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1.
J Cancer Res Clin Oncol ; 146(4): 945-951, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31980928

RESUMO

PURPOSE: Systemic mastocytosis (SM) is characterized by the expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) defined by a nearly normal life expectancy and advanced SM (AdvSM) defined by poor prognosis. In ISM, measurement of the bone mineral density (BMD) frequently reveals osteoporosis. In contrast, the clinical implication of an increased BMD and osteosclerosis remains unclear. METHODS: BMD was evaluated in 61 patients with mastocytosis (ISM, n = 29, 48%; AdvSM, n = 32, 52%). We correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters, disease variant and prognosis. RESULTS: Osteoporosis was detected in 11/29 (38%) patients with ISM but only in 2/32 (6%) patients with AdvSM (p = 0.004). An increased BMD was detected in 1/29 (3%) patients with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD had higher levels of bone marrow mast cell infiltration, higher serum tryptase and alkaline phosphatase levels compared to ISM as well as higher number of high-molecular risk mutations (p < 0.05). In addition, we found that the prognosis of AdvSM patients with increased BMD is inferior compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031). CONCLUSIONS: Osteoporosis is a common feature in ISM but not in AdvSM. An increased BMD is frequently present in AdvSM but not in ISM and is associated with more advanced disease and inferior outcome.


Assuntos
Mastocitose Sistêmica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/patologia , Estudos de Coortes , Humanos , Masculino , Mastocitose Sistêmica/sangue , Mastocitose Sistêmica/diagnóstico por imagem , Pessoa de Meia-Idade , Osteoporose/sangue , Osteoporose/diagnóstico por imagem , Osteoporose/patologia , Osteosclerose/sangue , Osteosclerose/diagnóstico por imagem , Osteosclerose/patologia , Prognóstico , Estudos Retrospectivos
2.
Int J Mol Sci ; 20(24)2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31847438

RESUMO

Patients with gastrointestinal diseases frequently suffer from skeletal abnormality, characterized by reduced bone mineral density, increased fracture risk, and/or joint inflammation. This pathological process is characterized by altered immune cell activity and elevated inflammatory cytokines in the bone marrow microenvironment due to disrupted gut immune response. Gastrointestinal disease is recognized as an immune malfunction driven by multiple factors, including cytokines and signaling molecules. However, the mechanism by which intestinal inflammation magnified by gut-residing actors stimulates bone loss remains to be elucidated. In this article, we discuss the main risk factors potentially contributing to intestinal disease-associated bone loss, and summarize current animal models, illustrating gut-bone axis to bridge the gap between intestinal inflammation and skeletal disease.


Assuntos
Doenças Ósseas Metabólicas/patologia , Osso e Ossos/patologia , Gastroenteropatias/patologia , Inflamação/patologia , Intestinos/patologia , Animais , Humanos
3.
Neurochirurgie ; 65(5): 258-263, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31562881

RESUMO

INTRODUCTION: Some metabolic bone disorders may result in the premature closure of one or more calvarial sutures during childhood, potentially leading to a cranioencephalic disproportion. The aim of this paper is to review the characteristics and consequences of craniosynostosis associated with metabolic disorder. MATERIAL AND METHODS: A review of the literature on metabolic forms of craniosynostosis was performed. RESULTS: The most common forms of craniosynostosis associated with metabolic bone disorder were isolated sagittal suture fusion with or without scaphocephaly, and sagittal suture fusion associated with coronal suture fusion (oxycephaly) or also with lambdoid suture fusion (pansynostosis). Synostosis may be well-tolerated, but in some subjects results in neurodevelopmental and functional impairment that is sometimes severe. CONCLUSION: The impact of metabolic synostosis is very variable, depending on the specific underlying metabolic disease, with a large spectrum of morphological and functional consequences. Diagnosis should be early and management should be carried out by a multidisciplinary team with expertise in both rare skeletal disorders and craniosynostosis. The impact of emergent medical therapies recently developed for some of these diseases will be assessed by systematic coherent follow-up of international registries.


Assuntos
Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/patologia , Craniossinostoses/etiologia , Craniossinostoses/patologia , Suturas Cranianas/patologia , Humanos , Minerais/metabolismo , Mucopolissacaridoses/complicações , Mucopolissacaridoses/patologia , Raquitismo/complicações
4.
Klin Lab Diagn ; 64(7): 417-423, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31408594

RESUMO

Recently, they increasingly began to pay attention to the role of a nonspecific immune-inflammatory vascular response as a link in general pathogenetic mechanisms with a change in the elastic properties of arteries and phenomena of destructive bone changes, which at the subclinical level is of great importance for the prevention of the development of socially significant diseases. A total of 104 patients were examined (mean age 57.45 years), which were divided into three groups. The first group included 39 healthy women, the second group included 30 patients with hypertension and osteopenia, and the third group included 35 women with hypertension and osteoporosis. The analysis of markers of the immune inflammatory response, endothelial dysfunction, hormonal and mineral-vitamin status parameters was conducted against the background of the study of parameters of daily monitoring of arterial pressure, study of parameters of vascular wall stiffness and densitometry to clarify the predictors of cardiovascular and degenerative bone changes in postmenopausal women. A significant increase in the concentration of HF-CRP, the level of homocystemine, IL-8, parathyroid hormone, against the background of a significant decrease in the level of estrogen, progesterone, testosterone, with a persistent tendency to increase in total cholesterol, atherogenic lipid fractions, myeloperoxidase, endothelin-1 and decrease was recorded calcitonin, total and ionized calcium, with a significantly minimal value of vitamin D in the 3rd group of patients. The risks of development and progression of bone destructive changes were calculated using the logistic regression method for the group of AH with osteopenia and osteoporosis. Thus, for patients with hypertension and osteopenia, a significantly significant parameter associated with the risk of developing osteoporosis was an indicator of the velocity of the pulse wave, an increase in the level of which exceeds 12.05 m/s is associated with an increased risk of developing osteoporosis by 3.8 times. Increased levels of pro-inflammatory parameters, IL-6 and 8, TNF-α, HB-SRB, parathyroid hormone and reduced levels of progesterone and IL10, took the most active part in aggravating the degree of available bone tissue destruction. Timely specialized multidirectional study of biochemical and instrumental parameters (in particular, the study of the speed of the pulse wave and densitometry) can be the basis for the development of personalized prevention and treatment tactics for women in order to prevent socially dangerous cardiovascular and bone complications.


Assuntos
Hipertensão/patologia , Inflamação/patologia , Osteoporose/patologia , Densidade Óssea , Doenças Ósseas Metabólicas/imunologia , Doenças Ósseas Metabólicas/patologia , Osso e Ossos , Estudos de Casos e Controles , Citocinas/sangue , Feminino , Hormônios/sangue , Humanos , Hipertensão/imunologia , Pessoa de Meia-Idade , Osteoporose/imunologia , Pós-Menopausa
5.
J Zoo Wildl Med ; 50(2): 447-452, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31260212

RESUMO

Giant South American turtles (Podocnemis expansa) are at a risk of extinction because of the rapid decline in their population over the last few decades. Metabolic bone disease (MBD) is common in captive testudines, but is often not diagnosed until a later stage. The authors present the cases of four captive giant South American turtles with carapace deformity secondary to MBD that underwent computed tomography (CT) scans of the carapace bones and vertebral column. Findings indicative of changes in geometry were found in both. The cancellous bone pattern was characterized by varying degrees of increased trabecular spacing and cortical thinning of the pleural bones. Bone densitometry analysis of the pleural and neural bones and at the level of the body of the third, fourth, and fifth dorsal vertebrae showed mean density values much lower than those found in two adult specimens of the same species that were considered healthy. In conclusion, CT contributed important information on the degree of demineralization and possible structural changes due to MBD and should be considered a relevant tool for diagnosis of this condition.


Assuntos
Densidade Óssea/fisiologia , Doenças Ósseas Metabólicas/veterinária , Tomografia Computadorizada por Raios X/veterinária , Tartarugas , Animais , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/patologia , Feminino , Masculino
7.
Pediatr Dermatol ; 36(5): 732-734, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31215057

RESUMO

We describe a 4-week-old baby boy who presented with white firm cutaneous nodules and failure to thrive. He did not have dysmorphic features, and laboratory tests including serum calcium, phosphorous, thyroid function, and parathyroid hormone level were within normal ranges. Whole exome sequencing revealed an inactivating mutation in GNAS that was previously described as causing pseudohypoparathyroidism.


Assuntos
Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/patologia , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Mutação/genética , Ossificação Heterotópica/genética , Ossificação Heterotópica/patologia , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/patologia , Humanos , Recém-Nascido , Masculino
8.
Osteoporos Int ; 30(9): 1893-1896, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147735

RESUMO

We describe a novel disease of diffuse skeletal histiocytosis associated with multiple fragility fractures and high osteoclast activity. Clinical, radiographic, biochemical, genetic, and histopathological investigations were performed to characterize the diagnosis of an Asian man who presented with hip fracture and diffuse skeletal lytic lesions. After excluding malignancy and other common metabolic bone diseases, open bone biopsy yielded several pathological samples all showing extensive skeletal histiocytosis likely to explain the diffuse axial and appendicular lytic lesions. Rare disorders such as Langerhans histiocytosis, Erdheim-Chester disease, and diffuse cystic skeletal angiomatosis were excluded through careful pathological examination and lack of CD1a and S-100 staining. Whole exome sequencing did not yield diagnostic findings to explain this likely acquired disease. High markers of osteoclast activity suggested excessive focal bone resorption but normalized after zoledronic acid treatment. A novel disease of skeletal histiocytosis with high bone turnover is differentiated from other histiocytic and lytic skeletal diseases.


Assuntos
Doenças Ósseas Metabólicas/diagnóstico , Fraturas Espontâneas/diagnóstico , Histiocitose/diagnóstico , Doenças Ósseas Metabólicas/patologia , Diagnóstico Diferencial , Fraturas Espontâneas/patologia , Histiocitose/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Recidiva
9.
PLoS One ; 14(5): e0216428, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31050690

RESUMO

INTRODUCTION: Sandblasting is one of the oldest implant surface modifications to enhance osseointegration. Regarding its superiority over machined surface controversies still exist. Our objective was to compare implant failures (IF) and marginal bone level (MBL) changes between sandblasted and machined dental implants by a meta-analysis utilizing the available data. The PROSPERO registration number of the meta-analysis is CRD42018084190. METHODS: The systematic search was performed in Cochrane, Embase and Pubmed. Inclusion criteria included participants with neither systemic diseases, nor excessive alcohol consumption, nor heavy smoking. We calculated pooled Risk Ratio (RRs) with confidence intervals of 95% (CIs) for dichotomous outcomes (implant failure) and weighted mean difference (WMD) CIs of 95% for continuous outcomes (marginal bone level change). We applied the random effect model with DerSimonian-Laird estimation. I2 and chi2 tests were used to quantify statistical heterogeneity and gain probability-values, respectively. RESULTS: Literature search revealed 130 records without duplicates. Out of these, seven studies met the inclusion criteria and all were included in data synthesis, involving 362 sand-blasted and 360 machined implants. The results indicate that there is an 80% (RR = 0.2 95% CI:0.06-0.67; I2 = 0.0% p = 0.986) lower among sandblasted compared to machined implants after one year of use and 74% (RR = 0.26 95% CI:0.09-0.74; I2 = 0.0% p = 0.968) five years of use, respectively. In contrast, there is no significant difference in MBL (WMD:-0.10mm, 95% CI:-0.20, 0.01; p>0.05; I2 = 0.0%, p = 0.560 and WMD:-0.01mm, 95% CI:-0.12, 0.09; p>0.05; I2 = 26.2%, p = 0.258) between the two implant surfaces after one and five years of use. CONCLUSIONS: This meta-analysis reveals that sandblasting is superior over machined surface in implant failure but not in marginal bone level in healthy subjects. It also points out the need for further randomized clinical trials with large sample size for objective determination of the clinical benefits of certain implant surface modifications.


Assuntos
Implantação Dentária Endo-Óssea/efeitos adversos , Implantes Dentários/efeitos adversos , Falha de Restauração Dentária , Osseointegração , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Humanos
11.
Phytother Res ; 33(4): 1233-1240, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30907034

RESUMO

French maritime pine bark extract (FMPBE; Oligopin®), a dietary supplement, is rich in procyanidin. The objective of this study was to determine the effects of FMPBE on bone remodeling in postmenopausal osteopenic women. This randomized, double-blinded, placebo-controlled clinical trial was conducted on 40 postmenopausal osteopenic women. Individuals were randomly assigned to either FMPBE (250 mg/day, n = 21) or placebo (250-mg starch/day, n = 19) for 12 weeks. Biochemical indices, including bone remodeling marker, were assessed before and after the intervention. After the 12-week intervention, that is, FMPBE supplementation, a significant increase in bone alkaline phosphatase (BAP), procollagen type 1 amino-terminal propeptide (P1NP) levels and a significant decrease in C-terminal telopeptide of type I collagen (CTx1) were observed. Compared with the control group, FMPBE supplementation resulted in a significant increase in P1NP (0.015), BAP levels (0.001), and BAP/CTx1 ratio (p = 0.001) and a significant decrease in CTx1 levels (0.006). FMPBE supplementation for 12 weeks in postmenopausal osteopenic women produced favorable effects on bone markers. Meanwhile, further research is needed to determine whether FMPBE supplements can be used as a preventive strategy for bone loss in postmenopausal osteopenic women.


Assuntos
Doenças Ósseas Metabólicas/tratamento farmacológico , Remodelação Óssea/efeitos dos fármacos , Suplementos Nutricionais/análise , Osteoporose Pós-Menopausa/tratamento farmacológico , Polifenóis/uso terapêutico , Idoso , Doenças Ósseas Metabólicas/patologia , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Polifenóis/farmacologia
12.
Endokrynol Pol ; 70(3): 248-254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30845341

RESUMO

INTRODUCTION: The primary objective of this study was to explore the association of pro-inflammatory cytokines with quantitative computed tomography (QCT)-measured bone mineral density (BMD) and its sexual difference in a Chinese population. MATERIAL AND METHODS: In a cross-sectional study, a total of 85 participants aged 48-85 years were recruited and classified into three groups: normal bone mass with BMD > 120 mg/cm³, osteopaenia with BMD 80-120 mg/cm³, and osteoporosis with BMD < 80 mg/cm³. ANOVA analysis and multivariable ordinal logistic regression was used to estimate the associations of interest. RESULTS: The proportions of osteoporosis, osteopaenia, and normal BMD were 29.41% (25), 37.65% (32), and 32.94% (28), respectively. Males had the highest proportion of osteopaenia while females had osteoporosis (p < 0.01). In contrast with the null findings in males, significant statistical difference was observed in females. Compared to the normal BMD, the OR for increasing IL-6 level of decreasing BMD groups (osteoporosis and/or osteopaenia) was 9.50 (95% CI: 1.44-62.80). TNF-a and IL-17 tended to show an increased risk (OR > 1) but did not reach significance. Current OR result cannot confirm these relationships of IL-1b, and ORs of PAI-1 and MCP-1 are too close to 1 to determine the practical meaning. CONCLUSIONS: IL-6 is an obviously independent risk factor of QCT-measured osteoporosis in Chinese females. Sex hormones and fat-related factors are important confounders in the research of osteoimmunology.


Assuntos
Densidade Óssea , Citocinas/sangue , Inflamação , Osteoporose/sangue , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/epidemiologia , Doenças Ósseas Metabólicas/patologia , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/epidemiologia , Osteoporose/patologia , Projetos Piloto , Fatores Sexuais , Tomografia Computadorizada por Raios X
13.
Am J Pathol ; 189(4): 753-761, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30664862

RESUMO

Glucocorticoid-induced secondary osteoporosis is the most predictable side effect of this anti-inflammatory. One of the main mechanisms by which glucocorticoids achieve such deleterious outcome in bone is by antagonizing Wnt/ß-catenin signaling. Sclerostin, encoded by Sost gene, is the main negative regulator of the proformative and antiresorptive role of the Wnt signaling pathway in the skeleton. It was hypothesized that the partial inactivation of sclerostin function by genetic manipulation will rescue the osteopenia induced by high endogenous glucocorticoid levels. Sost-deficient mice were crossed with an established mouse model of excess glucocorticoids, and the effects on bone mass and structure were evaluated. Sost haploinsufficiency did not rescue the low bone mass induced by high glucocorticoids. Intriguingly, the critical manifestation of Sost deficiency combined with glucocorticoid excess was sporadic, sudden, unprovoked, and nonconvulsive death. Detailed histopathologic analysis in a wide range of tissues identified peracute hemopericardium and cardiac tamponade to be the cause. These preclinical studies reveal outcomes with direct relevance to ongoing clinical trials that explore the use of antisclerostin antibodies as a treatment for osteoporosis. They particularly highlight a potential for increased cardiovascular risk and may inform improved stratification of patients who might otherwise benefit from antisclerostin antibody treatment.


Assuntos
Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/etiologia , Tamponamento Cardíaco/etiologia , Glucocorticoides/toxicidade , Haploinsuficiência , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Animais , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Tamponamento Cardíaco/metabolismo , Tamponamento Cardíaco/patologia , Modelos Animais de Doenças , Feminino , Marcadores Genéticos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Via de Sinalização Wnt
14.
Ultrasonics ; 94: 109-116, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30660337

RESUMO

PURPOSE: Axial transmission quantitative acoustics (ax-QA) has shown to be a promising tool for assessing bone health and properties in a safe, inexpensive, and portable manner. This study investigated the efficacy of low-frequency ax-QA measured at the tibia, paired with a support vector machine (SVM) approach for combining multiple acoustic indicators, to diagnose osteoporosis as defined by bone mineral density. METHODS: This pilot study measured 41 female subjects using ax-QA (flexural mode, 3 kHz) at the tibia and using dual X-ray absorptiometry (DXA) at the lumbar spine, femoral neck, and distal radius. For each location, a threshold classifier and SVM were trained to differentiate between healthy and non-healthy subjects based on the phase velocity at different frequencies. Receiver Operating Characteristics and area under curve values (AUC) were used to assess the classifiers' performances for various thresholds and class-weights. RESULTS: The SVM outperformed the threshold classifier for all three bone locations at low false positive rates. While differentiation between healthy and non-healthy bone states was poor for the spine (AUC: 0.56 ±â€¯0.04), good to moderate performances were observed for the radius (AUC: 0.83 ±â€¯0.03) and hip (AUC: 0.71 ±â€¯0.04). CONCLUSIONS: Low-frequency ax-QA has demonstrated potential for complementing DXA in screening for osteoporosis at the radius and hip. Through further addition of acoustic indicators ax-QA could provide a diagnostic alternative in third-world countries, and bring bone health screening and monitoring into the hands of clinicians and general health practitioners everywhere.


Assuntos
Doenças Ósseas Metabólicas/diagnóstico por imagem , Osteoporose/diagnóstico por imagem , Máquina de Vetores de Suporte , Tíbia/diagnóstico por imagem , Ultrassom/instrumentação , Absorciometria de Fóton , Adulto , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Doenças Ósseas Metabólicas/patologia , Diagnóstico Diferencial , Feminino , Colo do Fêmur/diagnóstico por imagem , Humanos , Vértebras Lombares/diagnóstico por imagem , Pessoa de Meia-Idade , Osteoporose/patologia , Projetos Piloto , Rádio (Anatomia)/diagnóstico por imagem , Tíbia/patologia
16.
J Pediatr Endocrinol Metab ; 32(1): 65-70, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30511932

RESUMO

Background It is known that thyroid hormones have effects on bone development. In particular, the effect of thyroid hormones on osteopenia of prematurity (OOP) has not been examined in preterm infants. Our study aimed to examine the relationship between OOP and congenital hypothyroidism (CH) in preterm infants. Methods Very low birth weight infants (VLBW, <1500 g) were included in the study. Thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels were measured on postnatal day 5. Serum calcium, phosphorus and alkaline phosphatase (ALP) levels were studied as standard screening parameters for OOP at postnatal week 4. Patients with serum ALP level >700 IU/L were included in the OOP group. We intended to figure out the relationship between OOP and CH in infants. Results In our study, OOP frequency was 14.9% among 543 VLBW infants. There was no statistically significant difference between groups with and without CH (21.7% and 14.8%, respectively) in terms of OOP (p=0.632). Gestational age (GA) was significantly lower in infants with diagnosed OOP (p<0.001, p<0.001, respectively). In addition, the prevalence rates of mothers with preeclampsia, small for gestational age (SGA), respiratory support requirement, late-onset neonatal sepsis (LOS), bronchopulmonary dysplasia (BPD) and full enteral feeding time were found to be higher in the OOP group (p<0.05). Conclusions We found that thyroid hormones had no effect on OOP in preterm infants. Therefore, future randomized controlled studies as well as long-term outcome studies are warranted on this topic.


Assuntos
Doenças Ósseas Metabólicas/etiologia , Hipotireoidismo Congênito/complicações , Doenças do Prematuro/etiologia , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Glândula Tireoide/fisiopatologia , Doenças Ósseas Metabólicas/patologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Doenças do Prematuro/patologia , Masculino , Gravidez , Prognóstico , Estudos Retrospectivos , Testes de Função Tireóidea
17.
J Steroid Biochem Mol Biol ; 186: 66-73, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30253225

RESUMO

Two novel 1α,25-dihydroxyvitamin D3 derivatives containing a α,α-difluorocyclopentanone (3) or α,α-difluorocyclohexanone (4) moiety at the CD-ring side chains were designed, synthesized, and evaluated for their biological properties on restoring bone mass in ovariectomized (OVX) rats with established osteopenia. The synthesis of compounds 3 and 4 utilized the Wittig-Horner coupling to build up the vitamin D conjugated triene system, followed by the introduction of the cycloketone fragments at the side chain, and subsequent α,α-difluorination of the ketone by the treatment of the derived silyl enol ether with Selectfluor, as the key synthetic steps. In comparison with the natural 1α,25-dihydroxyvitamin D3 (calcitriol; 200 ng/kg/day), oral administration of compounds 3 and 4 at the dose of 25 ng/kg/day for 6 weeks led to much improved bone mass and bone density related parameters, while maintaining normal serum calcium and serum phosphorus levels. The immunohistochemistry results showed that both compounds remarkably decreased in osteoclast number and moderately decreased in osteoblast number on trabecular bone surface. Therefore, our findings suggested that compounds 3 and 4 successfully rescue bone loss by suppression on bone turnover in OVX rat models.


Assuntos
Doenças Ósseas Metabólicas/tratamento farmacológico , Vitamina D/análogos & derivados , Vitaminas/química , Vitaminas/uso terapêutico , Animais , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/patologia , Doenças Ósseas Metabólicas/fisiopatologia , Cálcio/sangue , Feminino , Halogenação , Osteogênese/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Wistar , Vitamina D/síntese química , Vitamina D/química , Vitamina D/uso terapêutico , Vitaminas/síntese química
18.
FASEB J ; 33(3): 3330-3342, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30383451

RESUMO

Rheumatoid arthritis (RA) is an inflammatory joint disease that eventually leads to permanent bone and cartilage destruction. Fas has already been established as the regulator of inflammation in RA, but its role in bone formation under arthritic conditions is not completely defined. The aim of this study was to assess the effect of Fas inactivation on the bone damage during murine antigen-induced arthritis. Subchondral bone of wild-type (WT) and Fas-knockout (Fas-/-) mice was evaluated by histomorphometry and microcomputerized tomography. Proportions of synovial bone and cartilage progenitors were assessed by flow cytometry. Synovial bone and cartilage progenitors were purified by fluorescence-activated cell sorting and expression of Fas and Fas-induced apoptosis were analyzed in vitro. Results showed that Fas-/- mice developed attenuated arthritis characterized by preserved epiphyseal bone and cartilage. A proportion of the earliest CD200+ bone and cartilage progenitors was reduced in WT mice with arthritis and was unaltered in Fas-/- mice. During osteoblastic differentiation in vitro, CD200+ cells express the highest levels of Fas and are removed by Fas ligation. These results suggest that Fas-induced apoptosis of early CD200+ osteoprogenitor population represents potential mechanism underlying the impaired bone formation in arthritis, so their preservation may represent the bone-protective mechanism during arthritis.-Lazic Mosler, E., Lukac, N., Flegar, D., Fadljevic, M., Radanovic, I., Cvija, H., Kelava, T., Ivcevic, S., Sucur, A., Markotic, A., Katavic, V., Marusic, A., Grcevic, D., Kovacic, N. Fas receptor induces apoptosis of synovial bone and cartilage progenitor populations and promotes bone loss in antigen-induced arthritis.


Assuntos
Antígenos/metabolismo , Apoptose/fisiologia , Artrite Reumatoide/metabolismo , Osso e Ossos/metabolismo , Cartilagem/metabolismo , Células-Tronco/metabolismo , Membrana Sinovial/metabolismo , Receptor fas/metabolismo , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Osso e Ossos/fisiologia , Cartilagem/fisiologia , Células Cultivadas , Feminino , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Membrana Sinovial/patologia
19.
Toxicol Appl Pharmacol ; 363: 1-10, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30423288

RESUMO

This study was aimed to investigate whether and how prenatal caffeine exposure (PCE) could induce osteopenia in the adult offspring. Pregnant rats were treated with prenatal caffeine 12 mg/100 g body weight per day from pregnant day 9 to 20, while rat bone marrow mesenchymal stem cells (BMSCs) were treated with exogenous corticosterone during osteogenic induction. Shorter femur and primary ossification center was observed in the PCE offspring, as well as less bone trabecular and poor biomechanical intensity. Local gene expression of glucocorticoid receptor (GR) and angiotensin converting enzyme (ACE), as well as angiotensin 2 content, was found to be stimulated, while the expression of bone gamma-carboxyglutamate protein (BGLAP), alkaline phosphatase (ALP) and bone sialoprotein (BSP) was found to be suppressed, with hypomethylation of ACE promoter. Corticosterone (1250 nM) suppressed osteogenic differentiation of BMSCs and gene expression of BGLAP, ALP and BSP, which was attenuated by enalapril, while it stimulated ACE mRNA expression and induced hypomethylation of ACE promoter, which was attenuated by mifepristone. It indicated that PCE caused bone growth retardation and adult osteopenia in offspring, which might be triggered by the activation of local RAS induced by excessive maternal glucocorticoid, while the hypomethylation of ACE gene might be the key point of the sustained activation of the local RAS.


Assuntos
Doenças Ósseas Metabólicas/induzido quimicamente , Cafeína/efeitos adversos , Glucocorticoides/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Sistema Renina-Angiotensina/fisiologia , Animais , Doenças Ósseas Metabólicas/patologia , Células da Medula Óssea , Osso e Ossos/fisiologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/fisiologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Masculino , Células-Tronco Mesenquimais , Osteogênese/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Cultura Primária de Células , Ratos , Ratos Wistar , Receptores de Glucocorticoides/metabolismo , Organismos Livres de Patógenos Específicos
20.
Int J Paleopathol ; 24: 293-298, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30154045

RESUMO

Paget's disease of bone (PDB) is a metabolic bone disease that has been present in human populations for over 2000 years, with the earliest cases reported in Western Europe. Now present globally, PDB is one of the most common metabolic bone diseases in modern populations. This study details possible PDB of an adult male (MNR-EN Skull 3) with abnormally thickened cranial bones (17 mm). The skull was recovered from commingled skeletal remains excavated from the Robebus crypt at the Byzantine monastery of Mount Nebo, Jordan (c. late 4-7th C). Micro-CT imaging and histological sections of the bone samples revealed an abnormal pattern of bone remodeling, with atypical osteon formation, convoluted and enlarged trabeculae, and an overall pattern of highly vascularized bone. Polarized microscopy produced a mix of woven bone and lamellar bone, the mosaic pattern of atypical bone remodeling indicative of PDB. Coupled with the dense, thickened nature of the vault bones, these data suggest that the individual had PDB. To our knowledge, this represents the earliest evidence of PDB in the Middle East supported by micro-analysis, and adds to the emerging paleopathological literature involving commingled skeletal remains and the potential for identifying unique disease processes.


Assuntos
Doenças Ósseas Metabólicas/epidemiologia , Osteíte Deformante/epidemiologia , Adulto , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/história , Doenças Ósseas Metabólicas/patologia , Remodelação Óssea , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , História Antiga , História Medieval , Humanos , Jordânia/epidemiologia , Osteíte Deformante/diagnóstico por imagem , Osteíte Deformante/história , Osteíte Deformante/patologia , Crânio/diagnóstico por imagem , Crânio/patologia , Microtomografia por Raio-X
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