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1.
BMC Med Genomics ; 15(1): 128, 2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35668402

RESUMO

BACKGROUND: Gorham-Stout disease is a rare condition characterized by vascular proliferation and the massive destruction of bone tissue. With less than 400 cases in the literature of Gorham-Stout syndrome, we performed a unique study combining whole-genome sequencing and RNA-Seq to probe the genomic features and differentially expressed pathways of a presented case, revealing new possible drivers and biomarkers of the disease. CASE PRESENTATION: We present a case report of a white 45-year-old female patient with marked bone loss of the left humerus associated with vascular proliferation, diagnosed with Gorham-Stout disease. The analysis of whole-genome sequencing showed a dominance of large structural DNA rearrangements. Particularly, rearrangements in chromosomes seven, twelve, and twenty could contribute to the development of the disease, especially a gene fusion involving ATG101 that could affect macroautophagy. The study of RNA-sequencing data from the patient uncovered the PI3K/AKT/mTOR pathway as the most affected signaling cascade in the Gorham-Stout lesional tissue. Furthermore, M2 macrophage infiltration was detected using immunohistochemical staining and confirmed by deconvolution of the RNA-seq expression data. CONCLUSIONS: The way that DNA and RNA aberrations lead to Gorham-Stout disease is poorly understood due to the limited number of studies focusing on this rare disease. Our study provides the first glimpse into this facet of the disease, exposing new possible therapeutic targets and facilitating the clinicopathological diagnosis of Gorham-Stout disease.


Assuntos
Osteólise Essencial , Humanos , Pessoa de Meia-Idade , Osteólise Essencial/complicações , Osteólise Essencial/diagnóstico , Osteólise Essencial/genética , Fosfatidilinositol 3-Quinases , RNA
2.
EMBO J ; 41(13): e108719, 2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35702882

RESUMO

Cells need to rapidly and precisely react to multiple mechanical and chemical stimuli in order to ensure precise context-dependent responses. This requires dynamic cellular signalling events that ensure homeostasis and plasticity when needed. A less well-understood process is cellular response to elevated interstitial fluid pressure, where the cell senses and responds to changes in extracellular hydrostatic pressure. Here, using quantitative label-free digital holographic imaging, combined with genome editing, biochemical assays and confocal imaging, we analyse the temporal cellular response to hydrostatic pressure. Upon elevated cyclic hydrostatic pressure, the cell responds by rapid, dramatic and reversible changes in cellular volume. We show that YAP and TAZ, the co-transcriptional regulators of the Hippo signalling pathway, control cell volume and that cells without YAP and TAZ have lower plasma membrane tension. We present direct evidence that YAP/TAZ drive the cellular response to hydrostatic pressure, a process that is at least partly mediated via clathrin-dependent endocytosis. Additionally, upon elevated oscillating hydrostatic pressure, YAP/TAZ are activated and induce TEAD-mediated transcription and expression of cellular components involved in dynamic regulation of cell volume and extracellular matrix. This cellular response confers a feedback loop that allows the cell to robustly respond to changes in interstitial fluid pressure.


Assuntos
Via de Sinalização Hippo , Proteínas Serina-Treonina Quinases , Homeostase , Pressão Hidrostática , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Dis Model Mech ; 15(4)2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35229101

RESUMO

Paget's disease of bone (PDB) is characterized by focal increases in bone remodelling. Genome-wide association studies identified a susceptibility locus for PDB tagged by rs5742915, which is located within the PML gene. Here, we have assessed the candidacy of PML as the predisposing gene for PDB at this locus. We found that the PDB-risk allele of rs5742915 was associated with lower PML expression and that PML expression in blood cells from individuals with PDB was lower than in controls. The differentiation, survival and resorptive activity of osteoclasts prepared from Pml-/- mice was increased compared with wild type. Furthermore, the inhibitory effect of IFN-γ on osteoclast formation from Pml-/- was significantly blunted compared with wild type. Bone nodule formation was also increased in osteoblasts from Pml-/- mice when compared with wild type. Although microCT analysis of trabecular bone showed no differences between Pml-/- mice and wild type, bone histomorphometry showed that Pml-/- mice had high bone turnover with increased indices of bone resorption and increased mineral apposition rate. These data indicate that reduced expression of PML predisposes an individual to PDB and identify PML as a novel regulator of bone metabolism. This article has an associated First Person interview with the first author of the paper.


Assuntos
Reabsorção Óssea , Osteíte Deformante , Animais , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Osteíte Deformante/genética , Osteoclastos/metabolismo , Osteogênese , Proteína da Leucemia Promielocítica
4.
PLoS Genet ; 17(4): e1009275, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33819267

RESUMO

Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway in Drosophila. To investigate a possible role of UBR5 in regulation of the musculoskeletal system through modulation of mammalian HH signaling, we created a mouse model for specific loss of Ubr5 function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia. Ubr5 loss of function resulted in progressive and dramatic articular cartilage degradation, enlarged, abnormally shaped sesamoid bones and extensive heterotopic tissue metaplasia linked to calcification of tendons and ossification of synovium. Genetic suppression of smoothened (Smo), a key mediator of HH signalling, dramatically enhanced the Ubr5 mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss of Ubr5 stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations between UBR5 expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for the Ubr5 gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway.


Assuntos
Artrite Reumatoide/genética , Proteínas de Drosophila/genética , Músculo Esquelético/metabolismo , Receptor Smoothened/genética , Ubiquitina-Proteína Ligases/genética , Animais , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Cartilagem/crescimento & desenvolvimento , Cartilagem/metabolismo , Cartilagem/patologia , Condrócitos/metabolismo , Modelos Animais de Doenças , Drosophila melanogaster/genética , Proteínas Hedgehog/genética , Homeostase/genética , Humanos , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Camundongos , Músculo Esquelético/patologia , Osteogênese/genética , Transdução de Sinais/genética , Tendões/metabolismo , Tendões/patologia
5.
J Orthop Res ; 39(11): 2333-2339, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33484170

RESUMO

Obesity and osteoarthritis (OA) are well-known comorbidities and their precise molecular interactions are still unidentified. Adiponectin, a major adipokine, known to have an anti-inflammatory effect in atherosclerosis or Type 2 Diabetes Mellitus (T2DM), has also been postulated to be pro-inflammatory in OA. This dual role of adiponectin is still not explained. The precise mechanism by which adiponectin affects cartilage and chondrocytes remains to be elucidated. In the present observational study chondrocytes from 30 patients with OA (18 females and 12 males) undergoing total knee replacement (TKR) were isolated. Expression of adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) was examined both at gene and protein levels in chondrocytes. The difference in adiponectin receptor expression between lean and obese patients with OA and the role of adiponectin in regulating pro-inflammatory genes (MCP-1, IL-6, and VCAM-1, MMP-1, MMP-2, and TIMP-1) has been investigated. We found that ADIPOR1 represented the most abundant adiponectin receptor in primary OA chondrocytes. ADIPOR1 and ADIPOR2 genes and ADIPOR1 protein were differently expressed in OA chondrocytes obtained from obese compared with lean patients with OA. Adiponectin induced gene expression of MCP-1, IL-6, and MMP-1 in all OA patients' chondrocytes. In contrast, VCAM-1 and MMP-2 were differently regulated by adiponectin depending on the patient's body mass index. This study suggests that adiponectin and ADIPOR1 may have important roles in the pathogenesis of cartilage degeneration in OA of obese subjects.


Assuntos
Cartilagem Articular , Diabetes Mellitus Tipo 2 , Osteoartrite , Adiponectina , Cartilagem/metabolismo , Cartilagem Articular/patologia , Condrócitos/metabolismo , Feminino , Humanos , Interleucina-6/metabolismo , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Obesidade/metabolismo , Osteoartrite/metabolismo , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Molécula 1 de Adesão de Célula Vascular/farmacologia
6.
Aging (Albany NY) ; 12(21): 21446-21468, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33136552

RESUMO

Skeletal muscle wasting represents both a common phenotype of aging and a feature of pathological conditions such as chronic kidney disease (CKD). Although both clinical data and genetic experiments in mice suggest that hyperphosphatemia accelerates muscle wasting, the underlying mechanism remains unclear. Here, we showed that inorganic phosphate (Pi) dose-dependently decreases myotube size, fusion index, and myogenin expression in mouse C2C12 skeletal muscle cells. These changes were accompanied by increases in reactive oxygen species (ROS) production and Nrf2 and p62 expression, and reductions in mitochondrial membrane potential (MMP) and Keap1 expression. Inhibition of Pi entry, cytosolic ROS production, or Nrf2 activation reversed the effects of high Pi on Nrf2, p62, and myogenin expression. Overexpression of Nrf2 respectively increased and decreased the promoter activity of p62-Luc and myogenin-Luc reporters. Analysis of nuclear extracts from gastrocnemius muscles from mice fed a high-Pi (2% Pi) diet showed increased Nrf2 phosphorylation in sham-operated and 5/6 nephrectomized (CKD) mice, and both increased p62 phosphorylation and decreased myogenin expression in CKD mice. These data suggest that high Pi suppresses myogenic differentiation in vitro and promotes muscle atrophy in vivo through oxidative stress-mediated protein degradation and both canonical (ROS-mediated) and non-canonical (p62-mediated) activation of Nrf2 signaling.


Assuntos
Diferenciação Celular , Hiperfosfatemia/complicações , Desenvolvimento Muscular , Atrofia Muscular/etiologia , Mioblastos Esqueléticos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Animais , Linhagem Celular , Modelos Animais de Doenças , Hiperfosfatemia/induzido quimicamente , Hiperfosfatemia/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Mioblastos Esqueléticos/patologia , Miogenina/genética , Miogenina/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fosfatos , Fosforilação , Insuficiência Renal Crônica/complicações , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais
7.
Dis Model Mech ; 12(7)2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31221668

RESUMO

Angiosarcomas are a rare group of tumours which have poor prognosis and limited treatment options. The development of new therapies has been hampered by a lack of good preclinical models. Here, we describe the development of an autochthonous mouse model of angiosarcoma driven by loss of p53 in VE-cadherin-expressing endothelial cells. Using Cdh5-Cre to drive recombination in adult endothelial cells, mice developed angiosarcomas with 100% penetrance upon homozygous deletion of Trp53 with a median lifespan of 325 days. In contrast, expression of the R172H mutant p53 resulted in formation of thymic lymphomas with a more rapid onset (median lifespan 151 days). We also used Pdgfrb-Cre-expressing mice, allowing us to target predominantly pericytes, as these have been reported as the cell of origin for a number of soft tissue sarcomas. Pdgfrb-Cre also results in low levels of recombination in venous blood endothelial cells in multiple tissues during development. Upon deletion of Trp53 in Pdgfrb-Cre-expressing mice (Pdgfrb-Cre,Trp53fl/fl mice), 65% developed lymphomas and 21% developed pleomorphic undifferentiated soft tissue sarcomas. None developed angiosarcomas. In contrast, 75% of Pdgfrb-Cre,Trp53R172H/R172H mice developed angiosarcomas, with 60% of these mice also developing lymphomas. The median lifespan of the Pdgfrb-Cre,Trp53R172H/R172H mice was 151 days. Re-implantation of angiosarcoma tumour fragments from Cdh5-Cre, Trp53fl/fl mice provided a more consistent and rapid model of angiosarcoma than the two spontaneous models. The ability to passage tumour fragments through the mouse provides a novel model which is amenable to preclinical studies and will help the development of potential new therapies for angiosarcoma.


Assuntos
Modelos Animais de Doenças , Hemangiossarcoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Diferenciação Celular , Células Endoteliais/metabolismo , Hemangiossarcoma/patologia , Integrases/genética , Camundongos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Recombinação Genética , Proteína Supressora de Tumor p53/genética
8.
JBJS Case Connect ; 9(2): e0022, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31140983

RESUMO

CASE: We report a rare case of desmoplastic fibroma (DF) of the midshaft femur presenting as a pathological fracture. This rare benign bone tumor was treated with an acute en bloc excision and femoral shortening over an intramedullary nail. Once union of the acute shortening had been achieved, further surgery was undertaken to lengthen the femur with the use of Intramedullary Skeletal Kinetic Distractors. At 3 years after fracture, our patient had achieved equal leg lengths, had normal knee function, and was disease free. CONCLUSIONS: DF resulting in pathological fracture of the midshaft femur is extremely rare and has not been reported to occur in the femoral diaphysis. This location is important as preservation of the joint above and below is preferable and en bloc excision is recommended. Restoration of bone stock after en bloc excision is difficult and recurrence needs to be monitored.


Assuntos
Fêmur/patologia , Fibroma Desmoplásico/complicações , Fraturas Espontâneas/cirurgia , Assistência ao Convalescente , Fraturas do Fêmur/etiologia , Fraturas do Fêmur/cirurgia , Fêmur/diagnóstico por imagem , Fibroma Desmoplásico/patologia , Fixação Intramedular de Fraturas/instrumentação , Fraturas Espontâneas/diagnóstico por imagem , Fraturas Espontâneas/etiologia , Humanos , Desigualdade de Membros Inferiores/cirurgia , Imageamento por Ressonância Magnética/métodos , Masculino , Radiografia/métodos , Resultado do Tratamento , Adulto Jovem
9.
Calcif Tissue Int ; 105(1): 97-106, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30993375

RESUMO

A disintegrin and metalloproteinase 12 (ADAM12) is known to be involved in chondrocyte proliferation and maturation; however, the mechanisms are not fully understood. In this study, expression and localization of ADAM12 during chondrocyte differentiation were examined in the mouse growth plate by immunohistochemistry. Adam12 expression during ATDC5 chondrogenic differentiation was examined by real-time PCR and compared with the expression pattern of type X collagen. The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system was used to generate Adam12-knockout (KO) ATDC5 cells. Adam12-KO and Adam12 overexpressing cells were used for analyses of ADAM12 expression with or without TGF-ß1 stimulation. ADAM12 was identified predominantly in chondrocytes of the proliferative zone in mouse growth plates by immunohistochemistry. Adam12 was upregulated prior to Col10a1 during chondrogenic differentiation in wild-type ATDC5 cells. In Adam12-KO ATDC5 cells, following initiation of chondrogenic differentiation, we observed a reduction in Igf-1 expression along with an upregulation of hypertrophy-associated Runx2, Col10a1, and type X collagen protein expressions. In ATDC5 wild-type cells, stimulation with TGF-ß1 upregulated the expressions of Adam12 and Igf-1 and downregulated the expression of Runx2. In contrast, in Adam12-KO ATDC5 cells, these TGF-ß1-induced changes were suppressed. Adam12 overexpression resulted in an upregulation of Igf-1 and downregulation of Runx2 expression in ATDC5 cells. The findings suggest that ADAM12 has important role in the regulation of chondrocyte differentiation, potentially by regulation of TGF-ß1-dependent signaling and that targeting of ADAM12 may have a role in management of abnormal chondrocyte differentiation.


Assuntos
Proteína ADAM12/metabolismo , Diferenciação Celular/fisiologia , Condrócitos/citologia , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Células Cultivadas , Condrogênese/fisiologia , Colágeno Tipo II/metabolismo , Colágeno Tipo X/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
11.
Int J Mol Sci ; 19(10)2018 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-30322202

RESUMO

The magnetization of mesenchymal stem cells (MSC) has the potential to aid tissue engineering approaches by allowing tracking, targeting, and local retention of cells at the site of tissue damage. Commonly used methods for magnetizing cells include optimizing uptake and retention of superparamagnetic iron oxide nanoparticles (SPIONs). These appear to have minimal detrimental effects on the use of MSC function as assessed by in vitro assays. The cellular content of magnetic nanoparticles (MNPs) will, however, decrease with cell proliferation and the longer-term effects on MSC function are not entirely clear. An alternative approach to magnetizing MSCs involves genetic modification by transfection with one or more genes derived from Magnetospirillum magneticum AMB-1, a magnetotactic bacterium that synthesizes single-magnetic domain crystals which are incorporated into magnetosomes. MSCs with either or mms6 and mmsF genes are followed by bio-assimilated synthesis of intracytoplasmic magnetic nanoparticles which can be imaged by magnetic resonance (MR) and which have no deleterious effects on MSC proliferation, migration, or differentiation. The stable transfection of magnetosome-associated genes in MSCs promotes assimilation of magnetic nanoparticle synthesis into mammalian cells with the potential to allow MR-based cell tracking and, through external or internal magnetic targeting approaches, enhanced site-specific retention of cells for tissue engineering.


Assuntos
Genes Bacterianos , Magnetossomos/metabolismo , Magnetospirillum/genética , Células-Tronco Mesenquimais/citologia , Engenharia Tecidual/métodos , Animais , Diferenciação Celular , Proliferação de Células , Rastreamento de Células , Humanos , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita/química , Magnetospirillum/metabolismo , Células-Tronco Mesenquimais/química , Células-Tronco Mesenquimais/metabolismo , Transfecção
12.
J Orthop ; 15(2): 571-577, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29881196

RESUMO

Paget's sarcomatous transformation is a rare and potentially fatal complication of Paget's disease. Histologically, it is typically described as a high-grade and extremely aggressive malignancy. We present an unusual radiographic series from a patient diagnosed with a low-grade Paget's osteosarcoma, a very rare and poorly described variant of the disease.

13.
Int J Med Sci ; 15(5): 507-516, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29559840

RESUMO

Glucocorticoid therapy, especially at higher doses, is associated with significant adverse side effects including osteoporosis. Leptin, secreted from adipose tissue, has diverse effects on bone tissue regulation. As glucocorticoids stimulate leptin synthesis and secretion directly in adipose tissue we hypothesised that dexamethasone (DEX) induced osteoporosis may, in part, be mediated by an osteoblast dependent leptin-leptin receptor pathway. Human bone cells expressed leptin and leptin receptors (Ob-Ra and Ob-Rb). DEX increased leptin, Ob-Ra and Ob-Rb expression in a dose-dependent manner while decreasing expression of osteocalcin. In the presence of leptin, Cbfa1 and osteonectin expression showed no significant change, whereas osteocalcin expression was decreased. Recombinant human quadruple antagonist leptin suppressed DEX-induced osteocalcin downregulation. The signaling pathway involved up-regulation of JAK2. In conclusion, upregulation of leptin and Ob-Rb in human bone cells by DEX is associated with down-regulation of osteocalcin expression. The down regulation of osteocalcin by DEX was partially through a leptin autocrine/paracrine loop. Adverse effects of DEX on the skeleton may be modified by targeting leptin signaling pathways.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/genética , Leptina/genética , Osteocalcina/genética , Osteoporose/genética , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Técnicas de Cultura de Células , Dexametasona/efeitos adversos , Dexametasona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Janus Quinase 2/genética , Leptina/antagonistas & inibidores , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteócitos/efeitos dos fármacos , Osteoporose/induzido quimicamente , Osteoporose/patologia , Receptores para Leptina/genética , Transdução de Sinais/efeitos dos fármacos
14.
Cancer Res ; 78(6): 1484-1496, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29330144

RESUMO

In breast cancer, increased expression of the cytoskeletal adaptor protein Kindlin-1 has been linked to increased risks of lung metastasis, but the functional basis is unknown. Here, we show that in a mouse model of polyomavirus middle T antigen-induced mammary tumorigenesis, loss of Kindlin-1 reduced early pulmonary arrest and later development of lung metastasis. This phenotype relied on the ability of Kindlin-1 to bind and activate ß integrin heterodimers. Kindlin-1 loss reduced α4 integrin-mediated adhesion of mammary tumor cells to the adhesion molecule VCAM-1 on endothelial cells. Treating mice with an anti-VCAM-1 blocking antibody prevented early pulmonary arrest. Kindlin-1 loss also resulted in reduced secretion of several factors linked to metastatic spread, including the lung metastasis regulator tenascin-C, showing that Kindlin-1 regulated metastatic dissemination by an additional mechanism in the tumor microenvironment. Overall, our results show that Kindlin-1 contributes functionally to early pulmonary metastasis of breast cancer.Significance: These findings provide a mechanistic proof in mice that Kindin-1, an integrin-binding adaptor protein, is a critical mediator of early lung metastasis of breast cancer. Cancer Res; 78(6); 1484-96. ©2018 AACR.


Assuntos
Neoplasias da Mama/patologia , Proteínas de Transporte/metabolismo , Neoplasias Pulmonares/secundário , Animais , Anticorpos Monoclonais/farmacologia , Antígenos Transformantes de Poliomavirus/toxicidade , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteínas de Transporte/genética , Adesão Celular/efeitos dos fármacos , Células Endoteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Integrinas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/virologia , Camundongos Transgênicos , Molécula 1 de Adesão de Célula Vascular/imunologia
16.
BMC Complement Altern Med ; 17(1): 537, 2017 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-29246219

RESUMO

BACKGROUND: The standardized maritime pine bark extract (Pycnogenol®) has previously shown symptom alleviating effects in patients suffering from moderate forms of knee osteoarthritis (OA). The cellular mechanisms for this positive impact are so far unknown. The purpose of the present randomized pilot controlled study was to span the knowledge gap between the reported clinical effects of Pycnogenol® and its in vivo mechanism of action in OA patients. METHODS: Thirty three patients with severe OA scheduled for a knee arthroplasty either received 100 mg of Pycnogenol® twice daily or no treatment (control group) three weeks before surgery. Cartilage, synovial fluid and serum samples were collected during surgical intervention. Relative gene expression of cartilage homeostasis markers were analyzed in the patients' chondrocytes. Inflammatory and cartilage metabolism mediators were investigated in serum and synovial fluid samples. RESULTS: The oral intake of Pycnogenol® downregulated the gene expression of various cartilage degradation markers in the patients' chondrocytes, the decrease of MMP3, MMP13 and the pro-inflammatory cytokine IL1B were statistically significant (p ≤ 0.05). Additionally, protein concentrations of ADAMTS-5 in serum were reduced significantly (p ≤ 0.05) after three weeks intake of the pine bark extract. CONCLUSIONS: This is the first report about positive cellular effects of a dietary supplement on key catabolic and inflammatory markers in patients with severe OA. The results provide a rational basis for understanding previously reported clinical effects of Pycnogenol® on symptom scores of patients suffering from OA. TRIAL REGISTRATION: ISRCTN10754119 . Retrospectively registered 08/10/2015.


Assuntos
Cartilagem/efeitos dos fármacos , Flavonoides/farmacologia , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/metabolismo , Líquido Sinovial/efeitos dos fármacos , Idoso , Biomarcadores/análise , Cartilagem/química , Colagenases/sangue , Feminino , Flavonoides/administração & dosagem , Flavonoides/uso terapêutico , Humanos , Interleucina-1beta/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Extratos Vegetais , Líquido Sinovial/química
17.
J Endocrinol ; 234(3): 291-299, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28676523

RESUMO

11ß-Hydroxysteroid dehydrogenase-1 (11ß-HSD1) predominantly converts inert glucocorticoids into active forms, thereby contributing to intracellular glucocorticoid levels. 11ß-HSD1 is dynamically regulated during inflammation, including in macrophages where it regulates phagocytic capacity. The resolution of inflammation in some disease models including inflammatory arthritis is impaired by 11ß-HSD1 deficiency or inhibition. However, 11ß-HSD1 deficiency/inhibition also promotes angiogenesis, which is beneficial in mouse models of surgical wound healing, myocardial infarction or obesity. The cell types responsible for the anti-inflammatory and anti-angiogenic roles of 11ß-HSD1 have not been characterised. Here, we generated Hsd11b1MKO mice with LysM-Cre mediated deletion of Hsd11b1 to investigate whether 11ß-HSD1 deficiency in myeloid phagocytes is pro-angiogenic and/or affects the resolution of inflammation. Resolution of inflammatory K/BxN-induced arthritis was impaired in Hsd11b1MKO mice to a similar extent as in mice globally deficient in 11ß-HSD1. This was associated with >2-fold elevation in levels of the endothelial marker Cdh5 mRNA, suggesting increased angiogenesis in joints of Hsd11b1MKO mice following arthritis. A pro-angiogenic phenotype was confirmed by measuring angiogenesis in subcutaneously implanted polyurethane sponges, in which Hsd11b1MKO mice showed 20% greater vessel density than their littermate controls, associated with higher expression of Cdh5 Thus, 11ß-HSD1 deficiency in myeloid phagocytes promotes angiogenesis. Targeting 11ß-HSD1 in macrophages may be beneficial in tissue repair.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/deficiência , Inflamação/enzimologia , Macrófagos/enzimologia , Neovascularização Patológica/enzimologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/imunologia , Animais , Humanos , Inflamação/genética , Inflamação/imunologia , Macrófagos/imunologia , Camundongos , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia
18.
Arthritis Rheumatol ; 69(7): 1396-1406, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28320058

RESUMO

OBJECTIVE: Obesity is associated with an increased risk of developing osteoarthritis (OA), which is postulated to be secondary to adipose tissue-dependent inflammation. Periarticular adipose tissue depots are present in synovial joints, but the association of this tissue with OA has not been extensively explored. The aim of this study was to investigate differences in local adipose tissue depots in knees with OA and characterize the changes related to class II and class III obesity in patients with end-stage knee OA. METHODS: Synovium and the infrapatellar fat pad (IPFP) were collected during total knee replacement from 69 patients with end-stage OA. Histologic changes, changes in gene and protein expression of adiponectin, peroxisome proliferator-activated receptor γ (PPARγ), and Toll-like receptor 4 (TLR-4), and immune cell infiltration into the adipose tissue were investigated. RESULTS: IPFP and synovium adipose tissue depots differed significantly and were influenced by the patient's body mass index. Compared to adipocytes from the IPFP and synovium of lean patients, adipocytes from the IPFP of obese patients were significantly larger and the synovium of obese patients displayed marked fibrosis, increased macrophage infiltration, and higher levels of TLR4 gene expression. The adipose-related markers PPARγ in the IPFP and adiponectin and PPARγ in the synovium were expressed at lower levels in obese patients compared to lean patients. Furthermore, there were increased numbers of CD45+ hematopoietic cells, CD45+CD14+ total macrophages, and CD14+CD206+ M2-type macrophages in both the IPFP and synovial tissue of obese patients. CONCLUSION: These differences suggest that IPFP and synovium may contain 2 different white adipose tissue depots and support the theory of inflammation-induced OA in patients with class II or III obesity. These findings warrant further investigation as a potentially reversible, or at least suppressible, cause of OA in obese patients.


Assuntos
Tecido Adiposo/patologia , Articulação do Joelho/patologia , Obesidade Mórbida/complicações , Osteoartrite do Joelho/patologia , Adipócitos/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Artroplastia do Joelho , Western Blotting , Índice de Massa Corporal , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Expressão Gênica , Humanos , Imuno-Histoquímica , Articulação do Joelho/metabolismo , Macrófagos , Obesidade/complicações , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/cirurgia , PPAR gama/genética , PPAR gama/metabolismo , Patela , Reação em Cadeia da Polimerase em Tempo Real , Membrana Sinovial , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
19.
Skeletal Radiol ; 46(5): 687-691, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28194488

RESUMO

We report the case of a 23-year-old man diagnosed with adult-onset idiopathic chondrolysis of the hip. Chondrolysis of the hip is a disorder most frequently seen in children who have suffered with slipped capital femoral epiphyses. Idiopathic chondrolysis of the hip is extremely rare and to our knowledge, its onset has never been documented in adults aged over 20. With reference to the available medical literature, we summarise the current clinical management of this unusual but important cause of young adult hip pain.


Assuntos
Artroplastia de Quadril , Doenças das Cartilagens/diagnóstico , Doenças das Cartilagens/cirurgia , Articulação do Quadril/cirurgia , Artropatias/diagnóstico , Artropatias/cirurgia , Adulto , Idade de Início , Doenças das Cartilagens/diagnóstico por imagem , Diagnóstico Diferencial , Articulação do Quadril/diagnóstico por imagem , Humanos , Artropatias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Dor/etiologia , Radiografia , Adulto Jovem
20.
Sci Rep ; 7: 39755, 2017 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-28051139

RESUMO

The use of stem cells to support tissue repair is facilitated by loading of the therapeutic cells with magnetic nanoparticles (MNPs) enabling magnetic tracking and targeting. Current methods for magnetizing cells use artificial MNPs and have disadvantages of variable uptake, cellular cytotoxicity and loss of nanoparticles on cell division. Here we demonstrate a transgenic approach to magnetize human mesenchymal stem cells (MSCs). MSCs are genetically modified by transfection with the mms6 gene derived from Magnetospirillum magneticum AMB-1, a magnetotactic bacterium that synthesises single-magnetic domain crystals which are incorporated into magnetosomes. Following transfection of MSCs with the mms6 gene there is bio-assimilated synthesis of intracytoplasmic magnetic nanoparticles which can be imaged by MR and which have no deleterious effects on cell proliferation, migration or differentiation. The assimilation of magnetic nanoparticle synthesis into mammalian cells creates a real and compelling, cytocompatible, alternative to exogenous administration of MNPs.


Assuntos
Proteínas de Bactérias/metabolismo , Nanopartículas de Magnetita , Magnetossomos/metabolismo , Magnetospirillum/fisiologia , Células-Tronco Mesenquimais/fisiologia , Animais , Proteínas de Bactérias/genética , Diferenciação Celular , Movimento Celular , Proliferação de Células , Humanos , Imagens de Fantasmas , Transfecção
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