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1.
Nat Commun ; 11(1): 5596, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154378

RESUMO

Age-related osteoporosis is characterized by the deterioration in bone volume and strength, partly due to the dysfunction of bone marrow mesenchymal stromal/stem cells (MSCs) during aging. Alpha-ketoglutarate (αKG) is an essential intermediate in the tricarboxylic acid (TCA) cycle. Studies have revealed that αKG extends the lifespan of worms and maintains the pluripotency of embryonic stem cells (ESCs). Here, we show that the administration of αKG increases the bone mass of aged mice, attenuates age-related bone loss, and accelerates bone regeneration of aged rodents. αKG ameliorates the senescence-associated (SA) phenotypes of bone marrow MSCs derived from aged mice, as well as promoting their proliferation, colony formation, migration, and osteogenic potential. Mechanistically, αKG decreases the accumulations of H3K9me3 and H3K27me3, and subsequently upregulates BMP signaling and Nanog expression. Collectively, our findings illuminate the role of αKG in rejuvenating MSCs and ameliorating age-related osteoporosis, with a promising therapeutic potential in age-related diseases.


Assuntos
Envelhecimento , Histonas/metabolismo , Ácidos Cetoglutáricos/uso terapêutico , Osteoporose/tratamento farmacológico , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Biomarcadores/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Regeneração Óssea/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Feminino , Ácidos Cetoglutáricos/sangue , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Metilação/efeitos dos fármacos , Camundongos , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Osteoporose/patologia , Transdução de Sinais/efeitos dos fármacos
2.
Int J Nanomedicine ; 15: 7967-7977, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116512

RESUMO

Background: Current drugs used for osteoporosis therapy show strong adverse effects. Stem cell-derived extracellular vesicles (EVs) provide another choice for osteoporosis therapy. Mouse mesenchymal stem cells (mMSCs)-derived EVs promote bone regeneration; however, their clinical application is limited due to non-specific tissue targeting. Alendronate specifically targets bone tissue via hydroxyapatite. Therefore, EVs were combined with alendronate to generate Ale-EVs by "click chemistry" to facilitate EVs targeting bone via alendronate/hydroxyapatite binding. Methods: Ale-EVs were characterized based on size using dynamic light scattering analysis and morphology was visualized by transmission electron microscopy. Hydroxyapatite affinity of Ale-EVs was detected by flow cytometry. Bone targeting of Ale-EVs was tested by ex vivo fluorescent imaging. Cell viability was assessed by using WST-8 reduction assay kit for testing the ability of Ale-EVs to promote mMSCs proliferation. Alkaline phosphatase experiment was used to detect ability of Ale-EVs to promote differentiation of mouse mesenchymal stem cells in vitro. Western blotting and Q-PCR assay were used to detect the early marker of osteogenic differentiation. Antiosteoporotic effects of Ale-EVs were detected in ovariectomy (OVX)-induced osteoporosis rat model. The safety of the Ale-EVs in vivo was measured by H&E staining and serum markers assay. Results: In vitro, Ale-EVs had high affinity with hydroxyapatite. Also, ex vivo data indicated that Ale-EVs-DiD treatment of mice induced strong fluorescece in bone tissues compared with EVs-DiD group. Furthermore, results suggested that Ale-EVs promoted the growth and differentiation of mouse MSCs. They also protected against osteoporosis in ovariectomy (OVX)-induced osteoporotic rats. Ale-EVs were well tolerated and no side effects were found, indicating that Ale-EVs specifically target bone and can be used as a new therapeutic in osteoporosis treatment. Conclusion: We used the Ale-N3 to modify mouse mesenchymal stem cells-derived extracellular vesicles by copper-free "click chemistry" to generate a Ale-EVs system. The Ale-EVs had a high affinity for bone and have great potential for clinical applications in osteoporosis therapy with low systemic toxicity.


Assuntos
Osso e Ossos/patologia , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/citologia , Osteoporose/patologia , Osteoporose/terapia , Animais , Regeneração Óssea , Diferenciação Celular , Sobrevivência Celular , Feminino , Humanos , Camundongos , Osteogênese , Osteoporose/fisiopatologia , Ratos
3.
PLoS One ; 15(9): e0237984, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881882

RESUMO

BACKGROUND: Human immunodeficiency virus (HIV) infected individuals may have osteoporosis. We aimed to evaluate the bone mineral density (BMD) in naïve antiretroviral (ARV) treated HIV positive patients comparing native Italian group (ItG) to a Migrants group (MiG) upon arrival in Italy. METHODS: We conducted a cross-sectional study on 83 HIV patients less than 50 years old. We used the dual-energy X-ray absorptiometry (DXA) within six months from the HIV diagnosis. Participants were categorized as having low BMD if the femoral neck or total lumbar spine Z-score was- 2 or less. RESULTS: MiG showed low BMD more often than ItG (37.5% vs.13.6%), especially for the female gender (16.7% vs. 0.0%). A low CD4 rate (<200 cells/µl) was most often detected in MiG than ItG. In particular, we found most often male Italians with abnormal CD4 than male migrants (67.8% vs. 33.3%) and vice versa for females (30.5% vs. 66.7%). We found an abnormal bone mineral density at the lumbar site. Low BMD at the lumbar site was more frequently observed in female migrants than female Italians. Both male and female migrants had a Z-score value significantly lower than male and female Italians, respectively. By logistic regression low vitamin-D level was positively correlated to low BMD in ItG only. All data were verified and validated using a triple code identifier. CONCLUSIONS: Both DXA and vitamin-D evaluation should be offered after the diagnosis of HIV infection. Lumbar site low BMD is an initial condition of bone loss in HIV young patients, especially in female migrants. Vitamin D levels and supplementation may be considered after HIV diagnosis independently of age to improve bone health. HIGHLIGHTS: This study evaluates the frequency of bone mineral density in HIV positive patients naive to antiretroviral therapy. It compares the density of the native Italian population with that of HIV Migrants upon arrival in Italy. The results show that HIV positive migrants, even if younger than 50 years of age, are at risk for osteoporosis, especially if they are female.


Assuntos
Densidade Óssea/fisiologia , Infecções por HIV/diagnóstico , Absorciometria de Fóton , Adulto , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Itália , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Osteoporose/etnologia , Osteoporose/etiologia , Osteoporose/patologia , Fatores Sexuais , Migrantes , Vitamina D/sangue
4.
PLoS One ; 15(7): e0236891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730332

RESUMO

Signal Transducer and Activator of Transcription 3 (STAT3) has recently been shown to be involved in bone development and has been implicated in bone diseases, such as Job's Syndrome. Bone growth and changes have been known for many years to differ between sexes with male bones tending to have higher bone mass than female bones and older females tending to lose bone mass at faster rates than older males. Previous studies using conditional knock mice with Stat3 specifically deleted from the osteoblasts showed both sexes exhibited decreased bone mineral density (BMD) and strength. Using the Cre-Lox system with Cathepsin K promotor driving Cre to target the deletion of the Stat3 gene in mature osteoclasts (STAT3-cKO mice), we observed that 8-week old STAT3-cKO female femurs exhibited significantly lower BMD and bone mineral content (BMC) compared to littermate control (CN) females. There were no differences in BMD and BMC observed between male knock-out and male CN femurs. However, micro-computed tomography (µCT) analysis showed that both male and female STAT3-cKO mice had significant decreases in bone volume/tissue volume (BV/TV). Bone histomorphometry analysis of the distal femur, further revealed a decrease in bone formation rate and mineralizing surface/bone surface (MS/BS) with a significant decrease in osteoclast surface in female, but not male, STAT3-cKO mice. Profiling gene expression in an osteoclastic cell line with a knockdown of STAT3 showed an upregulation of a number of genes that are directly regulated by estrogen receptors. These data collectively suggest that regulation of STAT3 differs in male and female osteoclasts and that inactivation of STAT3 in osteoclasts affects bone turnover more in females than males, demonstrating the complicated nature of STAT3 signaling pathways in osteoclastogenesis. Drugs targeting the STAT3 pathway may be used for treatment of diseases such as Job's Syndrome and osteoporosis.


Assuntos
Reabsorção Óssea/patologia , Osso e Ossos/patologia , Osteoclastos/patologia , Osteogênese , Osteoporose/patologia , Fator de Transcrição STAT3/fisiologia , Animais , Densidade Óssea , Remodelação Óssea , Reabsorção Óssea/etiologia , Osso e Ossos/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoclastos/metabolismo , Osteoporose/etiologia
5.
Proc Natl Acad Sci U S A ; 117(29): 17187-17194, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32636266

RESUMO

Osteoprotegerin (OPG), a secreted decoy receptor for receptor activator of nuclear factor B ligand (RANKL), plays an essential role in regulating bone resorption. While much is known about the function of the N-terminal domains of OPG, which is responsible for binding to RANKL, the exact biological functions of the three C-terminal domains of OPG remain uncertain. We have previously shown that one likely function of the C-terminal domains of OPG is to bind cell surface heparan sulfate (HS), but the in vivo evidence was lacking. To investigate the biological significance of OPG-HS interaction in bone remodeling, we created OPG knock-in mice (opg AAA ). The mutated OPG is incapable of binding to HS but binds RANKL normally. Surprisingly, opg AAA/AAA mice displayed a severe osteoporotic phenotype that is very similar to opg-null mice, suggesting that the antiresorption activity of OPG requires HS. Mechanistically, we propose that the HS immobilizes secreted OPG at the surface of osteoblasts lineage cells, which facilitates binding of OPG to membrane-anchored RANKL. To further support this model, we altered the structure of osteoblast HS genetically to make it incapable of binding to OPG. Interestingly, osteocalcin-Cre;Hs2st f/f mice also displayed osteoporotic phenotype with similar severity to opg AAA/AAA mice. Combined, our data provide strong genetic evidence that OPG-HS interaction is indispensable for normal bone homeostasis.


Assuntos
Conservadores da Densidade Óssea/metabolismo , Conservadores da Densidade Óssea/farmacologia , Heparitina Sulfato/metabolismo , Osteoprotegerina/metabolismo , Osteoprotegerina/farmacologia , Animais , Sítios de Ligação , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Osso e Ossos/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese/genética , Osteogênese/fisiologia , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Osteoprotegerina/genética , Ligante RANK/metabolismo , Transcriptoma
6.
DNA Cell Biol ; 39(9): 1691-1699, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32700968

RESUMO

Long noncoding RNAs (lncRNAs) contribute toward regulating gene expression and cell differentiation and may be involved in the pathogenesis of several diseases. The objective of this study was to determine the expression patterns of lncRNAs in bone marrow mesenchymal stem cells (BMSCs) derived from patients with osteoporotic fractures and their relevance to osteogenic function. The BMSCs were isolated from the femoral head of patients with hip fractures (FRX) and controls with osteoarthritis (OA). We found 74 differentially expressed genes between FRX and OA, of which 33 were of the lncRNA type. Among them, 52 genes (20 lncRNAs) were replicated in another independent dataset. The differentially expressed lncRNAs were over-represented among those correlated with differentially expressed protein-coding genes. In addition, the comparison of pre- and post-differentiated paired samples revealed 163 differentially expressed genes, of which 99 were of the lncRNA type. Among them, the overexpression of LINC00341 induced an upregulation of typical osteoblastic genes. In conclusion, the analysis of lncRNA expression in BMSCs shows specific patterns in patients with osteoporotic fractures, as well as changes associated with osteogenic differentiation. The regulation of bone genes through lncRNAs might bring new opportunities for designing bone anabolic therapies in systemic and localized bone disorders.


Assuntos
Células da Medula Óssea/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteoporose/genética , RNA Longo não Codificante/metabolismo , Células da Medula Óssea/citologia , Diferenciação Celular , Células Cultivadas , Células HEK293 , Humanos , Células-Tronco Mesenquimais/citologia , Osteogênese , Osteoporose/patologia , RNA Longo não Codificante/genética , Transcriptoma
7.
Eur Rev Med Pharmacol Sci ; 24(10): 5778-5782, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32495915

RESUMO

Since the end of 2019, China and other regions around the world have been facing a pandemic of novel coronavirus pneumonia (COVID-19). The virus is highly transmissible, and the human population is generally susceptible. Most patients with osteoporosis are postmenopausal women or elderly people with hypoimmunity, so the osteoporosis clinic has become a new hotspot for corona virus infection. During the COVID-19 pandemic, it is necessary to establish standardized out-patient protocols to provide safe and effective treatment for osteoporosis patients and medical staff. In an osteoporosis clinic, we advocate the following suggestions to prevent and control osteoporosis during the pandemic period: (1) specialized diagnosis and treatment techniques for osteoporosis patients in the outpatient care, including enhancing the prevention for outpatient medical staff, strengthening awareness of COVID-19 prevention, strictly screening outpatients with COVID-19 infection, and insistent administration of anti-osteoporosis drugs during outbreaks; (2) home prevention for osteoporosis patients including keeping windows open, exposing them to sunlight, supplementing them with enough protein, exercising regularly, and administrating calcium supplements; and (3) simplifying the follow-up and evaluation of osteoporosis using online platforms.


Assuntos
Infecções por Coronavirus/diagnóstico , Osteoporose/patologia , Pneumonia Viral/diagnóstico , Betacoronavirus , Conservadores da Densidade Óssea/uso terapêutico , Cálcio/administração & dosagem , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Suplementos Nutricionais , Humanos , Estilo de Vida , Corpo Clínico/psicologia , Medicina Tradicional Chinesa , Osteoporose/complicações , Osteoporose/tratamento farmacológico , Pacientes Ambulatoriais , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Vitamina D/administração & dosagem
8.
PLoS Biol ; 18(6): e3000731, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32479501

RESUMO

The nuclear lamina protein lamin A/C is a key component of the nuclear envelope. Mutations in the lamin A/C gene (LMNA) are identified in patients with various types of laminopathy-containing diseases, which have features of accelerated aging and osteoporosis. However, the underlying mechanisms for laminopathy-associated osteoporosis remain largely unclear. Here, we provide evidence that loss of lamin A/C in skeletal muscles, but not osteoblast (OB)-lineage cells, results in not only muscle aging-like deficit but also trabecular bone loss, a feature of osteoporosis. The latter is due in large part to elevated bone resorption. Further cellular studies show an increase of osteoclast (OC) differentiation in cocultures of bone marrow macrophages/monocytes (BMMs) and OBs after treatment with the conditioned medium (CM) from lamin A/C-deficient muscle cells. Antibody array screening analysis of the CM proteins identifies interleukin (IL)-6, whose expression is markedly increased in lamin A/C-deficient muscles. Inhibition of IL-6 by its blocking antibody in BMM-OB cocultures diminishes the increase of osteoclastogenesis. Knockout (KO) of IL-6 in muscle lamin A/C-KO mice diminishes the deficits in trabecular bone mass but not muscle. Further mechanistic studies reveal an elevation of cellular senescence marked by senescence-associated beta-galactosidase (SA-ß-gal), p16Ink4a, and p53 in lamin A/C-deficient muscles and C2C12 muscle cells, and the p16Ink4a may induce senescence-associated secretory phenotype (SASP) and IL-6 expression. Taken together, these results suggest a critical role for skeletal muscle lamin A/C to prevent cellular senescence, IL-6 expression, hyperosteoclastogenesis, and trabecular bone loss, uncovering a pathological mechanism underlying the link between muscle aging/senescence and osteoporosis.


Assuntos
Envelhecimento/patologia , Lamina Tipo A/deficiência , Músculo Esquelético/patologia , Osteoporose/patologia , Animais , Anticorpos Bloqueadores/farmacologia , Fenômenos Biomecânicos , Reabsorção Óssea/complicações , Reabsorção Óssea/patologia , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/patologia , Diferenciação Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Interleucina-6/metabolismo , Camundongos Knockout , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Osteoporose/sangue , Fenótipo
9.
Sci Rep ; 10(1): 7786, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385316

RESUMO

Patients with ß-thalassemia have an increased risk of developing chronic kidney disease which is associated with osteoporosis and periodontitis. The purpose of this study was to evaluate mandibular and femoral bone change in heterozygous ß-globin knockout (BKO) mice following 5/6 nephrectomy (Nx). Female and male BKO mouse blood smears demonstrated microcytic hypochromic anemia. Serum urea nitrogen, creatinine, calcium, and phosphorus levels were not changed in BKO mice. Nx increased the serum levels of urea nitrogen in both wild type (WT) and BKO mice and the level was much higher in BKO males. Serum level of creatinine was increased in Nx WT but not BKO mice. However, serum calcium and phosphorus levels were not altered. Nx induced comparable renal fibrosis in BKO mice and WT controls. Bone loss was observed in mandibular cancellous bone but not cortical bone of both male and female BKO mice. Nx decreased cancellous bone volume and cortical thickness in WT. Interestingly, BKO mice were resistant to Nx-induced cancellous bone loss. However, cortical thickness and cortical bone mineral density were reduced in Nx male BKO mice. Nx increased mRNA levels of type I collagen, Osx and Trap in WT but not BKO mice. Similarly, Nx reduced cancellous bone volume in femurs and increased osteoblast number and osteoclast number in WT not BKO mice. Serum FGF23 and erythropoietin levels were markedly increased in BKO mice. Nx decreased serum erythropoietin but not FGF23 levels. Since WT treated with erythropoietin exhibited a significant reduction in cancellous bone volume, it was possible that lower level of erythropoietin in Nx BKO mice prevented the Nx-induced cancellous bone loss.


Assuntos
Osso Esponjoso/patologia , Nefrectomia/efeitos adversos , Osteoporose/etiologia , Osteoporose/patologia , Talassemia/complicações , Animais , Biomarcadores , Densidade Óssea , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/metabolismo , Modelos Animais de Doenças , Eritrócitos/metabolismo , Eritrócitos/patologia , Fêmur , Fibrose , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Camundongos , Camundongos Knockout , Nitrogênio/urina , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporose/metabolismo , Microtomografia por Raio-X , Talassemia beta/sangue , Talassemia beta/complicações , Talassemia beta/diagnóstico , Talassemia beta/genética
10.
Sci Rep ; 10(1): 7827, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385391

RESUMO

Zoledronic acid (ZOL) is a third generation bisphosphonate which can be used as a drug for the treatment of osteoporosis and metastasis. In this study, graphene oxide (GO) is conjugated with ZOL, and the nanostructured material is evaluated in terms viability, proliferation and differentiation. Furthermore, the associated morphological changes of bone marrow-derived mesenchymal stem cells (BM-MSC), and Michigan Cancer Foundation-7 (MCF-7) breast cancer cells, as well as the effect of the drugs on mineralization of BM-MSCs are investigated using a variety of characterization techniques including Fourier Transform Infrared Spectroscopy (FTIR), scanning electron microscopy (SEM) as well as alamar blue, acridine orange, and alizarin red assays. Nanostructured ZOL-GO with an optimum performance is synthesized using ZOL and GO suspensions with the concentration of 50 µM and 2.91 ng/ml, respectively. ZOL-GO nanostructures can facilitate the mineralization of BM-MSC cells, demonstrated by the formation of clusters around the cells. The results obtained confirm the performance of ZOL-GO nanostructures as promising drug complexes for the treatment of osteoporosis and metastasis.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Grafite/farmacologia , Nanoestruturas/química , Osteoporose/tratamento farmacológico , Ácido Zoledrônico/farmacologia , Neoplasias da Mama/patologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Grafite/química , Humanos , Células MCF-7 , Metástase Neoplásica , Osteoporose/patologia , Ácido Zoledrônico/química
11.
Cell Prolif ; 53(6): e12834, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32468637

RESUMO

OBJECTIVES: Advanced glycation end products (AGEs) are considered a cause of diabetic osteoporosis. Although adipose-derived stem cells (ASCs) are widely used in the research of bone regeneration, the mechanisms of the osteogenic differentiation of ASCs from diabetic osteoporosis model remain unclear. This work aimed to investigate the influence and the molecular mechanisms of AGEs on the osteogenic potential of ASCs. MATERIALS AND METHODS: Enzyme-linked immunosorbent assay was used to measure the change of AGEs in diabetic osteoporotic and control C57BL/6 mice. ASCs were obtained from the inguinal fat of C57BL/6 mice. AGEs, 5-aza2'-deoxycytidine (5-aza-dC) and DKK-1 were used to treat ASCs. Real-time cell analysis and cell counting kit-8 were used to monitor the proliferation of ASCs within and without AGEs. Real-time PCR, Western blot and Immunofluorescence were used to analyse the genes and proteins expression of osteogenic factors, DNA methylation factors and Wnt/ß-catenin signalling pathway among the different groups. RESULTS: The AGEs and DNA methylation were increased in the adipose and bone tissue of the diabetic osteoporosis group. Untreated ASCs had higher cell proliferation activity than AGEs-treatment group. The expression levels of osteogenic genes, Opn and Runx2, were lower, and mineralized nodules were less in AGEs-treatment group. Meanwhile, DNA methylation was increased, and the Wnt signalling pathway markers, including ß-Catenin, Lef1 and P-GSK-3ß, were inhibited. After treatment with 5-aza-dC, the osteogenic differentiation capacity of ASCs in the AGEs environment was restored and the Wnt signalling pathway was activated during this process. CONCLUSIONS: Advanced glycation end products inhibit the osteogenic differentiation ability of ASCs by activating DNA methylation and inhibiting Wnt/ß-catenin pathway in vitro. Therefore, DNA methylation may be promising targets for the bone regeneration of ASCs with diabetic osteoporosis.


Assuntos
Tecido Adiposo/citologia , Metilação de DNA , Complicações do Diabetes/metabolismo , Produtos Finais de Glicação Avançada/farmacologia , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Células-Tronco/metabolismo , Tecido Adiposo/metabolismo , Animais , Osso e Ossos/metabolismo , Proliferação de Células , Células Cultivadas , Decitabina/farmacologia , Complicações do Diabetes/patologia , Feminino , Produtos Finais de Glicação Avançada/metabolismo , Camundongos Endogâmicos C57BL , Osteoporose/patologia , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Via de Sinalização Wnt
12.
Breast Cancer Res Treat ; 181(2): 279-289, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32318956

RESUMO

PURPOSE: The data of head-to-head comparisons of the anti-fracture efficacy of bone modifying agents (BMAs) in patients with hormone receptor-positive breast cancer receiving aromatase inhibitor (AI) are not available. Therefore, we conducted a network meta-analysis to compare the efficacy of different BMAs in patients with breast cancer receiving adjuvant AI. METHODS: We performed a network meta-analysis to compare the change of bone mineral densities (BMDs) and the risk of fracture in the selected studies using a random effect model. The primary outcomes are the change of BMD of lumbar spine (LS) and total hip (TH) from the baseline (ΔBMD, %) at 1 and 2 years and the risk of fracture. RESULTS: We identified and included a total of 16 randomized controlled trials for this analysis. All BMAs included (risedronate, zoledronate, and denosumab) were associated with a significant increase in BMD of LS and TH at 1 and 2 years compared with no upfront treatment group. Among BMAs, zoledronate and denosumab use resulted in significantly higher BMD of LS and TH at 1 and 2 years compared with risedronate. The risk of fracture was significantly lower in the patients who received denosumab or risedronate compared with the patients without upfront treatment (Relative risk (RR) [95% CI] 0.51 [0.38-0.67] and 0.54 [0.35-0.83], respectively). CONCLUSION: Among the bisphosphonates, zoledronate increased BMD the most, but risedronate, not zoledronate, use was associated with lower risk of fracture. Denosumab increased BMD not only of LS but also of the cortical-bone-rich hip, and showed a significant reduction of fracture risk.


Assuntos
Inibidores da Aromatase/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Osteoporose/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Osteoporose/induzido quimicamente , Osteoporose/patologia , Prognóstico
13.
Arch Oral Biol ; 113: 104713, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32229339

RESUMO

OBJECTIVE: This work was aimed to investigate the effect of microRNA-141 (miR-141) overexpression in the jawbones of ovariectomized-induced osteoporosis rats and investigate the role of miR-141 in the Wnt/ß-catenin pathway. METHODS: Twenty-four female rats were randomly divided into the sham group, ovariectomized osteoporosis group (OP), miR-141 agonist group (miR-141), and miR-141 scramble group (Scramble). Bone mineral density (BMD) and pathological changes of the jaw were detected. Serum receptor activator of nuclear factor-B ligand (RANKL), osteoprotegerin, tartrate-resistant acid phosphatase (TRAP), and bone gla protein (BGP) levels were tested by ELISA. The expression of Runt-related transcription factor 2 (Runx2), and Osterix measured by immunohistochemistry and the expression of Wnt, ß-catenin, and Dickkopf1 (DKK1) proteins was measured by Western blot. Furhter, the Wnt agonist DKK2-C2, Wnt inhibitor Endostar were used to verify the effect of miR-141 overexpression on the Wnt/ß-catenin pathway. RESULT: Compared with the OP group, the content of osteoprotegerin increased while the levels of RANKL, BGP, TRAP decreased in the miR-141 and DKK2-C2 groups (p < 0.05). The levels of Runx2 and Osterix increased significantly in the miR-141 and DKK2-C2 groups when compared to the OP group (p < 0.05). Interestingly, the protein expression of Wnt and ß-catenin increased while DKK1 was remarkably down-regulated in the miR-141 and DKK2-C2 groups when compared to the OP group (p < 0.05). In contrast to the miR-141 group, the above results were reversed after treatment with the Endostar (p < 0.05). CONCLUSION: Overexpression of miR-141 could inhibit the osteoporosis of jawbones in ovariectomized rats by activating the Wnt/ß-catenin pathway.


Assuntos
Arcada Osseodentária/patologia , MicroRNAs/genética , Osteoporose/genética , Via de Sinalização Wnt , Animais , Feminino , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Osteoporose/patologia , Ovariectomia , Ratos , Ratos Sprague-Dawley , beta Catenina/metabolismo
14.
Sci Rep ; 10(1): 5692, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32231224

RESUMO

Interleukin (IL)-17A is a well-described mediator of bone resorption in inflammatory diseases, and postmenopausal osteoporosis is associated with increased serum levels of IL-17A. Ovariectomy (OVX) can be used as a model to study bone loss induced by estrogen deficiency and the role of IL-17A in osteoporosis development has previously been investigated using various methods to inhibit IL-17A signaling in this model. However, the studies show opposing results. While some publications reported IL-17A as a mediator of OVX-induced osteoporosis, others found a bone-protective role for IL-17 receptor signaling. In this study, we provide an explanation for the discrepancies in previous literature and show for the first time that loss of IL-17A has differential effects on OVX-induced osteoporosis; with IL-17A being important for cortical but not trabecular bone loss. Interestingly, the decrease in trabecular bone after OVX in IL-17A knock-out mice, was accompanied by increased adipogenesis depicted by elevated leptin levels. Additionally, the bone marrow adipose tissue expanded, and the bone-turnover decreased in ovariectomized mice lacking IL-17A compared to ovariectomized WT mice. Our results increase the understanding of how IL-17A signaling influences bone remodeling in the different bone compartments, which is of importance for the development of new treatments of post-menopausal osteoporosis.


Assuntos
Interleucina-17/fisiologia , Osteoporose/fisiopatologia , Absorciometria de Fóton , Animais , Osso Esponjoso/patologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Humanos , Camundongos , Camundongos Knockout , Osteogênese/efeitos dos fármacos , Osteoporose/diagnóstico por imagem , Osteoporose/etiologia , Osteoporose/patologia , Osteoporose Pós-Menopausa/etiologia , Osteoporose Pós-Menopausa/fisiopatologia , Ovariectomia/efeitos adversos , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina-17/fisiologia , Microtomografia por Raio-X
15.
Hum Cell ; 33(3): 569-581, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32253621

RESUMO

Osteoporosis (OP) is a systemic bone metabolic disorder, which negatively affects the quality of life in the elders and postmenopausal females. Healthy volunteers and postmenopausal females with OP were enrolled in the present study. Bone densitometry (BMD) was detected by dual-energy X-ray absorptiometry (DXA). CD14+PBMCs and C2C12 cells were cultured to induce osteoclast differentiation and osteoblast differentiation, respectively. The interaction between miR­140-3p and PTEN was predicted and verified by TargetScan 7.2 and dual luciferase reporter assay, respectively. miRNA/RNA level and protein level were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. Cell proliferation and apoptosis were detected by 5-ethynyl-2'-deoxyuridine (EdU) staining and flow cytometry, respectively. Cell differentiation of CD14+PBMCs and C2C12 cells were detected by tartrate-resistant acid phosphatase (TRAP) staining and alizarin red staining, respectively. The activity of alkaline phosphatase (ALP) was detected by ALP assay. Differences were observed in age, body mass index (BMI), and BMD between the OP group and the control group. Higher miR­140-3p level and lower PTEN level were found in PBMCs of OP group compared to control group; there was a negative correlation between them in the serum of OP group. miR-140-3p targeted and downregulated the expression of PTEN. miR-140-3p inhibitor inhibited cell proliferation, differentiation, and promoted cell apoptosis of CD14+PBMCs; while promoted cell proliferation, differentiation and inhibited cell apoptosis of C2C12 cells, by targeting PTEN and inactivating PTEN/PI3K/AKT signaling pathway. These findings suggested a potential therapeutic role of miR-140-3p in the treatment of patients with OP.


Assuntos
Osteoporose/genética , Osteoporose/patologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Apoptose , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Células HEK293 , Humanos , Terapia de Alvo Molecular , Osteoblastos , Osteoclastos , Osteoporose/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo
16.
Int J Nanomedicine ; 15: 1797-1807, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214812

RESUMO

Purpose: Enhancing osteointegration of implants in osteoporosis patients is a necessity since implantations frequently fail in these patients. The aim of this work is to study how simvastatin-strontium-hydroxyapatite coated implants perform in rabbits with osteoporosis. Materials and Methods: Crystalline HA and Sr-HA oxide film were prepared through micro-arc oxidation. Surface characterization including morphology, roughness, element composition, phase composition, hydrophilicity were then evaluated. Simvastatin loaded on porous films through immersion, and the effects of coatings on osteointegration in osteoporotic rabbits were investigated. All samples were obtained after 4, 8 and 12 weeks of healing. Some of them were subjected to biomechanical tests and others were subjected to histological and histomorphometric analysis. Results: Coatings exhibited a microporous network structure with appropriate roughness and high hydrophilicity. Compared to control HA and machined surface implants, simvastatin-Sr-HA coated implants exhibited marked improvements in osteointegration, which is characterized by a quicker mineralization deposition rate, good bone formation mode (large amount of contact osteogenesis and a small amount of distance osteogenesis) and increased bone-to-implant contact and pull-out strength. Conclusion: These biological parameters demonstrate the excellent osteoconductivity of simvastatin-Sr-HA coatings in the osteoporotic state. Overall, this suggests that simvastatin-Sr-HA coatings would be applicable in poor-quality bones of patients experiencing osteoporosis.


Assuntos
Osseointegração/efeitos dos fármacos , Osteoporose/patologia , Próteses e Implantes , Sinvastatina/farmacologia , Animais , Interface Osso-Implante , Materiais Revestidos Biocompatíveis/química , Feminino , Hidroxiapatitas/química , Osteogênese/efeitos dos fármacos , Oxirredução , Coelhos , Sinvastatina/química , Estrôncio/química , Tíbia/fisiopatologia
17.
Biomed Res Int ; 2020: 9467683, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149147

RESUMO

Yishen Bugu Ye (YSBGY), a traditional Chinese medicine comprising 12 types of medicinal herbs, is often prescribed in China to increase bone strength. In this study, the antiosteoporotic effects of YSBGY were investigated in C57BL/6 mice afflicted with dexamethasone- (Dex-) induced osteoporosis (OP). The results showed that YSBGY reduced the interstitial edema in the liver and kidney of mice with Dex-induced OP. It also increased the number of trabecular bone elements and chondrocytes in the femur, promoted cortical bone thickness and trabecular bone density, and modulated the OP-related indexes in the femur and tibia of OP mice. It also increased the serum concentrations of type I collagen, osteocalcin, osteopontin, bone morphogenetic protein-2, bone morphogenetic protein receptor type 2, C-terminal telopeptide of type I collagen, and runt-related transcription factor-2 and reduced those of tartrate-resistant acid phosphatase 5 and nuclear factor of activated T cells in these mice, suggesting that it improved osteoblast differentiation and suppressed osteoclast differentiation. The anti-inflammatory effect of YSBGY was confirmed by the increase in the serum concentrations of interleukin- (IL-) 33 and the decrease in concentrations of IL-1, IL-7, and tumor necrosis factor-α in OP mice. Furthermore, YSBGY enhanced the serum concentrations of superoxide dismutase and catalase in these mice, indicating that it also exerted antioxidative effects. This is the first study to confirm the antiosteoporotic effects of YSBGY in mice with Dex-induced OP, and it showed that these effects may be related to the YSBGY-induced modulation of the osteoblast/osteoclast balance and serum concentrations of inflammatory factors. These results provide experimental evidence supporting the use of YSBGY for supporting bone formation in the clinical setting.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Animais , Densidade Óssea , Proteína Morfogenética Óssea 2/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Osso Esponjoso , Colágeno Tipo I/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Osso Cortical/metabolismo , Osso Cortical/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteocalcina/metabolismo , Osteoclastos/metabolismo , Osteopontina/metabolismo , Osteoporose/diagnóstico por imagem , Osteoporose/patologia , Peptídeos , Superóxido Dismutase/sangue , Fosfatase Ácida Resistente a Tartarato/metabolismo
18.
Int J Mol Sci ; 21(5)2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32121265

RESUMO

Osteoporosis, the most common chronic metabolic bone disease, is characterized by low bone mass and increased bone fragility. Nowadays more than 200 million individuals are suffering from osteoporosis and still the number of affected people is dramatically increasing due to an aging population and longer life, representing a major public health problem. Current osteoporosis treatments are mainly designed to decrease bone resorption, presenting serious adverse effects that limit their safety for long-term use. Numerous studies with mesenchymal stem cells (MSCs) have helped to increase the knowledge regarding the mechanisms that underlie the progression of osteoporosis. Emerging clinical and molecular evidence suggests that inflammation exerts a significant influence on bone turnover, thereby on osteoporosis. In this regard, MSCs have proven to possess broad immunoregulatory capabilities, modulating both adaptive and innate immunity. Here, we will discuss the role that MSCs play in the etiopathology of osteoporosis and their potential use for the treatment of this disease.


Assuntos
Transplante de Células-Tronco Mesenquimais , Osteoporose/terapia , Biomarcadores/metabolismo , Remodelação Óssea , Humanos , Inflamação/patologia , Células-Tronco Mesenquimais/citologia , Osteoporose/patologia , Osteoporose/fisiopatologia
19.
Cell Mol Life Sci ; 77(17): 3293-3309, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32130428

RESUMO

Metallomics is a rapidly evolving field of bio-metal research that integrates techniques and perspectives from other "-omics" sciences (e.g. genomics, proteomics) and from research vocations further afield. Perhaps the most esoteric of this latter category has been the recent coupling of biomedicine with element and isotope geochemistry, commonly referred to as isotope metallomics. Over the course of less than two decades, isotope metallomics has produced numerous benchmark studies highlighting the use of stable metal isotope distribution in developing disease diagnostics-e.g. cancer, neurodegeneration, osteoporosis-as well as their utility in deciphering the underlying mechanisms of such diseases. These pioneering works indicate an enormous wealth of potential and provide a call to action for researchers to combine and leverage expertise and resources to create a clear and meaningful path forward. Doing so with efficacy and impact will require not only building on existing research, but also broadening collaborative networks, bolstering and deepening cross-disciplinary channels, and establishing unified and realizable objectives. The aim of this review is to briefly summarize the field and its underpinnings, provide a directory of the state of the art, outline the most encouraging paths forward, including their limitations, outlook and speculative upcoming breakthroughs, and finally to offer a vision of how to cultivate isotope metallomics for an impactful future.


Assuntos
Metais/metabolismo , Pesquisa Biomédica , Cromatografia por Troca Iônica , Humanos , Marcação por Isótopo , Espectrometria de Massas , Metais/análise , Neoplasias/metabolismo , Neoplasias/patologia , Osteoporose/metabolismo , Osteoporose/patologia
20.
J Nutr ; 150(6): 1370-1378, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32135009

RESUMO

BACKGROUND: Linoleic acid (LA; 18:2n-6) has been considered to promote low-grade chronic inflammation and adiposity. Studies show adiposity and inflammation are inversely associated with bone mass. OBJECTIVES: This study tested the hypothesis that decreasing the dietary ratio of LA to α-linolenic acid (ALA, 18:3n-3), while keeping ALA constant, mitigates high-fat diet (HF)-induced adiposity and bone loss. METHODS: Male C57BL/6 mice at 6 wk old were assigned to 4 treatment groups and fed 1 of the following diets ad libitum for 6 mo: a normal-fat diet (NF; 3.85 kcal/g and 10% energy as fat) with the ratio of the PUFAs LA to ALA at 6; or HFs (4.73 kcal/g and 45% energy as fat) with the ratio of LA to ALA at 10:1, 7:1, or 4:1, respectively. ALA content in the diets was kept the same for all groups at 1% energy. Bone structure, body composition, bone-related cytokines in serum, and gene expression in bone were measured. Data were analyzed using 1-factor ANOVA. RESULTS: Compared with those fed the NF, mice fed the HFs had 19.6% higher fat mass (P < 0.01) and 13.5% higher concentration of serum tartrate-resistant acid phosphatase (TRAP) (P < 0.05), a bone resorption cytokine. Mice fed the HFs had 19.5% and 12.2% lower tibial and second lumbar vertebral bone mass, respectively (P < 0.01). Decreasing the dietary ratio of LA to ALA from 10 to 4 did not affect body mass, fat mass, serum TRAP and TNF-α, or any bone structural parameters. CONCLUSIONS: These data indicate that decreasing the dietary ratio of LA to ALA from 10 to 4 by simply reducing LA intake does not prevent adiposity or improve bone structure in obese mice.


Assuntos
Adiposidade , Gorduras na Dieta/administração & dosagem , Ácido Linoleico/administração & dosagem , Obesidade/patologia , Osteoporose/patologia , Ácido alfa-Linoleico/administração & dosagem , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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