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1.
Int Immunopharmacol ; 97: 107706, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33933850

RESUMO

PURPOSE: To determine the role of galectin-3 (Gal-3) in cornea infected by Aspergillus fumigatus (A. fumigatus). METHODS: Gal-3 was tested in normal and infected corneas of C57BL/6 mice. Mice corneas were pretreated with or without rmGal-3 or Gal-3 siRNA and infected with A. fumigatus. Recombinant mouse (rm) Gal-3 stimulated polymorphonuclear neutrophilic leukocytes (PMNs). PMNs were stimulated with 75% ethanol-killed A. fumigatus with or without pretreatment of Gal-3 siRNA. Disease severity was documented by clinical score and photographs with a slit lamp. PCR, Western blot, and ELISA tested expression of Gal-3, interleukin (IL)-1ß, IL-6, macrophage inflammatory protein 2 (MIP-2) and p-p38. PMNs infiltration was assessed by flow cytometry and myeloperoxidase (MPO) assay. RESULTS: Gal-3 expression was significantly elevated by A. fumigatus in mice corneas. rmGal-3 treatment increased clinical scores, PMNs infiltration, and cytokines expression, which were decreased by Gal-3 siRNA treatment. In PMNs, Gal-3 expression was also significantly increased by A. fumigatus. The rmGal-3 treatment upregulated proinflammatory cytokines secretion and p-p38 expression, which was significantly inhibited by Gal-3 siRNA. CONCLUSION: These data proved that A. fumigatus increased Gal-3 expression and elevated disease clinical scores, PMNs infiltration and cytokines expression through Gal-3. In PMNs, A. fumigatus upregulated IL-1ß and IL-6 secretion through the Gal-3 / p38 pathway.


Assuntos
Aspergilose/imunologia , Aspergillus fumigatus/imunologia , Galectina 3/metabolismo , Ceratite/imunologia , Neutrófilos/imunologia , Animais , Aspergilose/microbiologia , Aspergilose/patologia , Modelos Animais de Doenças , Feminino , Galectina 3/administração & dosagem , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Ceratite/microbiologia , Ceratite/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/metabolismo , Regulação para Cima/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
J Cereb Blood Flow Metab ; 41(4): 857-873, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33736511

RESUMO

Post-stroke neurological deficits and mortality are often associated with vascular disruption and neuronal apoptosis. Galectin-3 (Gal3) is a potent pro-survival and angiogenic factor. However, little is known about its protective role in the cerebral ischemia/reperfusion (I/R) injury. We have previously shown significant up-regulation of Gal3 in the post-stroke rat brain, and that blocking of Gal3 with neutralizing antibody decreases the cerebral blood vessel density. Our current study demonstrates that intracerebral local delivery of the Gal3 into rat brain at the time of reperfusion exerts neuroprotection. Ischemic lesion volume and neuronal cell death were significantly reduced as compared with the vehicle-treated MCAO rat brains. Gal3 increased vessel density and neuronal survival after I/R in rat brains. Importantly, Gal3-treated groups showed significant improvement in motor and sensory functional recovery. Gal3 increased neuronal cell viability under in vitro oxygen-glucose deprivation conditions in association with increased phosphorylated-Akt, decreased phosphorylated-ERK1/2, and reduced caspase-3 activity. Gene expression analysis showed down regulation of pro-apoptotic and inflammatory genes including Fas-ligand, and upregulation of pro-survival and pro-angiogenic genes including Bcl-2, PECAM, and occludin. These results indicate a key role for Gal3 in neuro-vascular protection and functional recovery following ischemic stroke through modulation of angiogenic and apoptotic pathways.


Assuntos
Indutores da Angiogênese/farmacologia , Apoptose/efeitos dos fármacos , Caspases/efeitos dos fármacos , Galectina 3/uso terapêutico , AVC Isquêmico/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Encéfalo , Morte Celular/efeitos dos fármacos , Galectina 3/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Hipóxia Encefálica/tratamento farmacológico , Microinjeções , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Endogâmicos SHR , Traumatismo por Reperfusão/prevenção & controle
3.
Pediatr Res ; 85(4): 527-532, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30679793

RESUMO

BACKGROUND: Invasive candidiasis is an important cause of fungal infections in immunocompromised patients, including premature infants. The S-type lectin, galectin-3 (gal3), is increasingly recognized for its role in antifungal host defense. This study tested the hypothesis that tissue gal3 expression is affected by disseminated infection with Candida albicans and that supplementation with gal3 will provide a benefit in this setting. METHODS: To determine the expression of gal3 at the tissue level in response to disseminated infection with C. albicans, adult and neonatal mice were infected using previously established models. End points were chosen that reflected substantive tissue fungal burden but before mortality. RESULTS: No differences in gal3 were detected in tissues of adult animals relative to uninfected controls. In neonatal animals, gal3 concentration was lower in the spleen of infected animals compared to uninfected. Pretreatment of neonatal mice with recombinant gal3 was associated with reduced mortality and reduced fungal burden in the kidney, spleen, and lung at 24 h following infection. CONCLUSION: These findings suggest that gal3 has an active role in host defense against candidiasis and that neonatal animals can benefit from supplementation with this lectin in the setting of disseminated candidiasis.


Assuntos
Candida albicans/isolamento & purificação , Candidíase/metabolismo , Galectina 3/metabolismo , Animais , Animais Recém-Nascidos , Candidíase/microbiologia , Feminino , Galectina 3/administração & dosagem , Rim/microbiologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/metabolismo , Baço/microbiologia
4.
J Autoimmun ; 89: 30-40, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29167025

RESUMO

Psoriasis-specific proteins dysregulated in keratinocytes and involved in the pathophysiological process of psoriasis remains elusive. We report here that epidermal galectin-3 expression is significantly downregulated in lesional skin, but not in non-lesional skin in psoriasis patients, nor in a group of diseases known as psoriasiform dermatitis clinically and histologically similar to psoriasis. The deficiency of epidermal galectin-3 is sufficient to promote development of psoriatic lesions, as evidenced by more severe skin inflammation in galectin-3 knockout (gal3-/-) mice, compared to wild-type mice, after imiquimod treatment, and in skin from gal3-/- mice grafted onto wildtype mice. The development of psoriatic-like lesions is attributable to 1) the spontaneously tuning up of psoriasis signatures in keratinocytes through JNK pathway; and 2) neutrophil accumulation caused by the enhanced leukocyte-recruiting capacity associated with overexpression of S100A7-9 and CXCL-1, 8 in keratinocytes with impaired galectin-3 expression. Psoriasis-like skin inflammation is significantly improved in gal-3-/- mice both by inhibition of neutrophils accumulation with a selective CXCR2 antagonist of SB225002, and by intracutaneous injection of recombinant galectin-3. Overall, these findings offer promising galectin-3-related diagnostic and therapeutic resolutions of psoriasis.


Assuntos
Biomarcadores/metabolismo , Galectina 3/metabolismo , Inflamação/diagnóstico , Queratinócitos/fisiologia , Neutrófilos/imunologia , Psoríase/diagnóstico , Pele/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Galectina 3/administração & dosagem , Galectina 3/genética , Humanos , Imiquimode , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Compostos de Fenilureia/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Transdução de Sinais
5.
PLoS One ; 12(10): e0184378, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29016609

RESUMO

Glycoprotein receptors are influenced by myriad intermolecular interactions at the cell surface. Specific glycan structures may interact with endogenous lectins that enforce or disrupt receptor-receptor interactions. Glycoproteins bound by multivalent lectins may form extended oligomers or lattices, altering the lateral mobility of the receptor and influencing its function through endocytosis or changes in activation. In this study, we have examined the interaction of Galectin-3 (Gal-3), a human lectin, with adhesion receptors. We measured the effect of recombinant Gal-3 added exogenously on the lateral mobility of the α5ß1 integrin on HeLa cells. Using single-particle tracking (SPT) we detected increased lateral mobility of the integrin in the presence of Gal-3, while its truncated C-terminal domain (Gal-3C) showed only minor reductions in lateral mobility. Treatment of cells with Gal-3 increased ß1-integrin mediated migration with no apparent changes in viability. In contrast, Gal-3C decreased both cell migration and viability. Fluorescence microscopy allowed us to confirm that exogenous Gal-3 resulted in reorganization of the integrin into larger clusters. We used a proteomics analysis to confirm that cells expressed endogenous Gal-3, and found that addition of competitive oligosaccharide ligands for the lectin altered the lateral mobility of the integrin. Together, our results are consistent with a Gal-3-integrin lattice model of binding and confirm that the lateral mobility of integrins is natively regulated, in part, by galectins.


Assuntos
Endocitose/genética , Galectina 3/genética , Integrina alfa5beta1/metabolismo , Proteômica , Adesão Celular/genética , Movimento Celular/efeitos dos fármacos , Galectina 3/administração & dosagem , Regulação da Expressão Gênica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Células HeLa , Humanos , Integrina alfa5beta1/genética , Oligossacarídeos/metabolismo , Ligação Proteica
6.
J Immunol ; 198(11): 4458-4469, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28438899

RESUMO

In vivo and ex vivo imaging were used to investigate the function of galectin-3 (Gal-3) during the process of leukocyte recruitment to the inflamed microcirculation. The cremasteric microcirculation of wild-type (C57BL/6), Gal-3-/-, and CX3CR1gfp/+ mice were assessed by intravital microscopy after PBS, IL-1ß, TNF-α, or recombinant Gal-3 treatment. These cellular responses were investigated further using flow-chamber assays, confocal microscopy, flow cytometry, PCR analysis, and proteome array. We show that mechanisms mediating leukocyte slow rolling and emigration are impaired in Gal-3-/- mice, which could be because of impaired expression of cell adhesion molecules and an altered cell surface glycoproteome. Local (intrascrotal) administration of recombinant Gal-3 to wild-type mice resulted in a dose-dependent reduction in rolling velocity associated with increased numbers of adherent and emigrated leukocytes, ∼50% of which were Ly6G+ neutrophils. Intrascrotal administration of Gal-3 to CX3CR1gfp/+ mice confirmed that approximately equal numbers of monocytes are also recruited in response to this lectin. Exogenous Gal-3 treatment was accompanied by increased proinflammatory cytokines and chemokines within the local tissue. In conclusion, this study unveils novel biology for both exogenous and endogenous Gal-3 in promoting leukocyte recruitment during acute inflammation.


Assuntos
Galectina 3/metabolismo , Migração e Rolagem de Leucócitos , Leucócitos/fisiologia , Microcirculação/imunologia , Infiltração de Neutrófilos , Neutrófilos/fisiologia , Vasculite/imunologia , Animais , Adesão Celular , Comunicação Celular , Movimento Celular , Galectina 3/administração & dosagem , Galectina 3/deficiência , Galectina 3/genética , Regulação da Expressão Gênica , Leucócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo
7.
Chembiochem ; 17(18): 1759-70, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27356186

RESUMO

Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin-3 accumulation at damaged vesicles, hence revealing galectin-3-glycan interactions involved in fibrosis progression and in intracellular galectin-3 activities, is reported. 3,3'-Bis-(4-aryltriazol-1-yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin-1, -2, -3, and -4 N-terminal, -4 C-terminal, -7 and -8 N-terminal, -9 N-terminal, and -9 C-terminal domains. Compounds displaying low-nanomolar affinities for galectins-1 and -3 were identified in a competitive fluorescence anisotropy assay. X-ray structural analysis of selected compounds in complex with galectin-3, together with galectin-3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin-3. The most potent galectin-3 antagonist was demonstrated to act in an assay monitoring galectin-3 accumulation upon amitriptyline-induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin-carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin-induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone.


Assuntos
Bleomicina , Galectina 3/metabolismo , Polissacarídeos/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , Tioglicosídeos/farmacologia , Administração Oral , Animais , Sítios de Ligação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Galectina 3/administração & dosagem , Galectina 3/química , Camundongos , Conformação Molecular , Polissacarídeos/análise , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Relação Estrutura-Atividade , Tioglicosídeos/administração & dosagem , Tioglicosídeos/química , Tioglicosídeos/uso terapêutico
8.
J Am Heart Assoc ; 3(5): e000962, 2014 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-25237044

RESUMO

BACKGROUND: Galectin-3 is a biomarker for prognostication and risk stratification of patients with heart failure (HF). It has been suggested that renal function strongly relates to galectin-3 levels. We aimed to describe galectin-3 renal handling in HF. METHODS AND RESULTS: In Sprague-Dawley rats, we infused galectin-3 and studied distribution and renal clearance. Furthermore, galectin-3 was measured in urine and plasma of healthy controls, HF patients and hemodialysis patients. To mimic the human situation, we measured galectin-3 before and after the artificial kidney. Infusion in rats resulted in a clear increase in plasma and urine galectin-3. Plasma galectin-3 in HF patients (n=101; mean age 64 years; 93% male) was significantly higher compared to control subjects (n=20; mean age 58 years; 75% male) (16.6 ng/mL versus 9.7 ng/mL, P<0.001), while urinary galectin-3 in HF patients was comparable (28.1 ng/mL versus 35.1 ng/mL, P=0.830). The calculated galectin-3 excretion rate was lower in HF patient (2.3 mL/min [1.5 to 3.4] versus 3.9 mL/min [2.3 to 6.4] in control subjects; P=0.005). This corresponded with a significantly lower fractional excretion of galectin-3 in HF patients (2.4% [1.7 to 3.7] versus 3.0% [1.9 to 5.5]; P=0.018). These differences, however, were no longer significant after correction for age, gender, diabetes, and smoking. HF patients who received diuretics (49%) showed significantly higher aldosterone and galectin-3 levels. Hemodialysis patients (n=105; mean age 63 years; 65% male), without urinary galectin-3 excretion, had strongly increased median plasma galectin-3 levels (70.6 ng/mL). CONCLUSIONS: In this small cross-sectional study, we report that urine levels of galectin-3 are not increased in HF patients, despite substantially increased plasma galectin-3 levels. The impaired renal handling of galectin-3 in patients with HF may explain the described relation between renal function and galectin-3 and may account for the elevated plasma galectin-3 in HF.


Assuntos
Galectina 3/metabolismo , Insuficiência Cardíaca/metabolismo , Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia , Rim/metabolismo , Administração Intravenosa , Animais , Proteínas Sanguíneas , Estudos de Casos e Controles , Doença Crônica , Estudos Transversais , Feminino , Galectina 3/administração & dosagem , Galectina 3/sangue , Galectina 3/farmacocinética , Galectina 3/urina , Galectinas , Insuficiência Cardíaca/diagnóstico , Humanos , Rim/fisiopatologia , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ratos Sprague-Dawley , Diálise Renal , Eliminação Renal
9.
Small ; 10(21): 4281-6, 2014 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-25091699

RESUMO

Polymeric micelles with and without galactose are synthesized to study liver targeting ability in an orthotopic HCC rat model. Micelles with galactose accumulate more in the healthy liver tissue instead of HCC, while micelles without galactose amass in HCC by the EPR effect. These micelles show great potential as drug delivery carriers to target either the liver or HCC.


Assuntos
Plásticos Biodegradáveis , Permeabilidade da Membrana Celular/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/farmacocinética , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos , Galactose/química , Lectinas/química , Nanopartículas/química , Cimento de Policarboxilato/química , Animais , Plásticos Biodegradáveis/síntese química , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/farmacocinética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Materiais Revestidos Biocompatíveis/síntese química , Materiais Revestidos Biocompatíveis/química , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Galectina 3/administração & dosagem , Galectina 3/química , Galectina 3/farmacocinética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Micelas , Nanopartículas/uso terapêutico , Ratos , Ratos Endogâmicos BUF , Propriedades de Superfície , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/instrumentação , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
10.
Mol Biol (Mosk) ; 47(6): 1004-10, 2013.
Artigo em Russo | MEDLINE | ID: mdl-25509862

RESUMO

Now a number of CD4+ T-lymphocytes, known as Th1, Th2, Treg and Th17, is currently identified and well- studied. The methods basing on the targeted regulation of differentiation process of the Th-lymphocytes that carry out the immune response polarization attract an attention of scientists dealing with a correction of immune-mediated. In the present study, endogenous beta-galactoside-binding protein of the lectin family, galectin-3, was investigated as a regulator of T-cell homeostasis. A galectin-3 is known to be actively produced by tumor cells in malignant transformation and able to influence the processes of signal transduction, cell-cell cooperation and the implementation of programmed death. As cell differentiation processes are directly connected with the regulation of gene expression, we investigated the effect of recombinant galectin-3 on expression of mRNA of transcription.factors, which guide the differentiation of CD4+ lymphocytes. The study was performed on peripheral blood mononuclear cells of healthy individuals. The gene expression levels were evaluated by a real-time PCR. In the experiments in vitro, it has been first found the recombinant galectin-3 (0.5 mg/mL) up-regulating the expression of transcription factors Gata-3 and Rorc mRNAs and down-regulating the mRNA expression of transcription factors T-bet and FoxP3. Up to a concentration of 1 mg/mL recombinant galectin-3 stimulates Th-cells by dose-dependent manner, whereas at higher concentrations stimulating effect weakens, and inhibiting action starts prevailing. Thus, one can suppose that galectin-3 through regulation of lymphocytes differentiation promote development of allergic, autoimmune and neoplastic diseases that allows us to consider the galectin-3 as a.potential target for therapy of these diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , Galectina 3/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Feminino , Fator de Transcrição GATA3/biossíntese , Galectina 3/administração & dosagem , Galectina 3/genética , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/biossíntese
11.
Lab Invest ; 89(1): 26-37, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19015643

RESUMO

Galectin-3 is a beta-galactoside-binding animal lectin having pleiotropic effects on cell growth, differentiation, and apoptosis. This lectin has been shown to be involved in phagocytosis by macrophages and in inflammation. Here we investigated an involvement of galectin-3 in the regulatory process of inflammatory bone resorption in rats with adjuvant-induced arthritis (AA rats) accompanying severe bone destruction in the ankle joints. The protein level of galectin-3 in the ankle-joint extracts was markedly augmented at week 3 after adjuvant injection, at the time when severe bone destruction was observed. Immunohistochemical analysis revealed an extremely high expression of galectin-3 in macrophages and granulocytes infiltrated in the area of severe bone destruction. To estimate the role of galectin-3 in osteoclastogenesis and osteoclastic bone resorption, recombinant galectin-3 was added to in vitro culture systems. Galectin-3 markedly inhibited the formation of osteoclasts in cultures of murine osteoclast precursor cell line as well as in rat bone marrow culture systems. This inhibition was not observed by heat-inactivated galectin-3 or by galectin-7. Although recombinant galectin-3 did not affect signaling through mitogen-activated protein kinase (MAPK) or nuclear factor-kappaB (NF-kappaB), it specifically suppressed the induction of nuclear factor of activated T-cells c1 (NFATc1). Galectin-3 significantly inhibited dentine resorption by mature osteoclasts in vitro. Furthermore, in vivo studies clearly showed a significant suppression of bone destruction and osteoclast recruitment accompanying arthritis, when galectin-3 was injected into the cavity of ankle joint of AA rats. Thus, abundant galectin-3 observed in the area of severe bone destruction may act as a negative regulator for the upregulated osteoclastogenesis accompanying inflammation to prevent excess bone destruction.


Assuntos
Artrite Experimental/metabolismo , Artrite Experimental/patologia , Galectina 3/metabolismo , Osteoclastos/patologia , Animais , Células da Medula Óssea/citologia , Reabsorção Óssea/prevenção & controle , Metabolismo dos Carboidratos , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Galectina 3/administração & dosagem , Galectina 3/antagonistas & inibidores , Galectina 3/farmacologia , Injeções Intra-Articulares , Masculino , Fatores de Transcrição NFATC/antagonistas & inibidores , Fatores de Transcrição NFATC/biossíntese , Ligante RANK/metabolismo , Ligante RANK/farmacologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Índice de Gravidade de Doença , Células-Tronco/citologia , Tíbia/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
12.
Arthritis Res Ther ; 9(1): R20, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17326835

RESUMO

In this study we examine the extracellular role of galectin-3 (gal-3) in joint tissues. Following intra-articular injection of gal-3 or vehicle in knee joints of mice, histological evaluation of articular cartilage and subchondral bone was performed. Further studies were then performed using human osteoarthritic (OA) chondrocytes and subchondral bone osteoblasts, in which the effect of gal-3 (0 to 10 microg/ml) was analyzed. Osteoblasts were incubated in the presence of vitamin D3 (50 nM), which is an inducer of osteocalcin, encoded by an osteoblast terminal differentiation gene. Genes of interest mainly expressed in either chondrocytes or osteoblasts were analyzed with real-time RT-PCR and enzyme immunoassays. Signalling pathways regulating osteocalcin were analyzed in the presence of gal-3. Intra-articular injection of gal-3 induced knee swelling and lesions in both cartilage and subchondral bone. On human OA chondrocytes, gal-3 at 1 microg/ml stimulated ADAMTS-5 expression in chondrocytes and, at higher concentrations (5 and 10 microg/ml), matrix metalloproteinase-3 expression. Experiments performed with osteoblasts showed a weak but bipolar effect on alkaline phosphatase expression: stimulation at 1 microg/ml or inhibition at 10 microg/ml. In the absence of vitamin D3, type I collagen alpha 1 chain expression was inhibited by 10 microg/ml of gal-3. The vitamin D3 induced osteocalcin was strongly inhibited in a dose-dependent manner in the presence of gal-3, at both the mRNA and protein levels. This inhibition was mainly mediated by phosphatidylinositol-3-kinase. These findings indicate that high levels of extracellular gal-3, which could be encountered locally during the inflammatory process, have deleterious effects in both cartilage and subchondral bone tissues.


Assuntos
Líquido Extracelular/química , Líquido Extracelular/metabolismo , Galectina 3/metabolismo , Articulações/química , Articulações/metabolismo , Idoso , Animais , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Feminino , Galectina 3/administração & dosagem , Galectina 3/fisiologia , Humanos , Inflamação/metabolismo , Articulações/patologia , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Osteoblastos/metabolismo , Osteoblastos/patologia
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