RESUMO
Nicotine is developmentally toxic. Prenatal nicotine exposure (PNE) affects the development of multiple fetal organs and causes susceptibility to a variety of diseases in offspring. In this study, we aimed to investigate the effect of PNE on cartilage development and osteoarthritis susceptibility in female offspring rats. Wistar rats were orally gavaged with nicotine on days 9-20 of pregnancy. The articular cartilage was obtained at gestational day (GD) 20 and postnatal week (PW) 24, respectively. Further, the effect of nicotine on chondrogenic differentiation was explored by the chondrogenic differentiation model in human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs). The PNE group showed significantly shallower Safranin O staining and lower Collagen 2a1 content of articular cartilage in female offspring rats. Further, we found that PNE activated pyroptosis in the articular cartilage at GD20 and PW24. In vitro experiments revealed that nicotine inhibited chondrogenic differentiation and activated pyroptosis. After interfering with nod-like receptors3 (NLRP3) expression by SiRNA, it was found that pyroptosis mediated the chondrogenic differentiation inhibition of WJ-MSCs induced by nicotine. In addition, we found that α7-nAChR antagonist α-BTX reversed nicotine-induced NLRP3 and P300 high expression. And, P300 SiRNA reversed the increase of NLRP3 mRNA expression and histone acetylation level in its promoter region induced by nicotine. In conclusion, PNE caused chondrodysplasia and poor articular cartilage quality in female offspring rats. PNE increased the histone acetylation level of NLRP3 promoter region by α7-nAChR/P300, which resulting in the high expression of NLRP3. Further, NLRP3 mediated the inhibition of chondrogenic differentiation by activating pyroptosis.
Assuntos
Cartilagem Articular , Células-Tronco Mesenquimais , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nicotina , Efeitos Tardios da Exposição Pré-Natal , Piroptose , Ratos Wistar , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Nicotina/farmacologia , Nicotina/toxicidade , Feminino , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Gravidez , Piroptose/efeitos dos fármacos , Ratos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Condrogênese/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Humanos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/citologiaRESUMO
AIMS: Amoxicillin is a broad-spectrum beta-lactam antibiotic used to treat infectious diseases in pregnant women. Studies have shown that prenatal amoxicillin exposure (PAmE) has developmental toxicity on fetal development. However, the effect of PAmE on long bone development has not been reported. This study aimed to investigate the "toxic window" of PAmE on long bone development and explore its possible mechanism in fetal mice. MATERIALS AND METHODS: Pregnant mice were administered amoxicillin by gavage at different stages (gestational day (GD)10-12 and GD16-18), different doses (150 and 300 mg/kg·d) and different courses (single and multiple courses). Fetal femurs were collected at GD18 and bone development related indicators were detected. KEY FINDINGS: The results showed that PAmE significantly reduced the length of the femur and primary ossification center of fetal mice, and inhibited the development of fetal growth plate. Meanwhile, PAmE inhibited the development of bone marrow mesenchymal stem cells, osteoclasts and endothelial cells in fetal long bone. Further, we found the fetal long bone developmental toxicity induced by PAmE was most significant at late-pregnancy (GD16-18), high dose (300 mg/kg·d) and multiple-course group. Besides, PAmE inhibited the expression of Wnt/ß-catenin signaling pathway in fetal long bone. The ß-catenin mRNA expression was significantly positively correlated with the development indexes of fetal long bone. SIGNIFICANCE: PAmE has toxic effects on long bone development, and there was an obvious "toxic window" of PAmE on the long bone development in fetal mice. The Wnt/ß-catenin signaling pathway may mediate PAmE-induced fetal long bone development inhibition.
Assuntos
Amoxicilina , Antibacterianos , Desenvolvimento Ósseo , Via de Sinalização Wnt , Animais , Feminino , Gravidez , Camundongos , Amoxicilina/toxicidade , Desenvolvimento Ósseo/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Antibacterianos/toxicidade , Desenvolvimento Fetal/efeitos dos fármacos , Fêmur/efeitos dos fármacos , Fêmur/embriologia , Osteogênese/efeitos dos fármacos , beta Catenina/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Masculino , Feto/efeitos dos fármacosRESUMO
BACKGROUND: In cases where the upper arm exhibits an irregular cylindrical appearance with subcutaneous fat concentrated primarily in the posterior lateral aspect, traditional localized fat suction techniques may lead to uneven or disharmonious results when addressing this concern. Many practitioners have turned to circumferential fat suction methods using multi-incision approaches to ensure effective results and fat removal. However, these methods often involve numerous incisions and complex procedures, necessitating the development of new, more efficient surgical techniques. METHODS: We collected and screened patients who underwent upper arm circumferential liposuction with a double incision technique at our hospital from October 2020 to February 2023. A total of 496 cases were included in our retrospective analysis, in which we examined factors such as the length of surgery, arm circumference before and after surgery, subcutaneous tissue thickness before and after surgery, fat suction volume, postoperative satisfaction, and postoperative complications of the patients. RESULTS: The average length of surgery was 71.7 min. 458 cases (92.3%) showed significant improvement, 23 cases (4.6%) reported satisfaction, and 10 cases (2.0%) were essentially satisfied. Additionally, 339 cases (68.3%) experienced an improvement in skin laxity. Four cases (0.8%) developed localized hard nodules with slight tenderness in the early postoperative period, which resolved without special treatment after observation and follow-up for 1-3 months. Three cases (0.6%) reported localized pain or numbness, and they were given oral medication. Their symptoms disappeared after 1-3 months of observation and follow-up. Three cases (0.6%) had localized pain or numbness, and their symptoms disappeared. All of these cases improved and resolved after one month of taking mecobalamin tablets. There were also three cases (0.6%) with mild pigmentation of the incision and two cases (0.4%) with mild limitation of unilateral upper arm abduction movement. However, upper arm activities were not affected after three months to one year of follow-up. No serious complications were reported, resulting in an overall satisfaction rate of 99.0%. CONCLUSION: The double incision upper arm liposuction is safe, effective, time-saving, with high satisfaction and fewer complications, and is worthy of clinical popularization and application. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of contents or the online Instructions to Authors www.springer.com/00266 .
Assuntos
Braço , Lipectomia , Satisfação do Paciente , Humanos , Lipectomia/métodos , Estudos Retrospectivos , Feminino , Adulto , Masculino , Braço/cirurgia , Pessoa de Meia-Idade , Resultado do Tratamento , Satisfação do Paciente/estatística & dados numéricos , Estética , Adulto Jovem , Gordura Subcutânea/cirurgia , Duração da Cirurgia , Estudos de CoortesRESUMO
Chondrodysplasia is closely associated with low birth weight and increased susceptibility to osteoarthritis in adulthood. Prenatal prednisone exposure (PPE) can cause low birth weight; however, its effect on offspring cartilage development remains unexplored. Herein, rats are administered clinical doses of prednisone intragastrically on gestational days (GDs) 0-20 and underwent long-distance running during postnatal weeks (PWs) 24-28. Knee cartilage is assayed for quality and related index changes on GD20, PW12, and PW28. In vitro experiments are performed to elucidate the mechanism. PPE decreased cartilage proliferation and matrix synthesis, causing offspring chondrodysplasia. Following long-distance running, the PPE group exhibited more typical osteoarthritis-like changes. Molecular analysis revealed that PPE caused cartilage circRNomics imbalance in which circGtdc1 decreased most significantly and persisted postnatally. Mechanistically, prednisolone reduced circGtdc1 expression and binding with Srsf1 to promote degradation of Srsf1 via K48-linked polyubiquitination. This further inhibited the formation of EDA/B+Fn1 and activation of PI3K/AKT and TGFß pathways, reducing chondrocyte proliferation and matrix synthesis. Finally, intra-articular injection of offspring with AAV-circGtdc1 ameliorated PPE-induced chondrodysplasia, but this effect is reversed by Srsf1 knockout. Altogether, this study confirms that PPE causes chondrodysplasia and susceptibility to osteoarthritis by altering the circGtdc1-Srsf1-Fn1 axis; in vivo, overexpression of circGtdc1 can represent an effective intervention target for ameliorating PPE-induced chondrodysplasia.
Assuntos
Osteoartrite , Prednisona , Efeitos Tardios da Exposição Pré-Natal , RNA Circular , Transdução de Sinais , Animais , Feminino , Gravidez , Ratos , Modelos Animais de Doenças , Osteoartrite/induzido quimicamente , Osteoartrite/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos Sprague-Dawley , RNA Circular/administração & dosagem , Fatores de Processamento de Serina-Arginina/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Autophagy inhibition is known to be involved in the development of adult osteoarthritis. Dexamethasone, as a synthetic glucocorticoid, is widely used for premature delivery and related pregnancy diseases in clinics. We have previously shown that prenatal dexamethasone exposure (PDE) was associated with increased susceptibility to postnatal osteoarthritis in offspring. However, whether the occurrence of fetal-originated adult osteoarthritis induced by PDE is related to autophagy remains unclear. In this study, we first found that PDE could increase the mRNA and protein expression of cartilage matrix-degrading enzymes (MMP3, MMP13, and ADAMTS5) and decrease the cartilage matrix contents in adult offspring, and the in vitro results suggested that this might be related to the autophagy inhibition of chondrocytes. Further, we demonstrated a persistent autophagy inhibition with autolysosome accumulation, low expression of cathepsin D (CTSD), increased H3K9ac level, and expression of miR-1912-3p in the cartilage of PDE offspring from fetus to adulthood. In vitro experiments showed that dexamethasone inhibited autophagy flux and CTSD expression in fetal chondrocytes, while overexpression of CTSD could alleviate the inhibition of autophagic flux induced by dexamethasone. Finally, we confirmed that dexamethasone increased the H3K9ac level and expression of miR-1912-3p through activation of the glucocorticoid receptor (GR), resulting in the decreased expression of CTSD and inhibition of autophagy flux in fetal chondrocytes. In conclusion, intrauterine miR-1912-3p/CTSD programming-mediated autophagy inhibition promoted the susceptibility to osteoarthritis in PDE adult offspring rats. This study provides new ideas for exploring early prevention and therapeutic targets in fetal-originated osteoarthritis.
Assuntos
MicroRNAs , Osteoartrite , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Humanos , Feminino , Ratos , Masculino , Animais , Ratos Wistar , Catepsina D , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Osteoartrite/induzido quimicamente , Osteoartrite/genética , Osteoartrite/metabolismo , Dexametasona/toxicidade , MicroRNAs/genética , AutofagiaRESUMO
BACKGROUND: Osteoporosis is a degenerative disease characterized by reduced bone mass, with low peak bone mass being the predominant manifestation during development and having an intrauterine origin. Pregnant women at risk of preterm delivery are commonly treated with dexamethasone to promote fetal lung development. However, pregnant dexamethasone exposure (PDE) can lead to reduced peak bone mass and susceptibility to osteoporosis in offspring. In this study, we aimed to investigate the mechanism of PDE-induced low peak bone mass in female offspring from the perspective of altered osteoclast developmental programming. METHODS: 0.2 mg/kg.d dexamethasone was injected subcutaneously into rats on gestation days (GDs) 9-20. Some pregnant rats were killed at GD20 to remove fetal rat long bones, the rest were delivered naturally, and some adult offspring rats were given ice water swimming stimulation for two weeks. RESULTS: The results showed that the fetal rat osteoclast development was inhibited in the PDE group compared with the control group. In contrast, the adult rat osteoclast function was hyperactivation with reduced peak bone mass. We further found that the promoter region methylation levels of lysyl oxidase (LOX) were decreased, the expression was increased, and the production of reactive oxygen species (ROS) was raised in PDE offspring rat long bone before and after birth. Combined in vivo and in vitro experiments, we confirmed that intrauterine dexamethasone promoted the expression and binding of the glucocorticoid receptor (GR) and estrogen receptor ß (ERß) in osteoclasts and mediated the decrease of LOX methylation level and increase of expression through upregulation of 10-11 translocator protein 3 (Tet3). CONCLUSIONS: Taken together, we confirm that dexamethasone causes osteoclast LOX hypomethylation and high expression through the GR/ERß/Tet3 pathway, leading to elevated ROS production and that this intrauterine epigenetic programming effect can be carried over to postnatal mediating hyperactivation in osteoclast and reduced peak bone mass in adult offspring. This study provides an experimental basis for elucidating the mechanism of osteoclast-mediated intrauterine programming of low peak bone mass in female offspring of PDE and for exploring its early targets for prevention and treatment. Video Abstract.
Assuntos
Dexametasona , Osteoporose , Humanos , Ratos , Gravidez , Animais , Feminino , Ratos Wistar , Osteoclastos , Proteína-Lisina 6-Oxidase , Receptor beta de Estrogênio , Espécies Reativas de OxigênioRESUMO
PURPOSE: This study aims to further explore cartilage development in prenatal ethanol exposure (PEE) offspring at different times to explore the specific time points and mechanism of ethanol-induced fetal cartilage dysplasia. METHODS: On gestational day (GD)14, GD17, and GD20, PEE fetal cartilage was evaluated by morphological analysis. RT-qPCR, immunohistochemistry, and immunofluorescence were used to detect the expression of cartilage marker genes and their regulatory factors. Bone marrow mesenchymal stem cells (BMSCs) were used to explore the effect of ethanol on the differentiation of chondrocytes. Additionally, we used inhibitors, overexpression plasmids and a luciferase reporter assay on GD17 chondrocytes to verify the mechanism. RESULTS: PEE significantly reduced cartilage matrix content and the expression of marker genes on GD17 and GD20 but had no effect on GD14. The inhibition of chondrogenic differentiation by PEE mainly occurred on GD14-17. Furthermore, the expression of miR-200b-3p was increased, while that of ERG and PTHrP was markedly reduced in PEE fetal cartilage. In vitro, ethanol (30-120 mM) inhibited the differentiation of BMSCs into chondrocytes in a concentration-dependent manner, accompanied by strong expression of miR-200b-3p and low expression of ERG and PTHrP. Moreover, PTHLH and ERG overexpressed, as well as a miR-200b-3p inhibitor reversed the inhibitory effect of ethanol on the differentiation of fetal chondrocytes. Furthermore, miR-200b-3p could target and negatively regulate ERG. CONCLUSIONS: PEE can significantly inhibit the development of articular cartilage, especially during articular cartilage formation. The mechanism is related to the decreased differentiation of fetal cartilage into articular cartilage mediated by the miR-200b-3p/ERG/PTHrP axis.
Assuntos
Cartilagem Articular , MicroRNAs , Feminino , Gravidez , Cartilagem Articular/metabolismo , Condrócitos , Etanol/farmacologia , Etanol/metabolismo , MicroRNAs/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/genética , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Regulador Transcricional ERG/metabolismoRESUMO
Our previous study reported that prenatal caffeine exposure (PCE) could induce chondrodysplasia and increase the susceptibility to osteoarthritis in offspring rats. However, the potential mechanisms and initiating factors remain unknown. This study aims to investigate whether 11ß-HSD2, a glucocorticoid-metabolizing enzyme, is involved in the susceptibility of osteoarthritis induced by PCE and to further explore its potential mechanisms and initiating factors. Firstly, we found that PCE reduced cartilage matrix synthesis (aggrecan/Col2a1 expression) in male adult offspring rats and exhibited an osteoarthritis phenotype following chronic stress, which was associated with persistently reduced H3K9ac and H3K27ac levels at the promoter of 11ß-HSD2 as well as its expression in the cartilage from fetus to adulthood. The expression of 11ß-HSD2, aggrecan and Col2a1 were all decreased by corticosterone in the fetal chondrocytes, while overexpression of 11ß-HSD2 could partially alleviate the decrease of matrix synthesis induced by corticosterone in vitro. Furthermore, the glucocorticoid receptor (GR) activated by glucocorticoids directly bonded to the promoter region of 11ß-HSD2 to inhibit its expression. Meanwhile, the activated GR reduced the H3K9ac and H3K27ac levels of 11ß-HSD2 by recruiting HDAC4 and promoting GR-HDAC4 protein interaction to inhibit the 11ß-HSD2 expression. Moreover, caffeine could reduce the expression of 11ß-HSD2 by inhibiting the cAMP/PKA signaling pathway but without reducing the H3K9ac and H3K27ac levels of 11ß-HSD2, thereby synergistically enhancing the corticosterone effect. In conclusion, the persistently reduced H3K9ac and H3K27ac levels of 11ß-HSD2 from fetus to adulthood mediated the inhibition of cartilage matrix synthesis and the increased susceptibility to osteoarthritis. This epigenetic programming change in utero was induced by glucocorticoids with synergistic effect of caffeine.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2 , Osteoartrite , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Agrecanas , Animais , Cafeína/toxicidade , Cartilagem , Corticosterona , Feminino , Glucocorticoides/metabolismo , Masculino , Osteoartrite/induzido quimicamente , Osteoartrite/genética , Gravidez , RatosRESUMO
Epidemiological investigations have shown that individuals treated with dexamethasone during pregnancy have an increased risk of osteoporosis after birth. Our studies reported that peak bone mass was decreased in the prenatal dexamethasone exposure (PDE) offspring before chronic stress, while further decrease was observed after chronic stress. Simultaneously, increase of bone local active corticosterone was observed in the PDE offspring, while further increase was also observed after chronic stress. Moreover, the histone H3 lysine 9 acetylation (H3K9ac) level of 11-beta hydroxysteroid dehydrogenase 2 (11ß-HSD2) and its expression in bone tissue of PDE offspring rats remained lower than the control before and after birth. Injection of 11ß-HSD2 overexpression lentivirus into the bone marrow cavity could partially alleviate the accumulation of bone local active corticosterone and bone loss induced by PDE. In vitro, dexamethasone inhibited the expression of 11ß-HSD2 and aggravated the inhibitory effect of corticosterone on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Overexpression of 11ß-HSD2 partially alleviated the inhibitory effect of corticosterone. Moreover, dexamethasone promoted the nuclear translocation of glucocorticoid receptor (GR), which resulted in the stimulation of 11ß-HSD2 expression due to the binding of GR to the 11ß-HSD2 promoter region directly, as well as increasing H3K9ac level in the 11ß-HSD2 promoter region by recruiting histone deacetylase 11 (HDAC11). Our results indicated that low expression of 11ß-HSD2 in bone tissue is an important mediator for the high susceptibility to osteoporosis in PDE adult offspring.
Assuntos
Anti-Inflamatórios/efeitos adversos , Dexametasona/efeitos adversos , Glucocorticoides/efeitos adversos , Histona Desacetilases/genética , Osteoporose/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Corticosterona/sangue , Corticosterona/metabolismo , Feminino , Histona Desacetilases/metabolismo , Masculino , Osteoporose/genética , Osteoporose/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos Wistar , Estresse FisiológicoRESUMO
OBJECTIVE: To evaluate whether it is safe and effective for orthopaedic medical staff to provide support to the work against COVID-19. METHODS: One hundred and twenty-two orthopaedic medical staff from the orthopaedic center of Zhongnan Hospital of Wuhan University were included in this retrospective investigation. A total of 43 surgeons and 69 nurses provided medical support in the treatment of COVID-19 patients from 1 January 2020 to 8 April 2020 in four different hospitals in Wuhan. We collected data on the age, gender, and body temperature of orthopaedic medical staff, as well as the results for their chest CT scans, SARS-CoV-2 RNA, SARS-CoV-2 IgM and SARS-CoV-2 IgG tests, and training and examinations on COVID-19 knowledge. We also collected data on the time span of work, the number of infected staff during the support period, the number of COVID-19 patients the surgeons treated and the cure rate, the performance of the surgeons as assessed by the specialists and patients, and the number of infected staff during the pandemic. RESULTS: Among the 49 surgeons and 73 nurses, 43 surgeons and 69 nurses provided support against COVID-19. A total of 12 surgeons and 11 nurses provided support in the fields of respiration, intensive care, and emergency. A total of 34 surgeons and 58 nurses worked in the designated wards restructured for COVID-19 in the orthopaedic building. The average time span of work for the surgeons and nurses was 14.78 ± 3.64 days and 24.77 ± 7.58 days, respectively. No staff were infected during the support period. Over 1000 patients were received in the fever clinic by orthopaedic surgeons. The overall number of the treated hospitalized patients was 622. Among these patients, 226 cases were mild, 318 were mild to moderate, and 58 were severe or critical. The cure rate was 96.01%, 99.37%, and 52.00% respectively. The performance of the surgeons was scored 87.02 ± 3.17 and 90.69 ± 3.58 by the specialists and the patients, respectively. During the whole pandemic, 3 surgeons and 3 nurses who did not participate in the support work were infected in the early stages. The morbidity of all the orthopaedic staff was 4.92% during the whole pandemic, while no one was infected during the support work. CONCLUSION: Our investigation indicated that although they worked outside their specialty, it was safe and effective for the orthopaedic staff to provide medical support in the work against COVID-19 with adequate precautions and proper training.
Assuntos
COVID-19/terapia , Competência Clínica , Corpo Clínico Hospitalar , Ortopedia , Adulto , COVID-19/epidemiologia , China/epidemiologia , Feminino , Humanos , Masculino , Pandemias , Estudos Retrospectivos , SARS-CoV-2 , Adulto JovemRESUMO
Caffeine has developmental toxicity. Prenatal caffeine exposure (PCE) caused intrauterine growth retardation (IUGR) and multiple organ dysplasia. This study intended to explore the effect and mechanism of PCE on long bone development in female fetal rats. In vivo, the PCE group pregnant rats were given different concentrations of caffeine during the gestational Day 9-20. The mRNA expression of osteogenesis-related genes were significantly reduced in PCE group. In the PCE group (120 mg/kg·d), the length and primary center of fetal femur were shorter, and accompanied by H-type blood vessel abundance reducing. Meanwhile, connective tissue growth factor (CTGF) expression decreased in the growth plate of the PCE group (120 mg/kg·d). In contrast, the miR375 expression increased. In vitro, caffeine decreased CTGF and increased miR375 expression in fetal growth plate chondrocytes. After co-culture with caffeine-treated chondrocytes, the tube formation ability for the H-type endothelial cells was decreased. Furthermore, CTGF overexpression or miR375 inhibitor reversed caffeine-induced reduction of tube formation ability, and miR375 inhibitor reversed caffeine-induced CTGF expression inhibition. In summary, PCE decreased the expression of CTGF by miR375, ultimately resulting in H-type blood vessel-related long bone dysplasia.
Assuntos
Desenvolvimento Ósseo , Doenças do Desenvolvimento Ósseo/etiologia , Cafeína/toxicidade , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Endotélio Vascular/efeitos dos fármacos , MicroRNAs/metabolismo , Efeitos Tardios da Exposição Pré-Natal/etiologia , Animais , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Endotélio Vascular/metabolismo , Feminino , MicroRNAs/genética , Gravidez , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
BACKGROUND: Steroid-induced osteonecrosis of the femoral head (SONFH) is a chronic and crippling bone disease. This study aims to reveal novel diagnostic biomarkers of SONFH. METHODS: The GSE123568 dataset based on peripheral blood samples from 10 healthy individuals and 30 SONFH patients was used for weighted gene co-expression network analysis (WGCNA) and differentially expressed genes (DEGs) screening. The genes in the module related to SONFH and the DEGs were extracted for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Genes with |gene significance| > 0.7 and |module membership| > 0.8 were selected as hub genes in modules. The DEGs with the degree of connectivity ≥5 were chosen as hub genes in DEGs. Subsequently, the overlapping genes of hub genes in modules and hub genes in DEGs were selected as key genes for SONFH. And then, the key genes were verified in another dataset, and the diagnostic value of key genes was evaluated by receiver operating characteristic (ROC) curve. RESULTS: Nine gene co-expression modules were constructed via WGCNA. The brown module with 1258 genes was most significantly correlated with SONFH and was identified as the key module for SONFH. The results of functional enrichment analysis showed that the genes in the key module were mainly enriched in the inflammatory response, apoptotic process and osteoclast differentiation. A total of 91 genes were identified as hub genes in the key module. Besides, 145 DEGs were identified by DEGs screening and 26 genes were identified as hub genes of DEGs. Overlapping genes of hub genes in the key module and hub genes in DEGs, including RHAG, RNF14, HEMGN, and SLC2A1, were further selected as key genes for SONFH. The diagnostic value of these key genes for SONFH was confirmed by ROC curve. The validation results of these key genes in GSE26316 dataset showed that only HEMGN and SLC2A1 were downregulated in the SONFH group, suggesting that they were more likely to be diagnostic biomarkers of SOFNH than RHAG and RNF14. CONCLUSIONS: Our study identified that two key genes, HEMGN and SLC2A1, might be potential diagnostic biomarkers of SONFH.
Assuntos
Cabeça do Fêmur , Osteonecrose , Biomarcadores , Proteínas Sanguíneas , Redes Reguladoras de Genes , Transportador de Glucose Tipo 1 , Humanos , Glicoproteínas de Membrana , Proteínas Nucleares , EsteroidesRESUMO
AIMS: This study intends to explore the role of Vaspin and cholesterol metabolism in the process of osteoarthritis (OA) and its mechanism in vitro and in vivo. MAIN METHODS: In vitro, chondrocytes were treated with interleukin-1ß (IL-1ß, 20 ng/mL) in combination with Vaspin at different concentrations for 48 h. The expressions of Aggrecan (ACAN), Collagen 2a1 (Col2a1), A Disintegrin And Metalloproteinase with Thrombo Spondin type 1 motifs 5 (ADAMTS 5), and Matrix metalloproteinase 13 (MMP13) were detected. In vivo, the expression of liver X receptor (LXRα) and other Cholesterol efflux related genes were detected in the rat OA knee cartilage-induced by papain. KEY FINDINGS: In vitro, in a concentration-dependent manner, Vaspin reversed the decreased expression of ACAN and Col2a1, and the increased expression of ADAMTS 5 and MMP13 caused by IL-1ß. Besides, Vaspin promoted the expression of LXRα and other Cholesterol efflux related genes in a concentration-dependent manner in chondrocytes. However, miR155 mimics reversed the Vaspin-induced expression changes of cholesterol efflux pathway in chondrocytes. In vivo, the expression of LXRα and other Cholesterol efflux related genes were decreased in the rat OA knee cartilage-induced by papain. Besides, the level of Vaspin was reduced and the miroRNA155 (miR155) expression was increased in OA knee cartilage of rats. SIGNIFICANCE: In conclusion, the decreased expression of Vaspin inhibited the expression of Cholesterol efflux pathway via miR155/LXRα. Finally, the inhibited Cholesterol efflux pathway led to the cholesterol accumulation and OA in cartilage.
Assuntos
Artrite Experimental/patologia , Cartilagem Articular/patologia , Colesterol/metabolismo , Receptores X do Fígado/metabolismo , MicroRNAs/genética , Osteoartrite/patologia , Serpinas/metabolismo , Animais , Artrite Experimental/etiologia , Artrite Experimental/metabolismo , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos , Feminino , Regulação da Expressão Gênica , Receptores X do Fígado/genética , Osteoartrite/etiologia , Osteoartrite/metabolismo , Ratos , Ratos Wistar , Serpinas/genética , Transdução de SinaisRESUMO
BACKGROUND: To investigate the morphological parameters of the vastus medialis obliquus (VMO) muscle and delineate its importance in the maintenance of patellofemoral joint stability. METHODS: The magnetic resonance imaging data of seventy-five knees (fifty-four patients) with recurrent lateral patella dislocation (LPD) and seventy-five knees (seventy patients) without recurrent LPD were retrospectively analysed. Five morphological parameters related to the VMO (elevation in the sagittal plane and coronal plane, craniocaudal extent, muscle-fibre angulation, cross-sectional area ratio) and two patella tilt parameters (patella tilt angle, bisect offset ratio) were measured in MR images. The independent-samples t test or chi-square test was used for statistical comparisons. RESULTS: The mean ages of the patients in the recurrent LPD group and control group were 22.1 ± 9.9 years and 24.0 ± 6.5 years, respectively. Eighteen out of seventy-five (24%) patients MRI showed VMO injuries. Compared with the control group, the patients with recurrent LPD showed significantly higher sagittal VMO elevation (10.4 ± 2.3 mm vs. 4.1 ± 1.9 mm), coronal VMO elevation (15.9 ± 5.7 mm vs. 3.9 ± 3.7 mm), muscle-fibre angulation (35.4 ± 8.0° vs. 27.9 ± 6.3°), patella tilt angle (25.9 ± 10.7° vs. 9.1 ± 5.2°), and bisect offset ratio values (0.9 ± 0.3 vs. 0.5 ± 0.1) and significantly lower craniocaudal extent (13.7 ± 5.3 mm vs. 16.7 ± 5.1 mm) and cross-sectional area ratio values (0.05 ± 0.02 vs. 0.07 ± 0.02). CONCLUSIONS: The results showed that abnormalities in the VMO and patella tilt were clearly present in recurrent LPD patients compared with normal people.
Assuntos
Imageamento por Ressonância Magnética , Luxação Patelar/diagnóstico por imagem , Luxação Patelar/patologia , Músculo Quadríceps/diagnóstico por imagem , Músculo Quadríceps/patologia , Adolescente , Adulto , Atrofia/diagnóstico por imagem , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Patela/diagnóstico por imagem , Patela/patologia , Recidiva , Estudos Retrospectivos , Adulto JovemRESUMO
Dexamethasone is a common synthetic glucocorticoid drug that can promote foetal lung maturity. An increasing number of studies have shown that prenatal dexamethasone exposure (PDE) can cause a variety of short-term and long-term hazards to offspring, including bone development toxicity. H-type vessels are a newly discovered subtype of blood vessels associated with promoted bone formation and maintenance of bone mass. In this study, we aimed to explore whether H-type blood vessels are involved in PDE-induced long bone development toxicity in offspring and its mechanism. In vivo, we injected dexamethasone (0.2 mg/kg.d) subcutaneously at gestational days 9-20 and observed the H-type vessel abundance and bone mass at different time points in the offspring rats. In vitro, we investigated the effect of dexamethasone (0, 20, 100, and 500 nM) on the tube formation function of rat bone marrow-derived endothelial progenitor cells (EPCs) and explored its mechanism. Our results showed that the adult PDE female offspring rats were susceptible to osteoporosis. In addition, PDE inhibited bone mass, H-type vessel formation and the expression of bone platelet-derived growth factor receptor ß (PDGFRß)/focal adhesion kinase (FAK) pathway-related genes in antenatal and postnatal female offspring. Moreover, PDE promoted the expression of bone glucocorticoid receptor (GR), CCAAT and enhancer binding protein α (C/EBPα) and miR-34c in female foetuses. Dexamethasone suppressed the tube formation of rat bone marrow-derived EPCs and the activity of the PDGFRß/FAK pathway, which was mediated by GR/C/EBPα/miR-34c signalling activation. In summary, PDE can cause H-type vessel dysplasia and high susceptibility to osteoporosis in female offspring, and its mechanism is related to the low-activity programming of the PDGFRß/FAK pathway induced by GR/C/EBPα/miR-34c signalling activation. This study enhances the understanding of the molecular mechanism of dexamethasone-induced bone development toxicity and provides new insights for exploring the early intervention and therapeutic targets of foetal-derived osteoporosis.
Assuntos
Dexametasona/toxicidade , Fêmur/irrigação sanguínea , Fêmur/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Osteoporose/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/toxicidade , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Dexametasona/administração & dosagem , Feminino , Fêmur/efeitos dos fármacos , Masculino , Osteoporose/induzido quimicamente , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Aseptic necrosis of the femoral head (ANFH) has a high incidence in the community and causes substantial problems with health as well as economic and social stress. Core decompression is the most commonly used treatment for early ANFH. Although many studies have reported on the efficacy of femoral head core decompression surgery for ANFH, there are still some shortcomings in assessing the severity of femoral head necrosis, the location distribution, and changes in necrotic lesions before and after surgery. Magnetic resonance imaging (MRI) and equivalent sphere model analysis were used to further clarify the clinical efficacy of percutaneous multiple small-diameter drilling core decompression in patients with ANFH. METHODS: From July 2013 to November 2016, 24 patients (32 cases of the hip joint) with ANFH who underwent percutaneous multiple small-diameter drilling core decompression were selected, and a retrospective analysis was conducted. MRI as well as VAS, OHS-C, and HHS scores were used to evaluate joint function in all patients before and 6, 12, and 24 months after the operation. RESULTS: Twenty-four months after the operation, 10 hips were amputated. The survival rates of alcoholic femoral head necrosis (AFNH), idiopathic femoral head necrosis (IFHN), and steroid-induced femoral head necrosis (SIFHN) patients at 24 months were 100%, 85.7% (- 2 hips), and 0.0% (- 8 hips), respectively. The MRI and equivalent sphere analysis results revealed that the anterior superior medial quadrant was the area most prone to osteonecrosis, and the posterior superior medial quadrant was the area second most prone to necrosis. After the operation, the average percentage of the AFHN necrosis area in the total volume of the femoral head decreased from 14.5 to 10.3%, and the average percentage of the IFHN necrosis area decreased from 16.3 to 9.2%; however, the average percentage of the necrosis area for SIFHN increased from 30.4 to 33.1%. CONCLUSION: Percutaneous multiple small-diameter drilling core decompression significantly reduced the lesion volume for AFHN and IFHN, but the effect on SIFHN was not good.
Assuntos
Descompressão Cirúrgica/métodos , Necrose da Cabeça do Fêmur/cirurgia , Cabeça do Fêmur/cirurgia , Imageamento por Ressonância Magnética/métodos , Adulto , Feminino , Necrose da Cabeça do Fêmur/diagnóstico por imagem , Necrose da Cabeça do Fêmur/etiologia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
This study was aimed to investigate the effect of prenatal ethanol exposure (PEE) on the susceptibility of offspring rats to glomerulosclerosis and to explore the mechanism. Pregnant Wistar rats were intragastrically administered ethanol (4g/kg·d) from gestational day (GD) 9 to GD 20, and the control group was given equal volume of normal saline. The offspring rats were all fed with high-fat diet after weaning, and were sacrificed at postnatal week 24 (PW24). The results revealed that the adult offspring kidneys in the male and female PEE groups exhibited higher glomerulosclerosis index and interstitial fibrosis index compared with the high-fat diet control groups, accompanied by elevated serum creatinine level. The protein expression of Nephrin and WT1, which were the marker genes of podocytes, was significantly decreased, whereas the protein expression of desmin and α-SMA, the marker genes of mesenchymal cells, was remarked enhanced in the male and female PEE groups. Compared with the high-fat diet control groups, the mRNA and protein expressions of renal angiotensin II receptor type 2 (AT2R) were decreased in the male PEE group, but increased in the female PEE group. PEE increased the mRNA and protein expressions of glucocorticoid (GC) activation system and inhibited the expression of insulin-like growth factor 1 (IGF1) signaling pathway in male offspring kidney; on the contrary, in female offspring kidney, PEE inhibited the mRNA and protein expression of glucocorticoid activation system and increased the expression of IGF1 signaling pathway. Taken together, PEE increased the susceptibility of the adult offspring to glomerulosclerosis, and the programming of renal AT2R or GC-IGF1 is respectively involved in the toxicity of PEE to the male or female offspring.
Assuntos
Dieta Hiperlipídica , Etanol/toxicidade , Glomerulonefrite/etiologia , Glomérulos Renais/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Transdução de Sinais/efeitos dos fármacos , Animais , Feminino , Fibrose , Regulação da Expressão Gênica , Idade Gestacional , Glomerulonefrite/genética , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Glucocorticoides/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Gravidez , Ratos Wistar , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais/genéticaRESUMO
This study aimed to verify the toxic effects of prenatal caffeine exposure (PCE) on the podocyte development in male offspring, and to explore the underlying intrauterine programming mechanisms. The pregnant rats were administered with caffeine (30 to 120 mg/kgâ d) during gestational day (GD) 9 to 20. The male fetus on GD20 and the offspring at postnatal week (PW) 6 and PW28 were sacrificed. The results indicated that PCE caused ultrastructural abnormalities on podocyte, and inhibited the expression of podocyte marker genes such as Nephrin, Wilms tumor 1 (WT1), the histone 3 lysine 9 acetylation (H3K9ac) level in the Kruppel-like factor 4 (KLF4) promoter and its expression in the male offspring from GD20 to PW28. Meanwhile, the expression of glucocorticoid receptor (GR) and histone deacetylase 7 (HDAC7) in the fetus were increased by PCE. In vitro, corticosterone increased GR and HDAC7 whereas reduced the H3K9ac level of KLF4 and KLF4/Nephrin expression. KLF4 over-expression reversed the reduction of Nephrin expression, knockdown of HDAC7 and GR antagonist RU486 partially reversed the inhibitory effects of corticosterone on H3K9ac level and KLF4 expression. In conclusion, PCE caused podocyte developmental toxicity in male offspring, which was associated with corticosterone-induced low-functional programming of KLF4 through GR/HDAC7/H3K9ac pathway.