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1.
Toxicol Lett ; 321: 122-130, 2020 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-31874197

RESUMEN

Our previous studies confirmed that prenatal caffeine exposure (PCE) could induce susceptibility to osteoarthritis in adult offspring rats due to poor chondrocyte differentiation, but its mechanism remains to be further investigated. This study aimed to explore whether subchondral bone dysplasia mediates susceptibility to osteoarthritis in adult offspring rats induced by PCE. Pregnant Wistar rats were treated with caffeine (120 mg/kg.d) or saline from gestational day (GD) 9 to 20. The female offspring were euthanized to collect femurs at GD20, postnatal week (PW) 6, and PW28 (non-ovariectomy and ovariectomy groups) to detect osteoarthritis-like phenotype, subchondral bone mass, ossification center development, and other evidence. The results showed that PCE increased the Mankin score of pathological articular cartilage, but decreased articular cartilage thickness and subchondral bone mass, which were more obvious after ovariectomy. Meanwhile, the correlation analysis results demonstrated that the Mankin score of articular cartilage was significantly negatively correlated with subchondral bone mass, and the thickness of articular cartilage was significantly positively correlated with subchondral bone mass. Further, the length and area of the primary and secondary ossification centers, the number of osteoblasts, and the related genes' expression of osteogenic differentiation (e.g., Runx2, BSP, ALP, and OCN) were all significantly decreased in the PCE group before and after birth. Taken together, PCE induced susceptibility to osteoarthritis in adult female offspring, which was likely related to the subchondral bone dysplasia and reduction of subchondral bone mass production due to developmental disorder of primary and secondary ossification centers caused by osteoblast differentiation disability before and after birth.


Asunto(s)
Enfermedades del Desarrollo Óseo/inducido químicamente , Cafeína/toxicidad , Cartílago Articular/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/toxicidad , Osteoartritis/inducido químicamente , Osteogénesis/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Factores de Edad , Animales , Enfermedades del Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/metabolismo , Enfermedades del Desarrollo Óseo/patología , Cartílago Articular/patología , Diferenciación Celular/efectos de los fármacos , Femenino , Fémur/efectos de los fármacos , Fémur/metabolismo , Fémur/patología , Edad Gestacional , Osteoartritis/genética , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteoblastos/patología , Osteogénesis/genética , Ovariectomía , Embarazo , Ratas Wistar , Factores Sexuales , Tibia/efectos de los fármacos , Tibia/metabolismo , Tibia/patología
2.
Int. j. morphol ; 37(4): 1551-1556, Dec. 2019. graf
Artículo en Español | LILACS | ID: biblio-1040168

RESUMEN

La inyección con monoiodo acetato de sodio (MIA) es ampliamente utilizada para producir osteoartritis en diversas articulaciones. El objetivo fue describir los daños histológicos provocados por MIA en la articulación humeral de rata. Se inyectó 0,1 mL de mezcla de 0,5 mg de MIA disuelto en 10 mL de solución fisiológica en la articulación humeral izquierda de 21 ratas SpragueDawley. Como control se utilizó la articulación derecha de cada rata. Se realizó la eutanasia a las 4, 8 y 12 semanas post inyección en grupos de 7 ratas. Los miembros mantenidos en formalina tamponada al 10% fueron descalcificados con EDTA por tres meses. Para la evaluación histológica se realizó la inclusión en parafina y se realizaron cortes coronales de 5 µm de espesor, para posterior tinción con azul de toluidina. En el cartílago sano, se observó una superficie lisa sin fisuras, todas las células de las zonas del cartílago se observaron normales. Se observaron cambios en el cartílago articular a partir de las 4 semanas post inyección, los condrocitos de la zona radial hipertróficos con gran producción de proteoglicanos. A las 12 semanas post inyección, se observa un gran deterioro, el espacio articular se ve disminuido, La superficie del cartílago se observa con fisuras y grietas que llegan hasta la zona radial. Las células alrededor de estas fisuras han desaparecido. Se observa una pérdida prominente de proteoglicanos debido a la débil tinción con azul de toluidina. La inyección articular con MIA produce lesiones similares a la OA. La gran ventaja de la OA inducida por MIA, es la facilidad de su aplicación y la rapidez en la progresión de OA.


Injection with monoiode sodium acetate (MIA) is widely used to produce osteoarthritis in various joints. The aim of this work was to describe the histological damage caused by MIA in the rat humeral joint; 0.1 mL of 0.5 mg mixture of MIA dissolved in 10 mL of physiological solution was injected into the left humeral joint of 21 Sprague-Dawley rats. As a control, the right joint of each rat was used. Euthanasia was performed at 4, 8 and 12 weeks post injection in groups of 7 rats. The samples maintained in 10 % buffered formalin were descaled with EDTA for three months. For histological evaluation, paraffin inclusion was performed and 5 µm thick coronal cuts were made for subsequent staining with toluidine blue. In the healthy cartilage, a smooth surface was observed, all cells in the cartilage areas were normal. Changes in articular cartilage were observed after 4 weeks post injection, hypertrophic radial chondrocytes with high proteoglycan production. At 12 weeks post injection, a great deterioration was observed, the articular space was diminished. The surface of the cartilage was observed with fissures and cracks that reach the radial zone. The cells around these fissures have disappeared. A prominent loss of proteoglycans was observed due to weak toluidine blue staining. Joint injection with MIA produced lesions similar to OA. The great advantage of the OA induced by MIA, is the ease of its application and the rapidity in the progression of OA.


Asunto(s)
Animales , Femenino , Ratas , Osteoartritis/inducido químicamente , Articulación del Hombro/patología , Ácido Yodoacético/farmacología , Osteoartritis/patología , Articulación del Hombro/efectos de los fármacos , Cartílago Articular/patología , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Húmero/patología
3.
BMC Complement Altern Med ; 19(1): 325, 2019 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-31752825

RESUMEN

BACKGROUND: Osteoarthritis (OA) is an age-related joint disease with characteristics that involve the progressive degradation of articular cartilage and resulting chronic pain. Previously, we reported that Astragalus membranaceus and Lithospermum erythrorhizon showed significant anti-inflammatory and anti-osteoarthritis activities. The objective of this study was to examine the protective effects of ALM16, a new herbal mixture (7:3) of ethanol extracts of A. membranaceus and L. erythrorhizon, against OA in in vitro and in vivo models. METHODS: The levels of matrix metalloproteinase (MMP)-1, -3 and - 13 and glycosaminoglycan (GAG) in interleukin (IL)-1ß or ALM16 treated SW1353 cells were determined using an enzyme-linked immunosorbent and quantitative kit, respectively. In vivo, the anti-analgesic and anti-inflammatory activities of ALM16 were assessed via the acetic acid-induced writhing response and in a carrageenan-induced paw edema model in ICR mice, respectively. In addition, the chondroprotective effects of ALM16 were analyzed using a single-intra-articular injection of monosodium iodoacetate (MIA) in the right knee joint of Wister/ST rat. All samples were orally administered daily for 2 weeks starting 1 week after the MIA injection. The paw withdrawal threshold (PWT) in MIA-injected rats was measured by the von Frey test using the up-down method. Histopathological changes of the cartilage in OA rats were analyzed by hematoxylin and eosin (H&E) staining. RESULTS: ALM16 remarkably reduced the GAG degradation and MMP levels in IL-1ß treated SW1353 cells. ALM16 markedly decreased the thickness of the paw edema and writhing response in a dose-dependent manner in mice. In the MIA-induced OA rat model, ALM16 significantly reduced the PWT compared to the control group. In particular, from histological observations, ALM16 showed clear improvement of OA lesions, such as the loss of necrotic chondrocytes and cartilage erosion of more than 200 mg/kg b.w., comparable to or better than a positive drug control (JOINS™, 200 mg/kg) in the cartilage of MIA-OA rats. CONCLUSIONS: Our results demonstrate that ALM16 has a strong chondroprotective effect against the OA model in vitro and in vivo, likely attributed to its anti-inflammatory activity and inhibition of MMP production.


Asunto(s)
Analgésicos/farmacología , Antiinflamatorios/farmacología , Cartílago Articular/efectos de los fármacos , Osteoartritis , Extractos Vegetales/farmacología , Animales , Astragalus propinquus/química , Cartílago Articular/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Glicosaminoglicanos/análisis , Humanos , Ácido Yodoacético/efectos adversos , Lithospermum/química , Masculino , Metaloproteinasas de la Matriz/análisis , Medicina Tradicional de Asia Oriental , Ratones Endogámicos ICR , Osteoartritis/inducido químicamente , Osteoartritis/metabolismo , Osteoartritis/fisiopatología , Sustancias Protectoras/farmacología , Ratas
4.
Int J Mol Sci ; 20(19)2019 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-31547612

RESUMEN

The aim of this study was to analyze the analgesic potential of Arrabidaea chica extract (EHA) as an alternative to osteoarthritis (OA) treatment. Thus, the extract was initially evaluated by the cyclooxygenase inhibition test. The analgesic effect of the extract, in vivo, was also verified in a model of OA induced by sodium monoiodoacetate (2 mg). EHA was administered to rats at doses of 50, 150, and 450 mg/kg between 3 and 25 days after OA induction. The animals were clinically evaluated every 7 days, euthanized at 29 days, and the liver, spleen, kidney and knee collected for histopathological analysis. The chemical composition of EHA was identified by HPLC-MS and the identified compounds submitted to molecular docking study. The results showed that the extract promoted cyclooxygenase inhibition and produced significant improvements in disability, motor activity, hyperalgesia, and OA-induced allodynia parameters, in addition to improvements in the radiological condition of the knees (but not observed in the histopathological study). Chemically the extract is rich in flavonoids. Among them, we evidence that amentoflavone showed very favorable interactions with the enzyme COX-2 in the in silico analysis. Thus, it is concluded that A. chica has important analgesic properties for the treatment of OA.


Asunto(s)
Bignoniaceae/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Flavonoides/farmacología , Hiperalgesia/tratamiento farmacológico , Osteoartritis/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/química , Modelos Animales de Enfermedad , Flavonoides/química , Hiperalgesia/inducido químicamente , Hiperalgesia/diagnóstico por imagen , Ácido Yodoacético/toxicidad , Actividad Motora/efectos de los fármacos , Especificidad de Órganos/efectos de los fármacos , Osteoartritis/inducido químicamente , Osteoartritis/diagnóstico por imagen , Extractos Vegetales/química , Ratas , Ratas Wistar
5.
Int J Pharm ; 569: 118598, 2019 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-31394185

RESUMEN

Topical nonsteroidal anti-inflammatory drugs have been used in treatment of osteoarthritis but their efficacy is marginal. One major reason is because of limited drug direct penetration to affected joint and muscle tissues from the topical application. The main purpose of this study was to evaluate a new topical treatment through enhancing the direct drug penetration to local muscle and joint tissues for improving topical treatment of osteoarthritis. A cationic prodrug, ketoprofen choline chloride (KCC) was synthesized for iontophoretic topical delivery. Anodal iontophoretic delivery of KCC and cathodal iontophoretic delivery of ketoprofen to the knee of live hairless rats were evaluated and the drug concentrations in the joint and muscle tissues over the time were determined. In addition, a knee osteoarthritis rat model was induced with intra-articular injection of monosodium iodoacetate solution. Anodal iontophoretic delivery of KCC, cathodal iontophoretic delivery of ketoprofen, or anodal iontophoretic delivery of sodium chloride were applied to the affected knee joint of each rat group, respectively. Knee joint pain was evaluated through a hind paw weight bearing study and knee joint inflammation was evaluated through measuring of the knee diameter. Iontophoretic delivery of KCC showed much higher drug concentration in the knee joint and muscle tissues, compared to iontophoretic delivery of ketoprofen. Treatment of rat knee joint with anodal iontophoresis of KCC also showed significant pain relief and knee inflammation reduction comparing to the control group, while treatment results from cathodal iontophoresis of ketoprofen were mostly not significantly different from the control group.


Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Iontoforesis , Cetoprofeno/administración & dosificación , Osteoartritis/tratamiento farmacológico , Dolor/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Femenino , Yodoacetatos , Articulación de la Rodilla/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Osteoartritis/inducido químicamente , Dolor/inducido químicamente , Ratas , Ratas sin Pelo
6.
Artículo en Inglés | MEDLINE | ID: mdl-31412648

RESUMEN

Osteoarthritis is a degenerative joint disease which primarily affects the articular cartilage and subchondral bones. Since there is an underlying localized inflammatory component in the pathogenesis of osteoarthritis, compounds like tocotrienol with anti-inflammatory properties may be able to retard its progression. This study aimed to determine the effects of oral tocotrienol supplementation on the articular cartilage and subchondral bone in a rat model of osteoarthritis induced by monosodium iodoacetate (MIA). Thirty male Sprague-Dawley rats (three-month-old) were randomized into five groups. Four groups were induced with osteoarthritis (single injection of MIA at week 0) and another served as the sham group. Three of the four groups with osteoarthritis were supplemented with annatto tocotrienol at 50, 100 and 150 mg/kg/day orally for five weeks. At week 5, all rats were sacrificed, and their tibial-femoral joints were harvested for analysis. The results indicated that the groups which received annatto tocotrienol at 100 and 150 mg/kg/day had lower histological scores and cartilage remodeling markers. Annatto tocotrienol at 150 mg/kg/day significantly lowered the osteocalcin levels and osteoclast surface of subchondral bone. In conclusion, annatto tocotrienol may potentially retard the progression of osteoarthritis. Future studies to confirm its mechanism of joint protection should be performed.


Asunto(s)
Huesos/efectos de los fármacos , Carotenoides/farmacología , Cartílago Articular/efectos de los fármacos , Osteoartritis/tratamiento farmacológico , Extractos Vegetales/farmacología , Tocotrienoles/farmacología , Animales , Bixaceae , Huesos/patología , Cartílago Articular/patología , Modelos Animales de Enfermedad , Masculino , Osteoartritis/inducido químicamente , Osteoartritis/patología , Ratas , Ratas Sprague-Dawley
7.
Acta Cir Bras ; 34(6): e201900604, 2019 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-31432995

RESUMEN

PURPOSE: In view of the principal role of Toll-like receptor 4 (TLR4) in mediating sterile inflammatory response contributing to osteoarthritis (OA) pathogenesis, we used lipopolysaccharide (LPS), a known TLR4 activator, to clarify whether modulation of TLR4 contributed to the protective actions of intra-articular administration of curcumin in a classical rat OA model surgically induced by anterior cruciate ligament transection (ACLT). METHODS: The rats underwent ACLT and received 50µl of curcumin at the concentration of 1 mg mL-1 and 10 µg LPS by intra-articular injection once a week for 8 weeks. Morphological changes of the cartilage and synovial tissues were observed. Apoptotic chondrocytes were detected using TUNEL assay. The concentrations of IL-1ß and TNF-ɑ in synovial fluid were determined using ELISA kits. The mRNA and protein expression levels of TLR4 and NF-κB p65 were detected by real-time PCR and Western blotting, respectively. RESULTS: Intra-articular administration of curcumin significantly improved articular cartilage injury, suppressed synovial inflammation and down-regulated the overexpression of TLR4 and its downstream NF-κB caused by LPS-induced TLR4 activation in rat osteoarthritic knees. CONCLUSION: The data suggested that the inhibition of TLR4 signal might be an important mechanism underlying a protective effect of local curcumin administration on OA.


Asunto(s)
Ligamento Cruzado Anterior/cirugía , Curcumina/farmacología , Osteoartritis/prevención & control , Receptor Toll-Like 4/metabolismo , Animales , Ligamento Cruzado Anterior/patología , Western Blotting , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Inyecciones Intraarticulares , Interleucina-1beta/metabolismo , Lipopolisacáridos , Masculino , FN-kappa B/metabolismo , Osteoartritis/inducido químicamente , Osteoartritis/metabolismo , Reacción en Cadena de la Polimerasa , Ratas , Receptor Toll-Like 4/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo
8.
Toxicol Lett ; 314: 18-26, 2019 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-31299270

RESUMEN

Epidemiological investigations indicate that effects related to prenatal adverse environments on the organs of the offspring could continue to adulthood. This study intends to confirm that prenatal nicotine exposure (PNE) increases the susceptibility of osteoarthritis (OA) in the male offspring, and to explore the potential intrauterine programming mechanism. During pregnancy, rats were divided into a PNE group and a control group. After birth, rats were given a high-fat diet for 6 months and long-distance running for 6 weeks. The rats were euthanized at 18 months after birth (PM18) and on gestational day 20 (GD20), respectively. Knee joints were collected for histochemistry, immunohistochemistry, and quantitative polymerase chain reaction (qPCR) assays. Histological analyses and the Mankin's score showed increased cartilage destruction and accelerated OA progression in adult offspring from the PNE group. Immunohistochemistry results showed decreased expression of transforming growth factor beta (TGFß) signaling pathway. Furthermore, the expression of apoptosis factors (caspase-3 and caspase-8), inflammatory factors [interleukin (IL)-1, IL-6] and matrix degradation enzymes [matrix metalloproteinase (MMP)-3, MMP-13] were also significantly increased. Traced back to the intrauterine period, it was found that the number of chondrocytes and the contents of Col2A1 and aggrecan in the matrix in the PNE group were decreased. And, the expression of the TGFß signaling pathway was inhibited. These results suggested that PNE enhanced the susceptibility of OA in male elderly offspring rats by down-regulating TGFß signaling, which increased articular cartilage local inflammation, matrix degradation, and cell apoptosis. This study confirmed the developmental origin of OA, and clarified the congenital and the living environment impact on the occurrence and development of OA. Our findings provide a theoretical and experimental basis for OA early prevention.


Asunto(s)
Articulaciones/efectos de los fármacos , Nicotina/toxicidad , Agonistas Nicotínicos/toxicidad , Osteoartritis/inducido químicamente , Efectos Tardíos de la Exposición Prenatal , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Factores de Edad , Agrecanos/metabolismo , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Condrocitos/patología , Condrogénesis/efectos de los fármacos , Colágeno Tipo II/metabolismo , Femenino , Edad Gestacional , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Articulaciones/metabolismo , Articulaciones/patología , Masculino , Exposición Materna , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Osteoartritis/metabolismo , Osteoartritis/patología , Embarazo , Ratas Wistar , Factores de Riesgo , Factores Sexuales
9.
BMC Musculoskelet Disord ; 20(1): 335, 2019 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-31324245

RESUMEN

BACKGROUND: Previous basic research and clinical studies examined the effects of mesenchymal stem cells (MSCs) on regeneration and maintenance of articular cartilage. However, our pilot study suggested that MSCs are more effective at suppressing inflammation and pain rather than promoting cartilage regeneration in osteoarthritis. Adipose tissue is considered a useful source of MSCs; it can be harvested easily in larger quantities compared with the bone marrow. The present study was designed to evaluate the anti-inflammatory, analgesic, and regenerative effects of intra-articularly injected processed lipoaspirate (PLA) cells (containing adipose-derived MSCs) on degenerative cartilage in a rat osteoarthritis model. METHODS: PLA cells were isolated from subcutaneous adipose tissue of 12-week-old female Sprague-Dawley rats. Osteoarthritis was induced by injection of monoiodoacetate (MIA). Each rat received 1 × 106 MSCs into the joint at day 7 (early injection group) and day 14 (late injection group) post-MIA injection. At 7, 14, 21 days after MIA administration, pain was assessed by immunostaining and western blotting of dorsal root ganglion (DRG). Cartilage quality was assessed macroscopically and by safranin-O and H&E staining, and joint inflammation was assessed by western blotting of the synovium. RESULTS: The early injection group showed less cartilage degradation, whereas the late injection group showed cartilage damage similar to untreated OA group. The relative expression level of CGRP protein in DRG neurons was significantly lower in the two treatment groups, compared with the untreated group. CONCLUSIONS: Intra-articular injection of PLA cells prevented degenerative changes in the early injection group, but had little effect in promoting cartilage repair in the late injection group. Interestingly, intra-articular injection of PLA cells resulted in suppression of inflammation and pain in both OA groups. Further studies are needed to determine the long-term effects of intra-articular injection of PLA cells in osteoarthritis.


Asunto(s)
Artralgia/terapia , Artritis Experimental/terapia , Cartílago Articular/patología , Trasplante de Células Madre Mesenquimatosas/métodos , Osteoartritis/terapia , Tejido Adiposo/citología , Animales , Artralgia/diagnóstico , Artralgia/etiología , Artritis Experimental/inducido químicamente , Biomarcadores/análisis , Femenino , Ganglios Espinales/patología , Humanos , Inyecciones Intraarticulares , Ácido Yodoacético/toxicidad , Articulación de la Rodilla/inervación , Articulación de la Rodilla/patología , Osteoartritis/inducido químicamente , Osteoartritis/patología , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento
10.
Nutrients ; 11(7)2019 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-31311115

RESUMEN

The prevalence of osteoarthritis (OA) is rising worldwide, with the most pronounced increase being in the category of metabolic-associated osteoarthritis (MetOA). This is predicted to worsen with the global rise in aging societies and obesity. To address this health burden, research is being conducted to identify foods that can reduce the incidence or severity of MetOA. Oil from the Greenshell mussel (Perna canaliculus) (GSM), a native New Zealand shellfish, has been successfully used to reduce OA symptoms. The current study assessed the effect of including flash-dried powder from whole GSM meat as part of a normal (control) versus high-fat/high-sugar (HFHS) diet for 13 weeks on the development of MetOA in rats. Rats fed a HFHS diet developed metabolic dysregulation and obesity with elevated plasma leptin and HbA1C concentrations. Visible damage to knee joint cartilage was minimal, but plasma levels of C telopeptide of type II collagen (CTX-II), a biomarker of cartilage degradation, were markedly higher in HFHS-fed rats compared to control-fed rats. However, rats fed the HFHS diet containing GSM had significantly reduced serum CTX-II. Inclusion of GSM in rats fed the control diet also lowered CTX-II. These findings suggest that dietary GSM can reduce the incidence or slow the progression of early MetOA.


Asunto(s)
Dieta Alta en Grasa , Carbohidratos de la Dieta/administración & dosificación , Aceites/farmacología , Osteoartritis/inducido químicamente , Perna , Alimentación Animal , Animales , Dieta , Suplementos Dietéticos , Femenino , Valor Nutritivo , Aceites/administración & dosificación , Aceites/química , Osteoartritis/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley
11.
Oxid Med Cell Longev ; 2019: 4695381, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31231454

RESUMEN

Tricetin is a well-studied flavonoid with a wide range of pharmacological activities in cancer and inflammation. However, the ability of tricetin to ameliorate the inflammation that occurs in osteoarthritis (OA) has not been determined. This study explored the effects of tricetin on interleukin- (IL-) 1ß-induced rat chondrocytes. Chondrocytes harvested from rat cartilage were incubated in vitro with tricetin in the presence of IL-1ß. The expression of matrix metalloproteinase- (MMP-) 1, MMP-3, MMP-13, nitric oxide (NO), prostaglandin E2 (PGE2), Bax, and Bcl-2 was evaluated by real-time-PCR, ELISA, Griess reaction, and western blotting. Caspase-3 activity in chondrocytes was determined using a caspase-3 activity assay and MAPK pathway activity by western blotting. Tricetin decreased the expression of MMP-1, MMP-3, and MMP-13 at both the gene and protein level in IL-1ß-induced rat chondrocytes. It also inhibited IL-1ß-induced NO and PGE2 production, by modulating inducible NO synthase and cyclooxygenase 2 gene expression. An antiapoptotic role of tricetin involving the Bax/Bcl-2/caspase-3 pathway was also determined. The chondroprotective effect of tricetin was shown to be partly related to the suppression of the MAPK signaling pathway. The results of this study demonstrate the chondroprotective role of tricetin, based on its anticatabolic, anti-inflammatory, and antiapoptotic effects in chondrocytes. The therapeutic potential of tricetin in OA patients should be explored in future studies.


Asunto(s)
Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Condrocitos/efectos de los fármacos , Cromonas/farmacología , Inflamación/prevención & control , Interleucina-1beta/toxicidad , Osteoartritis/prevención & control , Sustancias Protectoras/farmacología , Animales , Condrocitos/metabolismo , Condrocitos/patología , Femenino , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Masculino , Osteoartritis/inducido químicamente , Osteoartritis/metabolismo , Osteoartritis/patología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos
12.
Ultrastruct Pathol ; 43(2-3): 126-134, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31177887

RESUMEN

We recently reported an animal model of osteoarthritis (OA) induced by a combination of the chondrocyte glycolysis inhibitor, monoiodoacetate (MIA) and the agent that induces diabetes mellitus, streptozotocin (STZ). Here we investigated the potential protective effect of the antioxidant and anti-inflammatory agent, vitamin E against MIA+STZ-induced OA. Therefore, rats were either injected once with MIA (2 mg/50 µL) + 65 mg/kg STZ before being sacrificed after 8 weeks (model group) or were treated immediately after MIA+STZ injections with vitamin E (600 mg/kg; thrice a week) before being sacrificed after 8 weeks (treatment group). Using scanning and transmission electron microscopy examinations, we observed in the model group a substantial damage to the articular cartilage of the knee joint as demonstrated by the destruction of the chondrocytes, territorial matrix, disrupted lacunae, collagen fibers, and profound chondrocyte ultrastructural alterations such as degenerated chondrocyte, irregular cytoplasmic membrane, damaged mitochondria and rough endoplasmic reticulum, vacuolated cytoplasm, presence of lipid droplets and different sizes of lysosomes, which were substantially but not completely protected by vitamin E. H&E stained sections of knee joint articular cartilage showed that MIA+STZ induced damage to the chondrocyte and territorial matrix. Vitamin E also significantly (p < .05) inhibited MIA+STZ-induced blood levels of the inflammatory biomarkers, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) that are known to be modulated in OA and diabetes. We conclude that vitamin E protects against MIA+STZ-induced knee joints injuries in rats, which is associated with the inhibition of biomarkers of inflammation.


Asunto(s)
Cartílago Articular/efectos de los fármacos , Articulación de la Rodilla/efectos de los fármacos , Osteoartritis/tratamiento farmacológico , Vitamina E/farmacología , Animales , Antioxidantes/farmacología , Condrocitos/efectos de los fármacos , Diabetes Mellitus/tratamiento farmacológico , Modelos Animales de Enfermedad , Ácido Yodoacético , Osteoartritis/inducido químicamente , Osteoartritis/patología , Ratas Sprague-Dawley
13.
Curr Med Sci ; 39(1): 75-80, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30868494

RESUMEN

Nowadays, the cumulative intake of glucocorticoids has become the most common pathogenic factor for non-traumatic osteonecrosis of the femoral head (ONFH). Apoptosis of osteoblasts is considered as the main reason of ONFH at the molecular level. Glycogen synthase kinase 3ß (GSK3ß) is an important regulator of cellular differentiation and apoptosis pathway, which can modulate the balance between osteoblasts and osteoclasts. Several studies have reported about its function in osteoporosis, but little is known about it in osteonecrosis. In our study, lipopolysaccharide and methylprednisolone were utilized to establish a rat ONFH model. The phosphorylation of GSK3ß Ser-9 was decreased in the model. Western blotting examination of ß-catenin, Bcl-2, Bax and caspase-3 revealed that the osteoblasts were apoptotic. In dexamethasone (Dex)-incubated primary osteoblasts, the expression profile of GSK3ß phosphorylation and apoptotic factors were consistent with those in the rat ONFH model. To further investigate the regulation of osteonecrosis caused by GSK3ß, the expression and function of GSK3ß were inhibited in Dex-incubated primary osteoblasts. The knockdown of GSK3ß by siRNA decreased the expression of Bax and cleaved caspase-3, but increased Bcl-2 and ß-catenin. On the other hand, selective inhibition of GSK3ß function by LiCl counteracted the activation of caspase-3 induced by Dex. Our work is the first study about the GSK3ß phosphorylation in ONFH, and provides evidence for further therapeutic methods.


Asunto(s)
Necrosis de la Cabeza Femoral/inducido químicamente , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Osteoartritis/inducido químicamente , Osteoblastos/citología , Serina/metabolismo , Animales , Apoptosis/efectos de los fármacos , Dexametasona , Modelos Animales de Enfermedad , Necrosis de la Cabeza Femoral/genética , Necrosis de la Cabeza Femoral/metabolismo , Técnicas de Silenciamiento del Gen , Lipopolisacáridos/efectos adversos , Cloruro de Litio/farmacología , Metilprednisolona/efectos adversos , Osteoartritis/genética , Osteoartritis/metabolismo , Osteoblastos/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Regulación hacia Arriba/efectos de los fármacos
14.
Methods Mol Biol ; 1914: 391-407, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30729479

RESUMEN

Bone pain is a prevalent issue in society today and also is one of the hardest types of pain to control. Pain originating in the bone can be caused by many different entities including metastatic and primary neoplasm, fracture, osteoarthritis as well as numerous other metabolic disorders. In this chapter we describe the methods and protocols that currently are accepted and validated for the study of bone pain in models of metastatic cancer, bicortical fracture and osteoarthritis. These animal models provide invaluable information as to the nature of bone pain and give rise to potential new targets for its treatment and management.


Asunto(s)
Modelos Animales de Enfermedad , Dimensión del Dolor/métodos , Dolor/diagnóstico , Animales , Conducta Animal , Neoplasias Óseas/complicaciones , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Huesos/patología , Técnicas de Cultivo de Célula/instrumentación , Técnicas de Cultivo de Célula/métodos , Línea Celular Tumoral/trasplante , Femenino , Fracturas Óseas/complicaciones , Fracturas Óseas/etiología , Humanos , Ácido Yodoacético/administración & dosificación , Ácido Yodoacético/toxicidad , Masculino , Neoplasias Mamarias Animales/patología , Ratones , Ratones Endogámicos BALB C , Osteoartritis/inducido químicamente , Osteoartritis/complicaciones , Dolor/etiología , Dimensión del Dolor/instrumentación , Ratas Sprague-Dawley
15.
Pharm Biol ; 57(1): 74-81, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30707846

RESUMEN

CONTEXT: Mollugo pentaphylla L. (Molluginaceae) extract (MPE) has been reported to have anti-inflammatory effect on MSU-induced gouty arthritis in a mouse model. OBJECTIVE: This study examined the anti-inflammatory activities of an MPE in vitro and anti-osteoarthritis effects on monosodium iodoacetate (MIA)-induced osteoarthritis (OA) in vivo. MATERIALS AND METHODS: The dried whole plants of M. pentaphylla were extracted with 70% ethanol under reflux. The anti-inflammatory effect of MPE was evaluated in vitro in lipopolysaccharide (LPS)-treated RAW264.7 cells. The anti-osteoarthritic effect of MPE was investigated in a Sprague-Dawley rat model of MIA-induced OA. Each seven male rats were orally administered MPE (75, 150 or 300 mg/kg) or the positive control drug indomethacin (1 mg/kg) 3 days before MIA injection and once daily for 11 days thereafter. After the treatment with MPE, no evidence of systemic adverse effects was observed in any study group. RESULTS: MPE exhibited anti-inflammatory activity via inhibition of the production of NO (57.8%), PGE2 (97.1%) and IL-6 (93.2%) in LPS-treated RAW264.7 cells at 200 µg/mL. In addition, MPE suppressed IL-1ß (60.9%), TNF-α (37.9%) and IL- 6 (40.9%) production and suppressed the synthesis of MMP-2, MMP-9 and COX-2 in the MIA-induced OA rat model. CONCLUSIONS: These results demonstrate that MPE exerts potent anti-inflammatory activities and protects cartilage in an OA rat model. This might be a potential candidate for therapeutic OA treatment.


Asunto(s)
Antiinflamatorios/farmacología , Molluginaceae/química , Osteoartritis/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Condrocitos , Indometacina/farmacología , Articulación de la Rodilla/patología , Lipopolisacáridos/farmacología , Masculino , Ratones , Osteoartritis/inducido químicamente , Células RAW 264.7 , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Soporte de Peso
16.
Int J Biol Sci ; 15(1): 229-238, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30662362

RESUMEN

Current study examined whether psoralen (PSO) exhibits anti-inflammatory responses, protection and activation of chondrocytes, and relieve osteoarthritis (OA). Rats chondrocytes and human synoviocytes were cultured in tumor necrosis factor-α (TNF-α) conditioned culture medium with/without PSO to test the cell morphologies and cytotoxicities in vitro. Cartilaginous extracellular matrix (ECM) and proliferative gene/protein expression levels were evaluated in chondrocytes. Meanwhile, matrix metalloproteinases (MMPs) and interleukins (ILs) gene/protein expression were analyzed in synoviocytes. SD rats of monosodium iodoacetate (MIA) induced OA model were used in order to assess the effects of PSO on attenuating degeneration of the articular cartilage in vivo. Results showed TNF-α conditioned culturing with/without PSO (1-100 µM) had no any toxicity on both the cell lines. PSO (10 µM) activated cartilaginous specific ECM expression along with up-regulation of proliferative genes at transcriptional levels. Interestingly, PSO significantly reversed TNF-α induced up-regulation of MMP13 and ILs synoviocytes in a dose-dependent manner (1 to 20 µM), while down-regulated cartilaginous ECM production. Following six weeks of PSO treatments to articular cartilage osteoarthritis, compared to MIA-induced group, the appearance and physiological structure of articular cartilage was more integrated with greatly organized chondrocytes and abundant cartilage matrix. In conclusion, PSO protects and activates chondrocytes, antagonizing the expression of MMPs and ILs secreted by synovial cells, and effectively attenuates MIA-induced OA.


Asunto(s)
Antiinflamatorios/farmacología , Condrocitos/efectos de los fármacos , Difosfatos/toxicidad , Ficusina/farmacología , Imidazoles/toxicidad , Osteoartritis/inducido químicamente , Sinoviocitos/efectos de los fármacos , Animales , Antiinflamatorios/uso terapéutico , Células Cultivadas , Ficusina/uso terapéutico , Osteoartritis/tratamiento farmacológico , Ratas
17.
BMC Musculoskelet Disord ; 20(1): 8, 2019 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-30611247

RESUMEN

BACKGROUND: Osteoarthritis (OA) is a common joint disease in aging societies, which is accompanied by chronic inflammation and degeneration of the joint structure. Inflammation of the infrapatellar fat pad (IFP) and synovial membrane (IFP surface) plays essential roles in persistent pain development in patients with OA. To identify the point during the inflammatory process critical for persistent pain development, we performed a time course histological analysis in a rat arthritis model. METHODS: Wistar rats received single intra-articular injection of monoiodoacetic acid (MIA, 0.2 or 1.0 mg/30 µL) in the right knees or phosphate-buffered saline (PBS, 30 µL) as a control in the left knees. Pain avoidance behaviors (weight-bearing asymmetry and tactile hypersensitivity of the plantar surface of the hind paw) were evaluated on days 0, 1, 3, 5, 7, and 14 after injection. Histological assessments of the knee joint were performed on days 0, 1, 3, 5, and 7 after MIA injection. RESULTS: Weight-bearing asymmetry was observed along with the onset of acute inflammation in both the low- (0.2 mg) and high-dose (1.0 mg) groups. In the low-dose group, weight-bearing asymmetry was completely reversed on day 10, indicating that joint pain seemed to alleviate between days 7 and 10. In contrast, we observed persistent joint pain after day 10 in the high-dose group. Histological assessments of the high-dose group indicated that the initial sign of inflammatory responses was observed in the perivascular region inside the IFP. Inflammatory cell infiltration from the perivascular region to the parenchymal region of the IFP was observed on day 3 and reached the IFP surface (synovial membrane) on day 7. Extensive fibrosis throughout the IFP was observed between days 5 and 7 after MIA injection. CONCLUSION: Our data indicated that acute joint pain occurs along with the onset of acute inflammatory process. Irreversible structural changes in the IFP, such as extensive fibrosis, are observed prior to persistent pain development. Thus, we consider that this process may play important roles in persistent pain development.


Asunto(s)
Tejido Adiposo/patología , Artralgia/patología , Artritis Experimental/patología , Osteoartritis/patología , Membrana Sinovial/patología , Tejido Adiposo/fisiopatología , Animales , Artralgia/inducido químicamente , Artralgia/fisiopatología , Artralgia/psicología , Artritis Experimental/inducido químicamente , Artritis Experimental/fisiopatología , Artritis Experimental/psicología , Conducta Animal , Progresión de la Enfermedad , Fibrosis , Ácido Yodoacético , Masculino , Osteoartritis/inducido químicamente , Osteoartritis/fisiopatología , Osteoartritis/psicología , Percepción del Dolor , Umbral del Dolor , Ratas Wistar , Membrana Sinovial/fisiopatología , Factores de Tiempo , Soporte de Peso
18.
Ann Rheum Dis ; 78(3): 421-428, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30610061

RESUMEN

OBJECTIVE: Osteoarthritis (OA) appears to be associated with various metabolic disorders, but the potential contribution of amino acid metabolism to OA pathogenesis has not been clearly elucidated. Here, we explored whether alterations in the amino acid metabolism of chondrocytes could regulate OA pathogenesis. METHODS: Expression profiles of amino acid metabolism-regulating genes in primary-culture passage 0 mouse chondrocytes were examined by microarray analysis, and selected genes were further characterised in mouse OA chondrocytes and OA cartilage of human and mouse models. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) or intra-articular (IA) injection of adenoviruses expressing catabolic regulators. The functional consequences of arginase II (Arg-II) were examined in Arg2-/- mice and those subjected to IA injection of an adenovirus encoding Arg-II (Ad-Arg-II). RESULTS: The gene encoding Arg-II, an arginine-metabolising enzyme, was specifically upregulated in chondrocytes under various pathological conditions and in OA cartilage from human patients with OA and various mouse models. Adenovirus-mediated overexpression of Arg-II in mouse joint tissues caused OA pathogenesis, whereas genetic ablation of Arg2 in mice (Arg2 -/-) abolished all manifestations of DMM-induced OA. Mechanistically, Arg-II appears to cause OA cartilage destruction at least partly by upregulating the expression of matrix-degrading enzymes (matrix metalloproteinase 3 [MMP3] and MMP13) in chondrocytes via the nuclear factor (NF)-κB pathway. CONCLUSIONS: Our results indicate that Arg-II is a crucial regulator of OA pathogenesis in mice. Although chondrocytes of human and mouse do not identically, but similarly, respond to Arg-II, our results suggest that Arg-II could be a therapeutic target of OA pathogenesis.


Asunto(s)
Arginasa/fisiología , Artritis Experimental/enzimología , Cartílago Articular/enzimología , Condrocitos/enzimología , Osteoartritis/enzimología , Animales , Artritis Experimental/inducido químicamente , Modelos Animales de Enfermedad , Humanos , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Ratones , Osteoartritis/inducido químicamente , Regulación hacia Arriba
19.
J Ethnopharmacol ; 229: 215-221, 2019 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-30342192

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Tougu Xiaotong capsule (TXC) is a Chinese herbal compound that belongs to a range of Chinese herbs functioning as 'kidney invigorators and liver softeners' commonly used to treat osteoarthritis (OA) in China. AIMS OF THE STUDY: The aims of the present study are to confirm the therapeutic effects of TXC in an OA cell model and to determine the mechanisms involved in such effects. MATERIALS AND METHODS: A tunicamycin (Tm)-exposed OA cell model was employed, and the effects of TXC were confirmed by observing cell viability and apoptosis. The reduced cell viability and increased apoptosis caused by Tm were improved by TXC, confirming the cellular protection of TXC. We then investigated the expression of biomarkers related to the endoplasmic reticulum (ER) stress pathway, including microRNA-211 (miR-211), a regulator in the ER stress pathway. RESULTS: Downregulation of X-box binding protein 1 (Xbp-1) and miR-211 expression following Tm administration was reversed by TXC. Moreover, the upregulation by Tm of the expression levels of binding immunoglobulin protein, Xbp-1, activating transcription factor 4, C/EBP-homologous protein, Caspase-9 and Caspase-3 was downregulated by TXC. These results indicated that the ER stress pathway-related mechanism may play a potential role in the therapeutic effects of TXC. CONCLUSIONS: The present study provides evidence of the therapeutic effects of TXC at the cell level and describes a cellular model for establishing the mechanisms of the effects of TXC used in the treatment of OA.


Asunto(s)
Condrocitos/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Osteoartritis/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Cápsulas , Línea Celular , Supervivencia Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Masculino , Osteoartritis/inducido químicamente , Ratas Sprague-Dawley , Tunicamicina
20.
Drug Deliv Transl Res ; 9(1): 357-365, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30430453

RESUMEN

The aim of this study was to develop a microemulsion-based hydrogel (MBH) formulation of 3,5,4'-trimethoxy-trans-stilbene (BTM) as topical delivery system for the treatment of osteoarthritis (OA). The pseudo-ternary phase diagrams were constructed to optimize the microemulsion (ME) formulation. The ME formulation containing 18.8% Cremopher EL35 (surfactant), 9.4% Transcutol HP (co-surfactant), 3.1% LABRAFIL M 1944 CS (oil), and 68.7% water was selected. The obtained BTM-loaded ME (BTM-ME) had a spherical morphology (17.5 ± 1.4 nm), with polydispersity index (PDI) value of 0.068 ± 0.016 and zeta potential of - 11.8 ± 0.5 mV, and was converted into BTM-loaded MBH (BTM-MBH) using Carbopol 940. Ex vivo skin permeation study showed that both ME and MBH formulations significantly enhanced the amount of BTM permeated. The cumulative amount of BTM permeated after 12 h (Q12) for ME, and MBH formulations were 3.25- and 1.96-fold higher than that for emulsion gel (EG). Pharmacokinetic study showed that the AUC of BTM suspension (oral) was three times higher than that of BTM-MBH (topical). Topical delivery of BTM-MBH demonstrated remarkable anti-OA effect in a rabbit model of OA induced by papain, with decreased levels of pro-inflammatory cytokines. The developed MBH formulation might be a promising strategy for topical delivery of BTM for treatment of OA.


Asunto(s)
Resinas Acrílicas/química , Hidrogeles/química , Osteoartritis/tratamiento farmacológico , Papaína/efectos adversos , Estilbenos/administración & dosificación , Administración Cutánea , Administración Oral , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Emulsiones , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Osteoartritis/inducido químicamente , Osteoartritis/metabolismo , Conejos , Estilbenos/química , Estilbenos/farmacocinética
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