos
Doenças Cardiovasculares/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Osteoporose Pós-Menopausa/metabolismo , Osteoprotegerina/metabolismo , Ovariectomia , Ligante RANK/metabolismo , Fosfatase Alcalina/metabolismo , Aminoácidos/metabolismo , Animais , Remodelação Óssea/genética , Colesterol/sangue , Osso Cortical/patologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/sangue , Inflamação/patologia , Lipoproteínas HDL/sangue , Metaloproteinase 9 da Matriz/genética , NF-kappa B/metabolismo , Osteocalcina/metabolismo , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/genética , Ratos , Fatores de Risco , Tíbia/patologia , Triglicerídeos/sangue
9.
Phytother Res ; 35(11): 6255-6269, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34704297

RESUMO

Experimental and clinical studies suggest a positive impact of anthocyanins on bone health; however, the mechanisms of anthocyanins altering the differentiation and function of osteoblasts and osteoclasts are not fully understood. This work demonstrates that dietary anthocyanins and resveratrol increased proliferation of cultured human hFOB 1.19 osteoblasts. In addition, treatment of serum starvation of hFOB osteoblasts with anthocyanins and resveratrol at 1.0 µg/ml reduced apoptosis, the Bax/Bcl-2 ratio, p53, and HDAC1 expression, but increased SIRT1/3 and PGC1α mRNA expression, suggesting mitochondrial and epigenetic regulation. In Sp7/osterix:mCherry transgenic medaka, peonidin-3-O-glucoside and resveratrol increased osteoblast differentiation and increased the expression of Sp7/osterix. Cyanidin, peonidin-3-O-glucoside, and resveratrol also reduced RANKL-induced ectopic osteoclast formation and bone resorption in col10α1:nlGFP/rankl:HSE:CFP medaka in doses of 1-4 µg/ml. The results indicate that both cyanidin and peonidin-3-O-glucoside have anabolic effects on bone, increasing osteoblast proliferation and differentiation, mitochondrial biogenesis, and by altering the osteoblast epigenome. Cyanidin and peonidin-3-O-glucoside also reduced RANKL-induced bone resorption in a transgenic medaka model of bone resorption. Thus, peonidin-3-O-glucoside and cyanidin appear to both increase bone formation and reduce bone loss, suggesting that they be further investigated as potential treatments for osteoporosis and osteomalacia.


Assuntos
Reabsorção Óssea , Oryzias , Animais , Antocianinas/farmacologia , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular , Epigênese Genética , Glucosídeos , Humanos , Oryzias/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese , Ligante RANK/metabolismo
10.
Nutrients ; 13(10)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34684352

RESUMO

Magnesium (Mg) deficiency may affect bone metabolism by increasing osteoclasts, decreasing osteoblasts, promoting inflammation/oxidative stress, and result in subsequent bone loss. The objective of the present study was to identify the molecular mechanism underlying the bone protective effect of different forms of Mg (inorganic magnesium oxide (MgO) versus organic magnesium picolinate (MgPic) compound) in rats fed with a high-fat diet (HFD). Forty-two Wistar albino male rats were divided into six group (n = 7): (i) control, (ii) MgO, (iii) MgPic, (iv) HFD, (v) HFD + MgO, and (vi) HFD + MgPic. Bone mineral density (BMD) increased in the Mg supplemented groups, especially MgPic, as compared with the HFD group (p < 0.001). As compared with the HFD + MgO group, the HFD + MgPic group had higher bone P (p < 0.05) and Mg levels (p < 0.001). In addition, as compared to MgO, MgPic improved bone formation by increasing the levels of osteogenetic proteins (COL1A1 (p < 0.001), BMP2 (p < 0.001), Runx2 (p < 0.001), OPG (p < 0.05), and OCN (p < 0.001), IGF-1 (p < 0.001)), while prevented bone resorption by reducing the levels of RANK and RANKL (p < 0.001). In conclusion, the present data showed that the MgPic could increase osteogenic protein levels in bone more effectively than MgO, prevent bone loss, and contribute to bone formation in HFD rats.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Comportamento Alimentar , Osteogênese , Osteoprotegerina/metabolismo , Ácidos Picolínicos/farmacologia , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Animais , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Dieta Hiperlipídica , Elementos Químicos , Masculino , Osteogênese/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
11.
Int J Mol Sci ; 22(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34502262

RESUMO

Intestinal microfold cells (M cells) are a dynamic lineage of epithelial cells that initiate mucosal immunity in the intestine. They are responsible for the uptake and transcytosis of microorganisms, pathogens, and other antigens in the gastrointestinal tract. A mature M cell expresses a receptor Gp2 which binds to pathogens and aids in the uptake. Due to the rarity of these cells in the intestine, their development and differentiation remain yet to be fully understood. We recently demonstrated that polycomb repressive complex 2 (PRC2) is an epigenetic regulator of M cell development, and 12 novel transcription factors including Atoh8 were revealed to be regulated by the PRC2. Here, we show that Atoh8 acts as a regulator of M cell differentiation; the absence of Atoh8 led to a significant increase in the number of Gp2+ mature M cells and other M cell-associated markers such as Spi-B and Sox8. In vitro organoid analysis of RankL treated organoid showed an increase of mature marker GP2 expression and other M cell-associated markers. Atoh8 null mice showed an increase in transcytosis capacity of luminal antigens. An increase in M cell population has been previously reported to be detrimental to mucosal immunity because some pathogens like orally acquired prions have been able to exploit the transcytosis capacity of M cells to infect the host; mice with an increased population of M cells are also susceptible to Salmonella infections. Our study here demonstrates that PRC2 regulated Atoh8 is one of the factors that regulate the population density of intestinal M cell in the Peyer's patch.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/genética , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Animais , Linfócitos B/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/imunologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Imunidade nas Mucosas/genética , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Camundongos , Camundongos Knockout , Nódulos Linfáticos Agregados/efeitos dos fármacos , Nódulos Linfáticos Agregados/metabolismo , Cultura Primária de Células , Ligante RANK/farmacologia , Receptor Ativador de Fator Nuclear kappa-B/farmacologia , Linfócitos T/metabolismo , Transcitose/genética
12.
J Transl Med ; 19(1): 392, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530864

RESUMO

BACKGROUND: Patients with rheumatoid arthritis (RA) have increased levels of interleukin-18 (IL-18) and decreased levels of IL-18 binding protein (IL-18BP) in the serum and synovial fluid (SF) compared to those in patients with osteoarthritis (OA) or in healthy controls. In this study, we evaluated the effects of IL-18BP on osteoclastogenesis and T cell differentiation in RA in vitro. METHODS: Serum and SF of patients with RA and OA were collected to compare IL-18 and IL-18BP levels by the enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMCs) and SF mononuclear cells (SFMCs) of RA patients were cultured under type 17 helper T cell (Th17) polarisation conditions with or without IL-18BP. In addition, PBMCs were cultured in the presence of receptor activator of nuclear factor kappa-Β ligand (RANKL) or IL-17A with or without IL-18BP, and tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative polymerase chain reaction for expression levels of osteoclast-related genes were performed. RESULTS: IL-18 levels were higher in the serum and SF of patients with RA, whereas IL-18BP was lower in the SF of patients with RA than in the control group. Treatment of patients' PBMCs with IL-18BP decreased the differentiation of CD4+ IL-17A+ and CD4+ RANKL+ T cells, whereas the differentiation of CD4+CD25highFOXP3+ T cell population increased in a dose-dependent manner. These changes in CD4+ T cell differentiation were also observed in the SFMCs of patients with RA. The levels IL-17A and soluble RANKL in the culture medium were significantly decreased by IL-18BP. IL-18BP administration decreased TRAP+ cell counts in a dose-dependent manner on the background of stimulation with RANKL-and IL-17A. In addition, expression levels of TRAP, NFATC1, CTSK, and TNFRSF11A (RANK) genes were lower in the IL-18BP treated cells. CONCLUSION: We showed that IL-18BP can rectify the Th17/Treg imbalance and decrease IL-17-induced osteoclastogenesis in PBMCs from patients with RA. Therefore, IL-18BP may have therapeutic potential for RA treatment.


Assuntos
Artrite Reumatoide , Interleucina-17 , Células Cultivadas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Leucócitos Mononucleares , Osteoclastos , Osteogênese , Ligante RANK , Linfócitos T Reguladores , Células Th17
13.
Biomed Res Int ; 2021: 5567666, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497849

RESUMO

Background: Fracture risk assessment tool (FRAX) index was developed for estimating of the 10-year risk of major or hip osteoporotic fracture. To date, there is insufficient information regarding the correlation between FRAX and serum bone turnover markers (BTMs), such as soluble ligand of receptor activator of nuclear factor-κB (sRANKL), osteoprotegerin (OPG), and other molecules related with secondary osteoporosis in rheumatoid arthritis (RA). Therefore, this study is aimed at assessing the correlation between the FRAX and serum levels of sRANKL, OPG, sRANKL/OPG ratio, Dickkopf-1 (DKK-1), and sclerostin (SOST) in RA. Methods: Cross-sectional study included 156 postmenopausal women with RA. Bone mineral density (BMD) was measured at lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA). RA patients were divided into (A) RA + osteoporosis and (B) RA without osteoporosis. FRAX scores were calculated including the total hip BMD. Serum sRANKL, OPG, DKK-1, and SOST levels were measured by ELISA. Pearson tests were used for assessing the correlation between serum levels of these molecules and FRAX scores in RA. Results: The RA + osteoporosis group had elevated sRANKL levels (p = 0.005), higher sRANKL/OPG ratio (p = 0.017), decreased DKK-1 (p = 0.028), and lower SOST levels (p < 0.001). Low total hip BMD correlated with high sRANKL (p = 0.001) and sRANKL/OPG ratio (p = 0.005). Total hip and lumbar spine BMD correlated with DKK-1 (p = 0.009 and p = 0.05, respectively) and SOST levels (p < 0.001 and p < 0.001, respectively). Higher sRANKL levels and sRANKL/OPG ratio correlated with estimated 10-year risk of a major osteoporotic fractures (p = 0.003 and p = 0.003, respectively) and hip fracture (p = 0.002 and p = 0.006, respectively). High serum SOST levels were associated with a low estimated 10-year risk of a major osteoporotic fracture (p = 0.003) and hip fracture (p = 0.009). Conclusion: High sRANKL levels and sRANKL/OPG ratio can be useful to detect a subgroup of RA patients who has an increased 10-year risk of major and hip osteoporotic fractures.


Assuntos
Artrite Reumatoide/sangue , Remodelação Óssea/fisiologia , Osteoporose/sangue , Fraturas por Osteoporose/diagnóstico , Osteoprotegerina/sangue , Ligante RANK/sangue , Artrite Reumatoide/complicações , Artrite Reumatoide/patologia , Biomarcadores/sangue , Densidade Óssea , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose/etiologia , Osteoporose/patologia , Fraturas por Osteoporose/sangue , Fraturas por Osteoporose/etiologia , Pós-Menopausa/sangue , Prognóstico
14.
Shanghai Kou Qiang Yi Xue ; 30(3): 237-242, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34476437

RESUMO

PURPOSE: To investigate the effect of chitosan oligosaccharide on alveolar bone resorption, Th17/Treg balance and OPG/RANKL/RANK pathway in rats with periodontitis. METHODS: Rat model of periodontitis was established, and the periodontitis rats were randomly divided into model group, low-dose chitosan oligosaccharide group, middle-dose chitosan oligosaccharide group, high-dose chitosan oligosaccharide group and metronidazole group, with 12 rats in each group, another 12 rats were set as control group. After treatment, gingival index and alveolar bone absorption were evaluated. H-E staining was used to observe the pathological changes of periodontal tissues. The ratio of Th17/Treg cells in peripheral blood was detected by flow cytometry, the levels of serum IL-17, TGF-ß, RANKL and OPG were detected by ELISA, and the expressions of OPG and RANKL mRNA in periodontal tissues of rats in each group were detected by real-time fluorescent quantitative PCR(qRT-PCR). SPSS 24.0 software package was used to analyze the data. RESULTS: Compared with the control group, the periodontal tissue of the model group showed periodontal membrane fiber bundle rupture, disordered arrangement, capillary expansion, proliferation, inflammatory cell infiltration and other pathological damage. Gingival index, alveolar bone resorption value, Th17/Treg ratio, serum RANKL and IL-17 levels, and periodontal RANKL mRNA level were significantly increased(P<0.05), while the levels of serum OPG, TGF-ß and OPG mRNA in periodontal tissues were significantly decreased (P<0.05). Compared with the model group, the pathological damage of periodontal tissue in the low-middle-and high-dose chitosan oligosaccharide groups and metronidazole group was reduced; gingival index, alveolar bone resorption value, Th17/Treg ratio, serum RANKL and IL-17 levels, and periodontal RANKL mRNA level were significantly decreased(P<0.05), while the levels of serum OPG, TGF-ß and OPG mRNA in periodontal tissues were significantly increased(P<0.05); there was a dose-dependent relationship between the chitosan oligosaccharide groups, and there was no significant difference between the high-dose chitosan oligosaccharide group and metronidazole group(P>0.05). CONCLUSIONS: Chitosan oligosaccharide can promote Th17/Treg balance to return to normal, up-regulate OPG expression, down-regulate RANKL expression, inhibit alveolar bone resorption in periodontitis rats and improve their clinical symptoms.


Assuntos
Perda do Osso Alveolar , Quitosana , Osteoprotegerina , Periodontite , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Animais , Oligossacarídeos , Osteoprotegerina/metabolismo , Periodontite/tratamento farmacológico , Ligante RANK/metabolismo , Ratos , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Linfócitos T Reguladores
15.
Breast Cancer Res Treat ; 190(3): 463-475, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34570303

RESUMO

PURPOSE: Emerging evidence suggests that the progesterone-mediated receptor activator of nuclear factor κB (RANK)/soluble RANK ligand (sRANKL)/osteoprotegerin (OPG) pathway plays an important role in mammary carcinogenesis and is hyperactivated in germline (g)BRCA1/2 mutation carriers. We analyzed the effects of a 3-month intensive lifestyle intervention within the LIBRE-1 study on the serum levels of OPG and sRANKL and hypothesized that the intervention program provides a beneficial impact on the biomarkers by increasing OPG and reducing sRANKL serum concentrations. METHODS: Serum levels of OPG and sRANKL of 49 gBRCA1/2 mutation carriers were quantified using enzyme-linked immunosorbent assays. We used previously collected blood samples from participants of the prospective LIBRE-1 study, who were randomized into an intervention group (IG), increasing physical activity and adherence to the Mediterranean diet (MedD) through supervised sessions from study entry to the first study visit after 3 months and a usual-care control group (CG). Differences in biomarker levels before and after the 3-month intervention were tested within and between study groups. RESULTS: The lifestyle intervention resulted in a significant increase in OPG for participants in both the IG (q = 0.022) and CG (q = 0.002). sRANKL decreased significantly in the IG (q = 0.0464) and seemed to decrease in the CG (q = 0.5584). An increase in the intake of Omega-3 polyunsaturated fatty acids was significantly associated with an increase in OPG (r = 0.579, q = 0.045). Baseline serum levels of sRANKL were a strong predictor for the change of sRANKL in the course of the intervention (ß-estimate = - 0.70; q = 0.0018). Baseline physical fitness (assessed as VO2peak) might predict the change of OPG in the course of the intervention program (ß-estimate = 0.133 pg/ml/ml/min/kg; p = 0.0319; q = 0.2871). CONCLUSION: Findings from this pilot study seem to confirm our hypothesis by showing an increase in OPG and decrease in sRANKL over a 3-month lifestyle intervention and suggest that increased physical activity and adherence to the MedD are potent modulators of the biomarkers OPG and potentially sRANKL.


Assuntos
Proteína BRCA1 , Neoplasias da Mama , Dieta Mediterrânea , Osteoprotegerina , Estudos Prospectivos , Proteína BRCA1/genética , Proteína BRCA2/genética , Exercício Físico , Feminino , Humanos , Estilo de Vida , Mutação , Osteoprotegerina/sangue , Osteoprotegerina/genética , Projetos Piloto , Ligante RANK/sangue , Ligante RANK/genética , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575866

RESUMO

Prior work demonstrated that Phlpp1 deficiency alters trabecular bone mass and enhances M-CSF responsiveness, but the cell types and requirement of Phlpp1 for this effect were unclear. To understand the function of Phlpp1 within myeloid lineage cells, we crossed Phlpp1 floxed mice with mice harboring LysM-Cre. Micro-computed tomography of the distal femur of 12-week-old mice revealed a 30% increase in bone volume per total volume of Phlpp1 female conditional knockouts, but we did not observe significant changes within male Phlpp1 cKOLysM mice. Bone histomorphmetry of the proximal tibia further revealed that Phlpp1 cKOLysM females exhibited elevated osteoclast numbers, but conversely had reduced levels of serum markers of bone resorption as compared to littermate controls. Osteoblast number and serum markers of bone formation were unchanged. In vitro assays confirmed that Phlpp1 ablation enhanced osteoclast number and area, but limited bone resorption. Additionally, reconstitution with exogenous Phlpp1 suppressed osteoclast numbers. Dose response assays demonstrated that Phlpp1-/- cells are more responsive to M-CSF, but reconstitution with Phlpp1 abrogated this effect. Furthermore, small molecule-mediated Phlpp inhibition enhanced osteoclast numbers and size. Enhanced phosphorylation of Phlpp substrates-including Akt, ERK1/2, and PKCζ-accompanied these observations. In contrast, actin cytoskeleton disruption occurred within Phlpp inhibitor treated osteoclasts. Moreover, Phlpp inhibition reduced resorption of cells cultured on bovine bone slices in vitro. Our results demonstrate that Phlpp1 deficiency within myeloid lineage cells enhances bone mass by limiting bone resorption while leaving osteoclast numbers intact; moreover, we show that Phlpp1 represses osteoclastogenesis and controls responses to M-CSF.


Assuntos
Reabsorção Óssea , Osso e Ossos/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Células Mieloides/metabolismo , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Animais , Linhagem da Célula , Citoplasma/metabolismo , Feminino , Fêmur/metabolismo , Deleção de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Fosforilação , Ligante RANK/metabolismo , Transdução de Sinais/efeitos dos fármacos , Microtomografia por Raio-X
17.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361069

RESUMO

Postmenopausal osteoporosis is closely associated with excessive osteoclast formation and function, resulting in the loss of bone mass. Osteoclast-targeting agents have been developed to manage this disease. We examined the effects of ciclopirox on osteoclast differentiation and bone resorption in vitro and in vivo. Ciclopirox significantly inhibited osteoclast formation from primary murine bone marrow macrophages (BMMs) in response to receptor activator of nuclear factor kappa B ligand (RANKL), and the expression of genes associated with osteoclastogenesis and function was decreased. The formation of actin rings and resorption pits was suppressed by ciclopirox. Analysis of RANKL-mediated early signaling events in BMMs revealed that ciclopirox attenuates IκBα phosphorylation without affecting mitogen-activated protein kinase activation. Furthermore, the administration of ciclopirox suppressed osteoclast formation and bone loss in ovariectomy-induced osteoporosis in mice and reduced serum levels of osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus. These results indicate that ciclopirox exhibits antiosteoclastogenic activity both in vitro and in vivo and represents a new candidate compound for protection against osteoporosis and other osteoclast-related bone diseases.


Assuntos
Antifúngicos/farmacologia , Reabsorção Óssea/tratamento farmacológico , Ciclopirox/farmacologia , Osteoclastos/citologia , Osteogênese , Ovariectomia/efeitos adversos , Substâncias Protetoras/farmacologia , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/patologia , Diferenciação Celular , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Ligante RANK/genética , Ligante RANK/metabolismo
18.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443439

RESUMO

Ten polyketide derivatives (1-10), including a new natural product named (E)-2,4-dihydroxy-3-methyl-6-(2-oxopent-3-en-1-yl) benzaldehyde (1), and five known diketopiperazines (11-15), were isolated from the mangrove-sediment-derived fungus Aspergillus sp. SCSIO41407. The structures of 1-15 were determined via NMR and MS spectroscopic analysis. In a variety of bioactivity screening, 3 showed weak cytotoxicity against the A549 cell line, and 2 exhibited weak antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Compounds 3, 5, and 6 showed inhibition against acetylcholinesterase (AChE) with IC50 values of 23.9, 39.9, and 18.6 µM. Compounds 11, 12, and 14 exhibited obvious inhibitory activities of lipopolysaccharide (LPS)-induced nuclear factor-κB (NF-κB) with IC50 values of 19.2, 20.9, and 8.7 µM, and they also suppressed RANKL-induced osteoclast differentiation in bone marrow macrophages cells (BMMCs), with the concentration of 5 µM. In silico molecular docking with AChE and NF-κB p65 protein were also performed to understand the inhibitory activities, and 1, 11-14 showed obvious protein/ligand-binding effects to the NF-κB p65 protein.


Assuntos
Aspergillus/efeitos dos fármacos , Dicetopiperazinas/farmacologia , Sedimentos Geológicos/microbiologia , Policetídeos/farmacologia , Rhizophoraceae/química , Células A549 , Acetilcolinesterase/metabolismo , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Dicetopiperazinas/química , Humanos , Lipopolissacarídeos/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Policetídeos/química , Espectroscopia de Prótons por Ressonância Magnética , Ligante RANK/farmacologia
19.
Molecules ; 26(16)2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34443530

RESUMO

Ageing-related bone impairment due to exposure to hyperglycemic environment is scarcely researched. The aim was to confirm the improvement effects of undenatured type II collagen (UC II) on bone impairment in ageing db/db mice, and the ageing model was established by normal feeding for 48-week-old. Then, the ageing db/db mice were randomly assigned to UC II intervention, the ageing model, and the chondroitin sulfate + glucosamine hydrochloride control groups. After 12 weeks of treatment, femoral microarchitecture and biomechanical parameters were observed, biomarkers including bone metabolism, inflammatory cytokines, and oxidative stress were measured, and the gastrocnemius function and expressions of interleukin (IL) 1ß, receptor activator of nuclear factor (NF)-κB ligand (RANKL), and tartrate-resistant acid phosphatase (TRAP) were analyzed. The results showed that the mice in the UC II intervention group showed significantly superior bone and gastrocnemius properties than those in the ageing model group, including bone mineral density (287.65 ± 72.77 vs. 186.97 ± 32.2 mg/cm3), gastrocnemius index (0.46 ± 0.07 vs. 0.18 ± 0.01%), muscle fiber diameter (0.0415 ± 0.005 vs. 0.0330 ± 0.002 mm), and cross-sectional area (0.0011 ± 0.00007 vs. 0.00038 ± 0.00004 mm2). The UC II intervention elevated bone mineralization and formation and decreased bone resorption, inflammatory cytokines, and the oxidative stress. In addition, lower protein expression of IL-1ß, RANKL, and TRAP in the UC II intervention group was observed. These findings suggested that UC II improved bones impaired by T2DM during ageing, and the likely mechanism was partly due to inhibition of inflammation and oxidative stress.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Colágeno Tipo II/farmacologia , Interleucina-1beta/genética , Ligante RANK/genética , Fosfatase Ácida Resistente a Tartarato/genética , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/patologia , Animais , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/etiologia , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Sulfatos de Condroitina/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosamina/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/genética , Inflamação/patologia , Camundongos , Camundongos Endogâmicos NOD/genética , Estresse Oxidativo/efeitos dos fármacos
20.
Phytomedicine ; 91: 153677, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34333329

RESUMO

BACKGROUND: M. pumilum has been claimed to protect the bone against the adverse effect of estrogen deficiency. Additionally, it also exhibits anti-diabetic activity. In view of these, this study aims to identify the mechanisms underlying the bone protective effect of M. pumilum in the presence of both estrogen deficiency and diabetes mellitus (DM). METHODS: Ovariectomized, diabetic female rats were given M. pumilum leave aqueous extract (MPLA) (50 and 100 mg/kg/day), estrogen, glibenclamide and estrogen plus glibenclamide for 28 consecutive days. At the end of the treatment, fasting blood glucose (FBG), serum insulin, Ca2+, PO43- and bone alkaline phosphatase (BALP) levels were measured. Rats were sacrificed and femur bones were harvested for determination of expression level and distribution of RANK, RANKL, OPG and oxidative stress and inflammatory proteins by molecular biological techniques. RESULTS: 100 mg/kg/day MPLA treatment decreased the FBG and BALP levels but increased the serum insulin, Ca2+ and PO43- levels in estrogen deficient, diabetic rats. Expression and distribution of RANKL, NF-κB p65, IKKß, IL-6, IL-1ß and Keap-1 decreased however expression and distribution of RANK, OPG, BMP-2, Type-1 collagen, Runx2, TRAF6, Nrf2, NQO-1, HO-1, SOD and CAT increased in the bone of estrogen deficient, diabetic rats which received 100 mg/kg/day MPLA with greater effects than estrogen-only, glibenclamide-only and estrogen plus glibenclamide treatments. CONCLUSION: MPLA helps to overcome the adverse effect of estrogen deficiency and DM on the bone and thus this herb could potentially be used for the treatment and prevention of osteoporosis in postmenopausal women with diabetes.


Assuntos
Osso e Ossos/efeitos dos fármacos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Extratos Vegetais/farmacologia , Primulaceae/química , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estrogênios , Feminino , Inflamação , Osteoprotegerina/metabolismo , Ovariectomia , Estresse Oxidativo , Folhas de Planta/química , Ligante RANK/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de Sinais
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