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1.
Arch Osteoporos ; 16(1): 22, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33527234

RESUMO

We aimed to investigate the association between cadmium levels and the risk of osteopenia and osteoporosis in Korean post-menopausal women. There was a significant positive association between cadmium levels and the risk of osteopenia and osteoporosis, but further studies for dose response are required. PURPOSE: Cadmium exposure can exert detrimental effects on bone health, particularly in post-menopausal women. However, previous studies have failed to report an association in Korean post-menopausal women. We aimed to investigate the association between cadmium levels and the risk of osteopenia and osteoporosis in Korean post-menopausal women. METHODS: In total, 5432 participants from the 4th and 5th Korean National Health and Nutrition Examination Survey (KNHANES) were randomly sampled for measurements of heavy metal concentrations in the blood, bone mass density (BMD), and nutrient intake. We analyzed data for 1031 post-menopausal women ≥50 years of age. Blood cadmium levels were categorized into quartiles, and a multinomial logistic regression model was used for analysis. RESULTS: There was a significant positive association between cadmium levels and the risk of osteopenia and osteoporosis, but the odds ratio (OR) at the 4th level was lower than that at the 3rd level (OR and 95% confidence interval (CI) for osteopenia: 2nd quartile: 1.24, 0.88-1.74; 3rd quartile: 3.22, 2.24-4.64; 4th quartile: 1.27, 0.87-1.85; P for trend <0.001; OR and 95% CI for osteoporosis: 2nd quartile: 1.54, 1.05-2.25; 3rd quartile: 3.63, 2.31-5.69; 4th quartile: 1.70, 1.03-2.81; P for trend <0.001). This trend was consistent in the sensitivity analysis. CONCLUSION: Our findings suggest that there is an association between blood cadmium levels and the risk of osteopenia and osteoporosis in Korean post-menopausal women. However, further prospective studies are required to determine whether there is a dose-response relationship and address potential selection bias, especially in patients with femoral neck osteoporosis.


Assuntos
Doenças Ósseas Metabólicas , Osteoporose Pós-Menopausa , Osteoporose , Densidade Óssea , Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/epidemiologia , Cádmio , Estudos Transversais , Feminino , Humanos , Inquéritos Nutricionais , Osteoporose/induzido quimicamente , Osteoporose/epidemiologia , Osteoporose Pós-Menopausa/epidemiologia , Pós-Menopausa , Estudos Prospectivos , República da Coreia/epidemiologia
2.
AIDS ; 35(2): 213-218, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33394669

RESUMO

OBJECTIVES: Osteopenia is frequent in HIV-infected patients treated with antiretroviral therapy (ART) and has been linked to increased osteoclastogenesis. Little is known about the effects of ART on osteogenesis. DESIGN: We investigated the effect on human mesenchymal stem cells (hMSC) and osteoblasts of Darunavir and Dolutegravir, the most highly used as anchor drugs within a three-drug regimen, and Atazanavir, which was widely utilized in the past. RESULTS: We found that Atazanavir and Dolutegravir delay the osteogenic differentiation of hMSC, impair the activity of osteoblasts and inhibit their conversion into osteocytes, whereas Darunavir exerts no effect. CONCLUSION: Atazanavir and Dolutegravir impair osteogenesis. It is essential to diagnose impaired osteogenesis early and to devise effective therapeutic interventions to preserve bone health in ART-treated HIV patients, putting it in the context of a correct antiretroviral combination.


Assuntos
Fármacos Anti-HIV , Sulfato de Atazanavir/efeitos adversos , Doenças Ósseas Metabólicas , Darunavir/efeitos adversos , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Piridonas/efeitos adversos , Fármacos Anti-HIV/efeitos adversos , Sulfato de Atazanavir/uso terapêutico , Doenças Ósseas Metabólicas/induzido quimicamente , Darunavir/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Osteogênese , Oxazinas/uso terapêutico , Piperazinas/uso terapêutico , Piridonas/uso terapêutico
3.
Drug Discov Ther ; 14(2): 77-83, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32378649

RESUMO

Tacrolimus, a calcineurin inhibitor, affects bone metabolism and increases the risk of fracture due to marked bone loss. Bisphosphonates increase the bone mineral density (BMD) in osteoporosis patients. Menatetrenone has less positive effects on BMD but reduces the risk of fracture by improving bone quality. In this study, we investigated the effectiveness of the combined administration of risedronate and menatetrenone against bone loss induced by tacrolimus. Wistar rats were divided into four groups: [1] control, [2] tacrolimus at 1.5 mg/kg, [3] tacrolimus + risedronate at 1.0 mg/kg, and [4] tacrolimus + risedronate + menatetrenone at 20 mg/kg. After the drugs were administered for 4 weeks, bone histomorphometric analysis was performed and bone strength was evaluated using a three point bending method. BMD was measured using quantitative computed tomography. Tacrolimus significantly reduced the BMD and strength properties of the lower limb bones. These tacrolimusinduced decreases were suppressed by risedronate treatment. The combined administration of risedronate and menatetrenone more significantly improved bone strength properties than risedronate alone. Bone histomorphometric analysis revealed a significant increase in bone resorption with tacrolimus. Risedronate alone significantly suppressed the tacrolimus-induced increase in bone resorption but simultaneously reduced bone formation. On the other hand, the combined administration of risedronate and menatetrenone suppressed the tacrolimus-induced increase in bone resorption, in addition to the significant risedronate-induced decrease in bone formation. This study suggests that the combined administration of risedronate and menatetrenone improves bone strength in tacrolimus-treated rats by preventing and ameliorating the risedronate-induced suppression of bone formation.


Assuntos
Doenças Ósseas Metabólicas/tratamento farmacológico , Imunossupressores/efeitos adversos , Ácido Risedrônico/uso terapêutico , Tacrolimo/efeitos adversos , Vitamina K 2/análogos & derivados , Animais , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/induzido quimicamente , Quimioterapia Combinada , Fêmur/efeitos dos fármacos , Fêmur/fisiologia , Masculino , Osteogênese/efeitos dos fármacos , Ratos Wistar , Tíbia/efeitos dos fármacos , Tíbia/fisiologia , Vitamina K 2/uso terapêutico
4.
Sci Rep ; 10(1): 195, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932603

RESUMO

We recently reported that a butanol soluble fraction from the stem of Cassia occidentalis (CSE-Bu) consisting of osteogenic compounds mitigated methylprednisone (MP)-induced osteopenia in rats, albeit failed to afford complete protection thus leaving a substantial scope for further improvement. To this aim, we prepared an oral formulation that was a lipid-based self-nano emulsifying drug delivery system (CSE-BuF). The globule size of CSE-BuF was in the range of 100-180 nm of diluted emulsion and the zeta potential was -28 mV. CSE-BuF enhanced the circulating levels of five osteogenic compounds compared to CSE-Bu. CSE-BuF (50 mg/kg) promoted bone regeneration at the osteotomy site and completely prevented MP-induced loss of bone mass and strength by concomitant osteogenic and anti-resorptive mechanisms. The MP-induced downregulations of miR29a (the positive regulator of the osteoblast transcription factor, Runx2) and miR17 and miR20a (the negative regulators of the osteoclastogenic cytokine RANKL) in bone was prevented by CSE-BuF. In addition, CSE-BuF protected rats from the MP-induced sarcopenia and/or muscle atrophy by downregulating the skeletal muscle atrogenes, adverse changes in body weight and composition. CSE-BuF did not impact the anti-inflammatory effect of MP. Our preclinical study established CSE-BuF as a prophylactic agent against MP-induced osteopenia and muscle atrophy.


Assuntos
Doenças Ósseas Metabólicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glucocorticoides/toxicidade , Atrofia Muscular/tratamento farmacológico , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Senna (Planta)/química , Animais , Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/patologia , Butanóis/química , Emulsões , Masculino , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/patologia , Fitoterapia , Extratos Vegetais/química , Caules de Planta/química , Substâncias Protetoras/química , Ratos , Ratos Sprague-Dawley
5.
Skeletal Radiol ; 49(3): 345-357, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31501957

RESUMO

Skeletal fluorosis is a rare toxic osteopathy characterized by massive bone fixation of fluoride. The disease occurs as an endemic problem in some parts of the world and is the result of prolonged ingestion or rarely by inhalation of high amounts of fluoride. Radiographic presentation is mainly characterized by bone changes with osteocondensation and later ossification of many ligaments and interosseous membranes. Skeletal fluorosis is not clinically obvious and can be confused with other rheumatologic disorders. Its severity lies in the development of skeletal deformities and neurological complications. Management of fluorosis generally focuses on symptom treatment.


Assuntos
Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/diagnóstico por imagem , Intoxicação por Flúor/diagnóstico por imagem , Doenças Ósseas Metabólicas/epidemiologia , Intoxicação por Flúor/epidemiologia , Humanos , Ossificação Heterotópica/induzido quimicamente , Ossificação Heterotópica/diagnóstico por imagem , Ossificação Heterotópica/epidemiologia , Osteosclerose/induzido quimicamente , Osteosclerose/diagnóstico por imagem , Osteosclerose/epidemiologia
6.
Int J Biol Sci ; 15(11): 2427-2437, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31595160

RESUMO

Excessive bone resorption plays a central role in the development of inflammatory bone diseases, including osteoporosis and rheumatoid arthritis. Thus, identification of agents that can effectively suppress excessive osteoclast formation and function is crucial for the prevention and treatment of inflammatory bone loss. Umbelliferone (Umb), a derivative of coumarin, is a natural bioactive compound with anti-inflammatory and antioxidant properties. However, the effect of Umb on metabolic bone diseases is unknown. In this study, we found that Umb exhibited a strong inhibitory effect on lipopolysaccharide (LPS)-induced inflammatory bone loss in vivo. Histological analysis confirmed that Umb prevented trabecular bone matrix degradation and osteoclast formation in bone tissue. In addition, Umb suppressed RANKL-induced osteoclast differentiation and abrogated bone resorption. We found that the anti-osteoclastic and anti-resorptive activities of Umb are mediated via suppression of the RANKL-induced Akt-c-Fos-NFATc1 signaling pathway and the attenuation of osteoclast-specific genes, such as TRAP, OSCAR, ATP6v0d2, and CtsK. In particular, Umb downregulated the stability of c-Fos and NFATc1 proteins, but did not suppress the expression of their mRNAs. These results indicate that Umb may be a potential therapeutic agent for inflammatory bone diseases associated with abnormal osteoclast formation and function.


Assuntos
Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/prevenção & controle , Lipopolissacarídeos/toxicidade , Fatores de Transcrição NFATC/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Umbeliferonas/uso terapêutico , Animais , Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/prevenção & controle , Reabsorção Óssea/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
7.
Clin Otolaryngol ; 44(6): 1011-1016, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31529761

RESUMO

OBJECTIVES: We aimed to investigate the bone mineral density (BMD) in a group of Swedish patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) with or without asthma, as well as to evaluate whether the treatment of this patient group is in accordance with the EPOS recommendations. DESIGN, SETTINGS AND PARTICIPANTS: Adult patients with a diagnosis of CRSwNP, and a history of at least two courses of oral corticosteroids (OCS) during the last year, were consecutively included in this study at five centres. MAIN OUTCOME MEASURES: The BMD of the patients was measured by Dual-energy X-ray absorptiometry (DXA), which is the only technology for classifying BMD according to the criteria established by WHO. RESULTS: A total of 51 patients, with an average number of 7 years with OCS treatment, were enrolled. During the last 12 months, the mean number of OCS courses was 2.76, and the total mean intake was 891 mg of Prednisone equivalents. According to the T-scores, 17 patients were measured to have ≤-1 SD T-score lumbar spine, which is considered to be osteopenia, and five patients had <-2.5 SD T-score, considered as osteoporosis. However, when taking age and gender into account and analysing the Z-scores, only 2 patients had a reduced density of the spine and none in the hip, which is no difference compared to a matched Swedish population. CONCLUSIONS: This prospective study shows that 2-3 moderate courses of OCS annually may be used without high risk of causing osteopenia/osteoporosis in patients with CRSwNP.


Assuntos
Corticosteroides/efeitos adversos , Doenças Ósseas Metabólicas/induzido quimicamente , Pólipos Nasais/tratamento farmacológico , Osteoporose/induzido quimicamente , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológico , Absorciometria de Fóton , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Doenças Ósseas Metabólicas/diagnóstico , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/complicações , Osteoporose/diagnóstico , Estudos Prospectivos , Rinite/complicações , Sinusite/complicações , Suécia
8.
Sci Rep ; 9(1): 13768, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551490

RESUMO

Accumulating evidence have shown the association of Parkinson's disease (PD) with osteoporosis. Bone loss in PD patients, considered to be multifactorial and a result of motor disfunction, is a hallmark symptom that causes immobility and decreased muscle strength, as well as malnutrition and medication. However, no known experimental evidence has been presented showing deleterious effects of anti-PD drugs on bone or involvement of dopaminergic degeneration in bone metabolism. Here, we show that osteoporosis associated with PD is caused by dopaminergic degeneration itself, with no deficit of motor activity, as well as treatment with levodopa, the current gold-standard medication for affected patients. Our findings show that neurotoxin-induced dopaminergic degeneration resulted in bone loss due to accelerated osteoclastogenesis and suppressed bone formation, which was associated with elevated prolactin. On the other hand, using an experimental model of postmenopausal osteoporosis, dopaminergic degeneration did not result in exacerbation of bone loss due to estrogen deficiency, but rather reduction of bone loss. Thus, this study provides evidence for the regulation of bone metabolism by the dopaminergic system through both gonadal steroid hormone-dependent and -independent functions, leading to possible early detection of osteoporosis development in individuals with PD.


Assuntos
Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/etiologia , Dopamina/metabolismo , Levodopa/efeitos adversos , Levodopa/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Animais , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/farmacologia , Doenças Ósseas Metabólicas/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Osteoporose/induzido quimicamente , Osteoporose/metabolismo , Osteoporose/patologia , Doença de Parkinson/patologia
9.
Alcohol Clin Exp Res ; 43(11): 2301-2311, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31479513

RESUMO

BACKGROUND: Estrogen signaling is essential for the sexual dimorphism of the skeleton, is required for normal bone remodeling balance in adults, and may influence the skeletal response to alcohol. High levels of alcohol consumption lower bone mass in ovary-intact but not ovariectomized (ovx) rats. However, the extremely rapid rate of bone loss immediately following ovx may obscure the effects of alcohol. We therefore determined (i) whether heavy alcohol consumption (35% caloric intake) influences bone in sexually mature ovx rats with established cancellous osteopenia and (ii) whether ICI 182,780 (ICI), a potent estrogen receptor signaling antagonist, alters the skeletal response to alcohol. METHODS: Three weeks following ovx, rats were randomized into 5 groups, (i) baseline, (ii) control + vehicle, (iii) control + ICI, (iv) ethanol (EtOH) + vehicle, or (v) EtOH + ICI, and treated accordingly for 4 weeks. Dual-energy X-ray absorptiometry, microcomputed tomography, blood measurements of markers of bone turnover, and gene expression in femur and uterus were used to evaluate response to alcohol and ICI. RESULTS: Rats consuming alcohol had lower bone mass and increased fat mass. Bone microarchitecture of the tibia and gene expression in femur were altered; specifically, there was reduced accrual of cortical bone, net loss of cancellous bone, and differential expression of 19/84 genes related to bone turnover. Furthermore, osteocalcin, a marker of bone turnover, was lower in alcohol-fed rats. ICI had no effect on weight gain, body composition, or cortical bone. ICI reduced cancellous bone loss and serum CTX-1, a biochemical marker of bone resorption; alcohol antagonized the latter 2 responses. Neither alcohol nor ICI affected uterine weight or gene expression. CONCLUSIONS: Alcohol exaggerated bone loss in ovx rats in the presence or absence of estrogen receptor blockade with ICI. The negligible effect of alcohol on uterus and limited effects of ICI on bone in alcohol-fed ovx rats suggest that estrogen receptor signaling plays a limited role in the action of alcohol on bone in a rat model for chronic alcohol abuse.


Assuntos
Doenças Ósseas Metabólicas/induzido quimicamente , Osso e Ossos/efeitos dos fármacos , Antagonistas do Receptor de Estrogênio/uso terapêutico , Etanol/efeitos adversos , Fulvestranto/uso terapêutico , Ovariectomia/efeitos adversos , Absorciometria de Fóton , Animais , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/prevenção & controle , Osso e Ossos/diagnóstico por imagem , Feminino , Ratos , Ratos Sprague-Dawley , Receptores Estrogênicos/antagonistas & inibidores , Microtomografia por Raio-X
10.
Eur J Pharmacol ; 863: 172669, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31542486

RESUMO

The antiresorptive agents still are the mainstay of osteoporosis treatment. This study aimed to investigate the efficacy of recombinant Lingzhi-8 (rLZ-8) on osteoclast in vitro and bone resorption in vivo. The rLZ-8 protein was derived from Ganoderma lucidum transformation and produced by a genetic system. Receptor activator of nuclear factor kappa-Β ligand induced RAW 264.7 cells to differentiate into osteoclastic cells in vitro. Cells were exposed to different doses of rLZ-8 for 7 days to measure differences of osteoclastic differentiation, apoptosis rate and gene expression. rLZ-8 was labeled with Alexa Fluor 568 to observe its intracellular distribution under super-resolution light microscopy. In addition, retinoic acid was administered to female rats for 14 days to develop osteopenia changes. Different doses of rLZ-8 were simultaneously administered to rats treated with retinoic acid to observe changes of bone mineral density, biochemical parameters and organ weight ratio. Results indicated that rLZ-8 regulated receptor activator of nuclear factor kappa-Β (RANK) - tumor necrosis factor receptor-associated factor 6 (TRAF6) - c-Jun N-terminal kinase (JNK) signaling pathway, by which rLZ-8 inhibited osteoclastic differentiation and promoted osteoclastic apoptosis. Through 3D-structured illumination microscopy, it was observed that rLZ-8 entered RAW264.7 cells and accumulated gradually into the cytoplasm but little into nucleus. Administration with rLZ-8 reversed loss of bone mass and improved ALP activity in osteoporotic rats. Low-to high-dose rLZ-8 treatments displayed little toxic effects on rat organs and did not seem to impact their overall health. All data suggested that rLZ-8 has possible action against osteoporosis.


Assuntos
Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/tratamento farmacológico , Proteínas de Plantas/farmacologia , Proteínas Recombinantes/farmacologia , Reishi/química , Tretinoína/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Proteínas de Plantas/uso terapêutico , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/uso terapêutico
11.
FASEB J ; 33(11): 12972-12982, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31500447

RESUMO

Prenatal nicotine exposure (PNE) induces developmental toxicity in offspring. However, the long-term harmful effects on bone development and the intrauterine programming mechanism attributed to PNE remain unclear. In the present research, pregnant Wistar rats were injected subcutaneously with nicotine (2 mg/kg/d) to obtain and analyze bone samples from the fetal and adult offspring. Bone marrow mesenchymal stem cells (BMSCs) were treated with nicotine during osteogenic differentiation to clarify the related molecular mechanisms. The results indicated that PNE led to bone dysplasia in the fetuses and reduced bone mass in the adult offspring, which was mediated by the sustained activation of the local bone renin angiotensin system (RAS) and suppressed osteogenic differentiation before and after birth. In vitro, nicotine suppressed BMSCs' osteogenic function through promoting angiotensin-converting enzyme (ACE) expression and activating RAS. Furthermore, nicotine induced histone acetylase p300 into the nuclei of the BMSCs by acting on the α4ß2-nicotinic acetylcholine receptor (α4ß2-nAChR), leading to the increased histone 3 lysine 9 acetylation level of ACE and RAS activation. Taken together, the sustained activation of local bone RAS mediated prenatal nicotine-induced osteopenia in adult offspring via the α4ß2-nAChR-p300-ACE pathway.-Xiao, H., Wen, Y., Pan, Z., Shangguan, Y., Magdalou, J., Wang, H., Chen, L. Nicotine exposure during pregnancy programs osteopenia in male offspring rats via α4ß2-nAChR-p300-ACE pathway.


Assuntos
Doenças Ósseas Metabólicas/induzido quimicamente , Antígenos CD18/metabolismo , Integrina alfa4/metabolismo , Exposição Materna , Nicotina/administração & dosagem , Peptidil Dipeptidase A/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Feminino , Masculino , Gravidez , Ratos , Ratos Wistar
12.
Cell Death Dis ; 10(8): 581, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31378783

RESUMO

Histone arginine methylation, which is catalyzed by protein arginine methyltransferases (PRMTs), plays a key regulatory role in various biological processes. Several PRMTs are involved in skeletal development; however, their role in the osteogenic differentiation of mesenchymal stem cells (MSCs) is not completely clear. In this study, we aimed to elucidate the function of PRMT3, a type-I PRMT that catalyzes the formation of ω-mono- or asymmetric dimethyl arginine, in MSCs osteogenesis. We found that PRMT3 promoted MSCs osteogenic commitment and bone remodeling. PRMT3 activated the expression of miR-3648 by enhancing histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) levels at promoter region of the gene. Overexpression of miR-3648 rescued impaired osteogenesis in PRMT3-deficient cells. Moreover, administration of Prmt3 shRNA or a chemical inhibitor of PRMT3 (SGC707) caused an osteopenia phenotype in mice. These results indicate that PRMT3 is a potential therapeutic target for the treatment of bone regeneration and osteopenia disorders.


Assuntos
Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Osteogênese/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/genética , Regeneração Óssea/genética , Diferenciação Celular/genética , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Histonas/metabolismo , Humanos , Isoquinolinas/farmacologia , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Transfecção
13.
BMJ Case Rep ; 12(7)2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31352389

RESUMO

Fragility fractures are common in older adults and rare in children. Recent studies have demonstrated that hyponatraemia is a novel risk factor for the development of osteoporosis and hip fractures in older people. Animal studies suggest that hyponatraemia can lead to decreased bone mineral density by stimulating osteoclastic activity in order to mobilise sodium from the bone. Reported is a 16-year-old man with intractable epilepsy and an 11-year history of chronic hyponatraemia (126-135 mEq/L) due to valproic acid induced syndrome of inappropriate antidiuresis who sustained low-impact fragility fractures and had evidence of osteopaenia on both X-ray and dual energy X-ray absorptiometry (DEXA). Hyponatraemia resolved following the discontinuation of valproic acid and bone mineral density normalised on a repeat DEXA 19 months later. This case provides evidence supporting the contention that chronic hyponatraemia contributes to osteopaenia and fragility fractures and that the bone abnormalities are potentially reversible following the correction of hyponatraemia.


Assuntos
Anticonvulsivantes/efeitos adversos , Doenças Ósseas Metabólicas/induzido quimicamente , Epilepsia/tratamento farmacológico , Fraturas do Quadril/cirurgia , Hiponatremia/induzido quimicamente , Fraturas por Osteoporose/cirurgia , Ácido Valproico/efeitos adversos , Absorciometria de Fóton , Adolescente , Anticonvulsivantes/uso terapêutico , Densidade Óssea , Fixação Interna de Fraturas , Fraturas do Quadril/diagnóstico por imagem , Humanos , Hiponatremia/complicações , Masculino , Fraturas por Osteoporose/diagnóstico por imagem , Fatores de Risco , Resultado do Tratamento , Ácido Valproico/uso terapêutico
14.
Pharmacol Res ; 147: 104354, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31306774

RESUMO

Bone loss is a typical consequence of Rheumatoid Arthritis (RA). It occurs not only locally, affecting the inflamed joints (erosions), but also systemically, leading to osteopenia and/or overt osteoporosis, with increased risk of fragility fractures. This complication, often underestimated, can worsen the burden of disability in RA patients. Moreover, systemic and local bone loss are closely intertwined as osteoporosis per se can facilitate the development of erosions. A fundamental role in this process is played by the osteoimmunologic dysregulation typical of RA and other chronic inflammatory conditions. The poor response to the DMARDs, in terms of progression of bone erosions, might depend on the concomitant osteoporosis and on other determinants of bone loss. Thus, we need a deeper investigation in RA patients of bone health and effects of DMARDs on it and, eventually, a specific anti-osteoporotic treatment, other than DMARDs, for the prevention of both fragility fractures and bone erosions. The present review summarizes the most relevant evidence on systemic bone loss of biological and targeted synthetic DMARDs.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Doenças Ósseas Metabólicas/induzido quimicamente , Inibidores de Janus Quinases/efeitos adversos , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Animais , Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia
15.
Osteoporos Int ; 30(8): 1607-1616, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31053927

RESUMO

Glucorticoid (GC) therapy is the commonest cause of secondary osteoporosis. Ovariectomized rabbits receiving the GC methylprednisolone for 6 weeks exhibited relatively lower vertebral and femoral bone mass. Treatment with the PTH receptor agonist abaloparatide for 12 weeks during ongoing methylprednisolone administration increased cortical and trabecular bone mass and femur bending strength. INTRODUCTION: Abaloparatide, an osteoanabolic PTHrP analog, increases bone mineral density (BMD) and reduces fracture risk in women with postmenopausal osteoporosis. This study assessed abaloparatide effects on BMD and bone strength in ovariectomized (OVX) rabbits with glucocorticoid (GC)-induced osteopenia. METHODS: Thirty-two rabbits underwent OVX and 8 underwent sham surgery. One day later, 24 OVX rabbits began daily s.c. GC injections (methylprednisolone, 1 mg/kg/day) for 6 weeks, while 8 OVX and 8 sham controls received no GC. GC-challenged rabbits (8/group) then received GC (0.5 mg/kg/day) along with daily s.c. vehicle (GC-OVX), abaloparatide 5 µg/kg/day (ABL5), or 25 µg/kg/day (ABL25) for 12 weeks, and the no-GC OVX and sham controls received daily vehicle. RESULTS: GC-OVX rabbits showed significant deficits in vertebral and proximal femur areal BMD, lower cortical area, thickness and volumetric BMD of the femur diaphysis, and reduced trabecular bone volume and volumetric BMD in the vertebra and distal femur versus sham controls. These deficits were significantly reversed in the ABL25 group, which also showed enhanced trabecular micro-architecture versus GC-OVX controls. Destructive bending tests showed significantly lower femur diaphysis ultimate load and bending rigidity of the femoral diaphysis in the GC-OVX group versus sham controls, whereas these parameters were similar in the ABL25 group vs sham controls. CONCLUSIONS: Abaloparatide 25 µg/kg/day mitigated the adverse effects of GC administration on cortical and trabecular bone and improved femoral strength in OVX rabbits. These results suggest potential promise for abaloparatide as an investigational therapy for glucocorticoid-induced osteoporosis.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/tratamento farmacológico , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Absorciometria de Fóton , Animais , Fenômenos Biomecânicos , Conservadores da Densidade Óssea/farmacologia , Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/fisiopatologia , Feminino , Fêmur/fisiopatologia , Glucocorticoides , Vértebras Lombares/fisiopatologia , Metilprednisolona , Ovariectomia , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Coelhos , Microtomografia por Raio-X
16.
AIDS Res Hum Retroviruses ; 35(8): 746-754, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31115244

RESUMO

Both HIV infection and tenofovir disoproxil fumarate (TDF) treatment adversely impact bone metabolism and may lead to osteopenia, which has critical implications for youth with HIV (YWH). This study evaluates changes in the biomarkers of bone metabolism and inflammation among YWH receiving initial treatment with TDF- and non-TDF-containing antiretroviral therapies (ARTs). YWH [n = 23, median age 21 years (range 18-24), 87% male, 61% African American] were assessed for inflammatory and bone metabolism biomarkers at enrollment, after 48 weeks of TDF-containing ART, and 96 weeks of ART without TDF with continued viral suppression. Spearman's rank correlation evaluated biomarker associations. Bone alkaline phosphatase, parathyroid hormone, and osteopontin increased after TDF treatment. All fell after TDF was discontinued. Levels of RANKL and osteoprotegerin did not change throughout the study. There was little correlation between biomarkers of bone metabolism and either macrophage or lymphocyte activation at any time point. Our results establish baseline associations between bone metabolism and immune biomarkers for this population, and find that before CD4 T cell decline chronic inflammation does not perturb biomarkers of bone metabolism among YWH. The adverse effects of TDF on bone health may be marginal for YWH at the early stages of disease.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Tenofovir/efeitos adversos , Adolescente , Fosfatase Alcalina/análise , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/análise , Osso e Ossos/metabolismo , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Osteopontina/análise , Osteoprotegerina/análise , Hormônio Paratireóideo/análise , Ligante RANK/análise , Tenofovir/uso terapêutico , Adulto Jovem
17.
PLoS One ; 14(4): e0214153, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30939140

RESUMO

INTRODUCTION: Osteoporosis (OP) risk factor assessment and bone mineral density (BMD) testing are frequently omitted at baseline in aromatase inhibitor (AI) studies, which may lead to misinterpretation of AI associated bone loss. The present study describes bone health of South African postmenopausal women of predominantly Mixed Ancestry, prior to AI treatment. METHODS: This descriptive baseline study, nested in a prospective AI cohort study, included postmenopausal women with endocrine sensitive breast cancer, aged 50 to 80 years. A baseline questionnaire documented demographic-, medical-, lifestyle- and fracture history. Body weight was assessed clinically, and body composition and BMD measured via dual energy absorptiometry (DXA). Data was analysed in STATA 14 using descriptive and inferential statistics. RESULTS: 101 participants were recruited, with a mean age of 61±7 years. Nearly a third (n = 32) of women at baseline fulfilled global criteria for bone protection (BMD T-score ≥-2SD (n = 18); BMD T-score -1.5SD to < -2SD with risk factors (n = 14). Lower body weight, body mass index (BMI), fat mass index and lean mass index were significantly associated with the participants with a BMD measurement in keeping with a diagnosis of OP (p <0.001). Low vitamin D was present in 93% of the cohort tested (n = 95), whilst deficient vitamin D status (<20ng/ml) was documented in 52 women (55%). CONCLUSIONS: In this study, a third of postmenopausal women considered for AI therapy fulfilled international criteria for bone protective pharmacological intervention. This emphasizes the need for clinical risk and BMD assessment in postmenopausal breast cancer patients at baseline. Body composition and bone health associations highlight bone fragility associated with lower body weight.


Assuntos
Inibidores da Aromatase/efeitos adversos , Doenças Ósseas Metabólicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Fraturas Ósseas/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico , Grupo com Ancestrais do Continente Africano , Idoso , Idoso de 80 Anos ou mais , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Doenças Ósseas Metabólicas/induzido quimicamente , Osso e Ossos/efeitos dos fármacos , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Fraturas Ósseas/induzido quimicamente , Fraturas Ósseas/fisiopatologia , Nível de Saúde , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/induzido quimicamente , Osteoporose Pós-Menopausa/fisiopatologia , Pós-Menopausa/efeitos dos fármacos , Vitamina D/administração & dosagem
18.
Sci Rep ; 9(1): 3895, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846868

RESUMO

Low bone mineral density (BMD) prevails among patients with schizophrenia. Antipsychotics use plays an important role in BMD. Previous cross-section study suggests that clozapine treatment may benefit BMD of women with schizophrenia. However, the effect of long-term clozapine therapy on BMD remains unknown. This prospective study compared clozapine and non-clozapine antipsychotics in long-term effects on BMD among both men and women with schizophrenia. Patients with schizophrenia and age-matched healthy individuals were enrolled from two centers. All patients, including clozapine receivers and non-clozapine antipsychotics recipients, kept clinically stable with unchanged antipsychotics and doses for at least 6 months at enrollment and during the follow-up period. BMD was examined by dual-energy X-ray absorptiometer upon enrollment and at 1- or 3-year follow-up. Thorough clinical and laboratory variables were measured too. The mean BMD of patients receiving clozapine was higher than that of the non-clozapine patients at both enrollment and follow-up. Overall, the patients in the clozapine group gained BMD, while those in the non-clozapine group lost BMD after 1-3 years (p = 0.015). There was no significant difference of BMD change between clozapine-treated patients and healthy controls. Factors associated with BMD change in the clozapine group included calcium level (B = -0.607, p = 0.021) and T3 level (B = -0.077, p = 0.007). This longitudinal study suggests that long-term clozapine treatment may protect BMD compared to prolactin-raising and non-clozapine prolactin-sparing antipsychotics among patients with schizophrenia. Future prospective studies are warranted to testify whether switching from non-clozapine antipsychotics to clozapine can rescue BMD.


Assuntos
Antipsicóticos/farmacologia , Densidade Óssea/efeitos dos fármacos , Clozapina/farmacologia , Substâncias Protetoras/farmacologia , Esquizofrenia/tratamento farmacológico , Absorciometria de Fóton , Adulto , Fosfatase Alcalina/sangue , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Doenças Ósseas Metabólicas/induzido quimicamente , Clozapina/uso terapêutico , Estradiol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Substâncias Protetoras/uso terapêutico , Testosterona/sangue
19.
J Musculoskelet Neuronal Interact ; 19(1): 112-117, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30839309

RESUMO

BACKGROUND: HIV infection and antiretroviral therapy (ART) are associated with bone mineral loss. DXA is the gold standard method to evaluate the status of bone mineral density (BMD). However, it is not always readily available. An easy method is needed to evaluate bone quality in those infected with HIV. OBJECTIVE: To evaluate portable quantitative ultrasonometry (QUS) as an alternative technique to provide information about bone density, bone strength, and the bone turnover markers in HIV-infected people. METHODS: A total of 69 men took part (34 HIV-infected men were matched with 35 non-HIV-infected men) in the study. Bone mineral status was assessed by the Achilles quantitative ultrasonometer at the calcaneal heel. The HIV status was recorded for all HIV-infected patients. Calcium-regulating hormones and bone turnover markers were assessed in all participants. RESULTS: The mean age was 47.8±7.8 years and 49.1±6.00 years for the HIV-infected and non-infected population, respectively. The bone quality expressed as Stiffness index (SI) was reduced in HIV-infected patients. Bone turnover markers were higher in the HIV-infected patients, P1NP (ng/mL) was 48.0±14.3 vs 41.1±15.2 (P=0.057), and the (CTx)) (ng/mL) was 0.41±0.18 vs 0.29±0.11 (P=0.002). CONCLUSIONS: QUS is easy to use. Hence, QUS could be used as alternative method for screening of HIV patients for altered bone status.


Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Densidade Óssea , Doenças Ósseas Metabólicas/diagnóstico por imagem , Infecções por HIV/tratamento farmacológico , Adulto , Doenças Ósseas Metabólicas/induzido quimicamente , Osso e Ossos/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Ultrassonografia
20.
Bone ; 123: 67-75, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30905745

RESUMO

AIM: Patients with epilepsy frequently develop hyponatremia due to the treatment with antiepileptic drugs and have an increased risk of developing metabolic bone disease. Hyponatremia is known to be associated with osteoporosis. The aim of the study was to investigate the association between hyponatremia and osteoporosis in patients with epilepsy. METHOD AND MATERIAL: This cross-sectional study included patients with epilepsy from a tertiary epilepsy out-patient clinic in Denmark, who had a Dual Energy X-ray Absorptiometry scan performed and an accompanying plasma sodium (p-Na) measured prior to or a maximum of 14 days after the scan. Information regarding the patients' health and medical conditions were obtained from their medical reports. RESULTS: A total of 695 patients (females 53.8%, age 49 (34:63) years (median (quartiles)) were included. 10.4% had hyponatremia (p-Na ≤ 135 mmol/L). The hyponatremic patients had significantly lower T-scores in the lumbar spine, femoral neck and total femur (all p < 0.023) and the odds ratio of osteoporosis (T-score < -2.5) was significantly increased (2.91 (1.61-5.27) (95% confidence interval) (p = 0.001)). When adjusting for potential confounders the patients with moderate and severe hyponatremia (p-Na < 129 mmol/L) had a significantly lower mean T-score in the lumbar spine (p = 0.030). CONCLUSION: We conclude that hyponatremia is common in patients with epilepsy and that moderate and severe hyponatremia is independently associated with decreased bone mineral density in the lumbar spine. Therefore, hyponatremia in a patient with epilepsy should warrant further examination of the patient for bone loss and osteoporosis.


Assuntos
Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/epidemiologia , Epilepsia/diagnóstico por imagem , Epilepsia/epidemiologia , Hiponatremia/diagnóstico por imagem , Hiponatremia/epidemiologia , Absorciometria de Fóton/métodos , Adulto , Anticonvulsivantes/efeitos adversos , Doenças Ósseas Metabólicas/induzido quimicamente , Estudos de Coortes , Estudos Transversais , Dinamarca/epidemiologia , Epilepsia/tratamento farmacológico , Feminino , Humanos , Hiponatremia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Osteoporose/induzido quimicamente , Osteoporose/diagnóstico por imagem , Osteoporose/epidemiologia
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