Anti-inflammatory effect of antidiabetic thiazolidinediones prevents bone resorption rather than cartilage changes in experimental polyarthritisReportar como inadecuado




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Arthritis Research and Therapy

, 10:R6

First Online: 16 January 2008Received: 18 July 2007Revised: 27 November 2007Accepted: 16 January 2008

Abstract

BackgroundRosiglitazone and pioglitazone are high-affinity peroxisome proliferator-activated receptor PPAR-γ agonists with potent anti-diabetic properties and potential anti-inflammatory effects. We compared the ability of a range of oral doses of these thiazolidinediones, including those sufficient to restore insulin sensitization, to inhibit the pathogenesis of adjuvant-induced arthritis AIA.

MethodsAIA was induced in Lewis rats by a subcutaneous injection of 1 mg of complete Freund-s adjuvant. Rats were treated orally for 21 days with pioglitazone 3, 10 or 30 mg-kg-day, rosiglitazone 3 or 10 mg-kg-day, or with vehicle only. The time course of AIA was evaluated by biotelemetry to monitor body temperature and locomotor activity, by clinical score and plethysmographic measurement of hindpaw oedema. At necropsy, RT-PCR analysis was performed on synovium, liver and subcutaneous fat. Changes in cartilage were evaluated by histological examination of ankle joints, radiolabelled sulphate incorporation proteoglycan synthesis, glycosaminoglycan content proteoglycan turnover and aggrecan expression in patellar cartilage. Whole-body bone mineral content was measured by dual-energy X-ray absorptiometry.

ResultsThe highest doses of rosiglitazone 10 mg-kg-day or pioglitazone 30 mg-kg-day were required to reduce fever peaks associated with acute or chronic inflammation, respectively, and to decrease arthritis severity. At these doses, thiazolidinediones reduced synovitis and synovial expression of TNF-α, IL-1β and basic fibroblast growth factor without affecting neovascularization or the expression of vascular endothelial growth factor. Thiazolidinediones failed to prevent cartilage lesions and arthritis-induced inhibition of proteoglycan synthesis, aggrecan mRNA level or glycosaminoglycan content in patellar cartilage, but reduced bone erosions and inflammatory bone loss. A trend towards lower urinary levels of deoxipyridinolin was also noted in arthritic rats treated with thiazolidinediones. Rosiglitazone 10 mg-kg-day or pioglitazone 30 mg-kg-day increased the expression of PPAR-γ and adiponectin in adipose tissue, confirming that they were activating PPAR-γ in inflammatory conditions, although an increase in fat mass percentage was observed for the most anti-arthritic dose.

ConclusionThese data emphasize that higher dosages of thiazolidinediones are required for the treatment of arthritis than for restoring insulin sensitivity but that thiazolidinediones prevent inflammatory bone loss despite exposing animals to increased fatness possibly resulting from excessive activation of PPAR-γ.

AbbreviationsACO= Acyl-CoenzymeA oxidase

AIA= adjuvant-induced arthritis

ANOVA= analysis of variance

bFGF= basic fibroblast growth factor

BMC= bone mineral content

DEXA= dual-energy X-ray absorptiometry

IL= interleukin

MCP-1= monocyte chemotactic protein-1

NF= nuclear factor

PLSD= protected least-squares difference

PIO= Pioglitazone

PPAR= peroxisome proliferator-activated receptor

RA= rheumatoid arthritis

RANKL= receptor activator of nuclear factor κB ligand

ROSI= rosiglitazone

RT-PCR= polymerase chain reaction with reverse transcription

TNF= tumour necrosis factor

TZD= thiazolidinedione

VEGF= vascular endothelial growth factor.

Electronic supplementary materialThe online version of this article doi:10.1186-ar2354 contains supplementary material, which is available to authorized users.

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Autor: Meriem Koufany - David Moulin - Arnaud Bianchi - Mikhaela Muresan - Sylvie Sebillaud - Patrick Netter - Georges Weryha - Je

Fuente: https://link.springer.com/







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