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1.
Int J Mol Sci ; 14(10): 20793-808, 2013 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-24135873

RESUMEN

Cartilage is an avascular tissue and cartilage metabolism depends on molecule diffusion from synovial fluid and subchondral bone. Thus, nutrient availability is limited by matrix permeability according to the size and charge of the molecules. Matrix composition limits the access of molecules to chondrocytes, determining cell metabolism and cartilage maintenance. Lipids are important nutrients in chondrocyte metabolism and are available for these cells through de novo synthesis but also through diffusion from surrounding tissues. Cartilage status and osteoarthritis development depend on lipid availability. This paper reviews lipid transport and metabolism in cartilage. We also analyze signalling pathways directly mediated by lipids and those that involve mTOR pathways, both in normal and osteoarthritic cartilage.


Asunto(s)
Transporte Biológico/fisiología , Cartílago/metabolismo , Metabolismo de los Lípidos/fisiología , Osteoartritis/metabolismo , Animales , Condrocitos/metabolismo , Humanos , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo
2.
Front Med (Lausanne) ; 7: 566250, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33102504

RESUMEN

Objective: Several studies have linked metabolic syndrome to the development of osteoarthritis (OA) through hypercholesterolemia, one of its components. However, epidemiological studies showed contradictory results, and it is not clear how hypercholesterolemia itself, or oxidized LDL (oxLDL)-a pathological molecule potentially involved in this relationship-could be affecting OA. The objectives of this study were to investigate the effect of hypercholesterolemia induced by high-fat diet (HFD) in cartilage from OA rabbits, and how oxLDL affect human chondrocyte inflammatory and catabolic responses. Design: New Zealand rabbits were fed with HFD for 18 weeks. On week 6, OA was surgically induced. At the end of the study, cartilage damage and IL-1ß, IL-6, MCP-1, MMP-13, and COX-2 expression in articular cartilage were evaluated. In addition, cultured human OA articular chondrocytes were treated with oxLDL at concentrations equivalent to those expected in synovial fluid from HFD rabbits, in the presence of IL-1ß and TNFα. The effect of oxLDL on cell viability, nitric oxide production and catabolic and pro-inflammatory gene expression was evaluated. Results: HFD intake did not modify cartilage structure or pro-inflammatory and catabolic gene expression and protein presence, both in healthy and OA animals. OxLDL did not affect human chondrocyte viability, ADAMTS5 and liver X receptor (LXR) α gene expression, but decreased the induction of IL-1ß, IL-6, MCP-1, MMP-13, iNOS, and COX-2 gene expression and MMP-13 and COX-2 protein presence, evoked by cytokines. Conclusions: Our data suggest that cholesterol intake per se may not be deleterious for articular cartilage. Instead, cholesterol de novo synthesis and altered cholesterol metabolism could be involved in the associations observed in human disease.

3.
Sci Rep ; 7(1): 6311, 2017 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-28740214

RESUMEN

Inflammatory activity in rheumatoid arthritis may alter the regulation of muscle mass leading to a secondary sarcopenia, commonly termed rheumatoid cachexia (RC). We characterized alterations to muscle structure and various pro-inflammatory, catabolic and regenerative markers in an animal model of RC. Antigen induced arthritis (AiA) was performed in 20 male adult rabbits. AiA animals exhibited significantly less weight gain, a markedly elevated serum C-reactive protein (CRP), lighter muscles with shorter cross-sectional diameter and increased myonuclei when compared to controls. Atrogin-1 and MuRF-1 were up-regulated alongside an increase in IL-1ß, active NF-κB and a higher ratio of phosphorylated to inactive p38 MAPK. CCL-2 and TNF levels were reduced and IL-6 was unchanged between groups. We observed decreased pSTAT3, unchanged pSTAT1 and Myf5, but increased Pax7, MyoD and myogenin. AiA rabbits had a reduction in myostatin from gastrocnemii and synovium with a congruent decrease in serum myostatin compared to controls. Chronic arthritis induced an RC-like secondary sarcopenia with increased muscle protein breakdown. Elevated IL-1ß may trigger proteolysis via elevated NF-κB and p38 MAPK signaling with a compensatory anabolic response suggested by myonuclear expansion, increased Pax7, MyoD and myogenin, reduced pSTAT3 as well as reduced serum, synovial and muscular myostatin.


Asunto(s)
Artritis Experimental/complicaciones , Proteína C-Reactiva/metabolismo , Redes y Vías Metabólicas , Sarcopenia/metabolismo , Animales , Artritis Experimental/metabolismo , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Masculino , Miostatina/metabolismo , Fosforilación , Conejos , Proteínas Ligasas SKP Cullina F-box/metabolismo , Sarcopenia/etiología , Proteínas de Motivos Tripartitos/metabolismo , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
4.
Nat Genet ; 49(5): 801-805, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28319091

RESUMEN

We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10-12, odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs*106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 × 10-18, OR = 7.71). On average, c.1141G>C heterozygotes and individuals homozygous for rs532464664 had their hip replacement operation 13.5 years and 4.9 years earlier than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense-mediated decay of the mutant transcripts.


Asunto(s)
Proteína de la Matriz Oligomérica del Cartílago/genética , Proteínas de la Matriz Extracelular/genética , Predisposición Genética a la Enfermedad/genética , Genoma Humano/genética , Osteoartritis de la Cadera/genética , Análisis de Secuencia de ADN/métodos , Artroplastia de Reemplazo de Cadera , Células Cultivadas , Codón sin Sentido , Mutación del Sistema de Lectura , Expresión Génica , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Islandia , Estimación de Kaplan-Meier , Mutación Missense , Osteoartritis de la Cadera/cirugía , Polimorfismo de Nucleótido Simple , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo
5.
Sci Rep ; 6: 29243, 2016 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-27385438

RESUMEN

Obesity and osteoarthritis (OA) form a vicious circle in which obesity contributes to cartilage destruction in OA, and OA-associated sedentary behaviour promotes weight gain. Lipocalin-2 (LCN2), a novel adipokine with catabolic activities in OA joints, contributes to the obesity and OA pathologies and is associated with other OA risk factors. LCN2 is highly induced in osteoblasts in the absence of mechanical loading, but its role in osteoblast metabolism is unclear. Therefore, because osteochondral junctions play a major role in OA development, we investigated the expression and role of LCN2 in osteoblasts and chondrocytes in the OA osteochondral junction environment. Our results showed that LCN2 expression in human osteoblasts and chondrocytes decreased throughout osteoblast differentiation and was induced by catabolic and inflammatory factors; however, TGF-ß1 and IGF-1 reversed this induction. LCN2 reduced osteoblast viability in the presence of iron and enhanced the activity of MMP-9 released by osteoblasts. Moreover, pre-stimulated human osteoblasts induced LCN2 expression in human chondrocytes, but the inverse was not observed. Thus, LCN2 is an important catabolic adipokine in osteoblast and chondrocyte metabolism that is regulated by differentiation, inflammation and catabolic and anabolic stimuli, and LCN2 expression in chondrocytes is regulated in a paracrine manner after osteoblast stimulation.


Asunto(s)
Condrocitos/metabolismo , Lipocalina 2/metabolismo , Osteoartritis/metabolismo , Osteoblastos/metabolismo , Adipoquinas/metabolismo , Cartílago Articular/metabolismo , Diferenciación Celular/fisiología , Células Cultivadas , Humanos , Inflamación/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Osteogénesis/fisiología , Factor de Crecimiento Transformador beta1/metabolismo
6.
Maturitas ; 85: 27-33, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26857876

RESUMEN

OBJECTIVES: Despite the high prevalence of osteoarthritis (OA) in postmenopausal women, a relationship between circulating estrogen levels and the development of OA has not been found. Therefore, the purpose of this study was to evaluate the expression and activity of aromatase, a key enzyme in local production of estrogens, in human OA cultured articular chondrocytes, and to determine the physiological relevance of this enzyme in cartilage. METHODS: Human OA articular chondrocytes were isolated and cultured. Local production of estradiol was measured after incubation with 100 ng/ml testosterone for 8 and 24h. Furthermore, chondrocytes were culture for 2h, 48 h, 7 days or 15 days, or in alginate beads for 10 days. Aromatase, type II and X collagen, aggrecan, alkaline phosphatase, and Runx2 expression were evaluated in cartilage, freshly isolated chondrocytes and cultured chondrocytes. RESULTS: Aromatase was expressed and active in cultured human chondrocytes. Human cartilage, freshly isolated chondrocytes, and chondrocytes cultured for 2h expressed an insignificant amount of aromatase; however, expression arose after 48 h of culture and remained increased thereafter. Aromatase expression was not related to estrogen deprivation and was inversely correlated with differentiation. Re-differentiation did not reduce its expression. CONCLUSIONS: Aromatase presents an almost undetectable expression in human cartilage but is induced in cultured chondrocytes. Therefore, human cartilage might act as a mere target for estrogens rather than a producer, and researchers using cell expansion in culture for latter therapies should consider these changes in estrogen metabolism which may not be reverted after re-differentiation.


Asunto(s)
Aromatasa/metabolismo , Cartílago Articular/enzimología , Condrocitos/enzimología , Osteoartritis/enzimología , Alginatos , Aromatasa/biosíntesis , Diferenciación Celular , Células Cultivadas , Inducción Enzimática , Estradiol/biosíntesis , Estrógenos/metabolismo , Femenino , Ácido Glucurónico , Ácidos Hexurónicos , Humanos , Persona de Mediana Edad , Cultivo Primario de Células , Testosterona/farmacología , Factores de Tiempo
7.
Nat Rev Rheumatol ; 11(3): 159-70, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25512010

RESUMEN

Osteoarthritis (OA), the most common rheumatic disease, is characterized by joint-space narrowing due to progressive cartilage degradation and alterations in subchondral bone and the synovial membrane. These articular disturbances can have severe consequences, including pain, disability and loss of joint architectural integrity. Although the aetiology of OA is not understood, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by damage-associated molecules are thought to be involved. In this Review, we examine the relationship between Toll-like receptor 4 (TLR4) and OA in cartilage as well as in other OA-affected tissues, such as subchondral bone and synovium. We also discuss the different TLR4 agonists associated with OA and their effects in joint tissues. Finally, we describe existing and novel strategies that might be used to develop TLR4-specific disease-modifying OA drugs (DMOADs).


Asunto(s)
Osteoartritis/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Humanos , Osteoartritis/patología , Transducción de Señal
8.
Expert Opin Ther Targets ; 18(9): 1077-87, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24950016

RESUMEN

INTRODUCTION: Stromal cell-derived factor 1 (SDF-1) is a potent chemoattractant cytokine with various biological functions such as stem cell mobilization, inflammatory cell infiltration and angiogenesis. Therefore, it has also been implicated in several pathological processes, from ischemic conditions to cancer. Remarkably, SDF-1 and its receptors, CXCR4 and CXCR7, are also present in joint tissues, where they play a role in the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA). AREAS COVERED: This review summarizes the physiological and pathological role of SDF-1 signaling and its involvement in RA and OA. That includes synovial inflammation, bone erosion, cartilage degradation and increased bone turnover. Although this cytokine could play different roles in these rheumatic diseases, specific and differentiated therapeutic targets in each process can be identified. Current therapeutic strategies to block SDF-1 signaling in several diseases and their possible use in rheumatic diseases are also discussed. EXPERT OPINION: Emerging drugs that block CXCR4 or CXCR7 in different disorders may represent promising therapies for rheumatic disease via inhibition of key pathological events involved in the progression of RA and OA.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Quimiocina CXCL12/metabolismo , Osteoartritis/tratamiento farmacológico , Animales , Antirreumáticos/farmacología , Artritis Reumatoide/fisiopatología , Diseño de Fármacos , Humanos , Terapia Molecular Dirigida , Osteoartritis/fisiopatología , Receptores CXCR/antagonistas & inhibidores , Receptores CXCR/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/metabolismo , Transducción de Señal
9.
Mol Nutr Food Res ; 58(2): 256-66, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24039109

RESUMEN

SCOPE: Ginger has long been used in traditional Asian medicine to treat osteoarthritis. Indeed, scientific research has reported that ginger derivatives (GDs) have the potential to control innate immune responses. Given the widespread use and demonstrated properties of GDs, we set out to study their anti-inflammatory and anticatabolic properties in chondrocytes. METHODS AND RESULTS: 6-shogaol (6-S), the most active GD, was obtained from ginger. 6-S was not toxic as measured by MTT assay, and inhibited NO production and IL-6 and MCP-1 induced gene expression in LPSbut not in IL-1ß-stimulated chondrocytes. 6-S also inhibited LPS-mediated ERK1/2 activation as well as NOS2 and MyD88 induced expression as determined by Western blot. Moreover, zymography revealed that 6-S inhibited matrix metalloproteinases (MMP) 2/9 induction in LPS-treated cells. Hydrated 6-S was modified to obtain a compound (SSi6) without 6-S potential anti-inflammatory properties. Both 6-S and SSi6 inhibited cathepsin-K activity. CONCLUSION: 6-S blocked TLR4-mediated innate immune responses and MMP induction in chondrocytes. These results, together with GDs-mediated cathepsin-K inhibition, suggest the potential for GDs use against cartilage and bone degradation. Therefore, considering that clinical trials involving oral administration of ginger achieved relevant nontoxic GDs serum concentrations, we suggest that a ginger-supplemented diet might reduce OA symptoms.


Asunto(s)
Catecoles/farmacología , Catepsina K/metabolismo , Condrocitos/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Extractos Vegetales/farmacología , Antiinflamatorios/farmacología , Catepsina K/antagonistas & inhibidores , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Quimiocina CCL2/metabolismo , Condrocitos/metabolismo , Zingiber officinale/química , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/efectos adversos , Sistema de Señalización de MAP Quinasas , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Receptor Toll-Like 4/metabolismo
10.
Life Sci ; 91(7-8): 264-70, 2012 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-22884805

RESUMEN

AIMS: The purpose of this study is to investigate circulating endothelial progenitor cells (EPCs) and the signaling pathways involved in their recruitment in the ischemic retina of the 50/10 rat model of oxygen-induced retinopathy (OIR). MAIN METHODS: Within 12h after birth, litters of Sprague-Dawley rats and their mothers were exposed to alternating oxygen concentrations, followed by a room air exposition, to induce OIR. Retinopathy was quantified by ADPase stain in flat-mounted retinas and pre-ILM nuclei count in retinal sections. Semiquantitative real-time PCR and immunofluorescence were assessed in retinas to study stromal cell-derived factor 1 (SDF-1), its receptor CXCR4 and vascular endothelial growth factor (VEGF) expression. Circulating EPCs were evaluated by flow cytometry in peripheral blood. KEY FINDINGS: Our results showed increased immunolabelling of SDF-1 in endothelial cells and strong expression of CXCR4 in Müller cells in OIR retinas as compared to control retinas. We found increased levels of CXCR4 and VEGF mRNA in OIR retinas, especially during the vascular attenuation stage. The number of circulating EPCs was decreased in OIR rats as compared to control rats. SIGNIFICANCE: The decrease in circulating EPCs could be implied in vessel growth arrest during normal retinal development in OIR rats, while pro-angionenic signals released by Müller cells in the hypoxic retina could drive pathological neovascularization in the ischemic retina. These data warrant further studies to investigate new therapeutic approaches for ROP.


Asunto(s)
Quimiocina CXCL12/fisiología , Células Endoteliales/citología , Neovascularización Patológica , Oxígeno/administración & dosificación , Receptores CXCR4/fisiología , Enfermedades de la Retina/etiología , Vasos Retinianos/fisiopatología , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , Células de la Médula Ósea/patología , Quimiocina CXCL12/genética , Citometría de Flujo , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Oxígeno/efectos adversos , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores CXCR4/genética , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/fisiopatología , Vasos Retinianos/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética
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