Anti-inflammatory effect of antidiabetic thiazolidinediones prevents bone resorption rather than cartilage changes in experimental polyarthritis.
BACKGROUND
Rosiglitazone and pioglitazone are high-affinity peroxisome proliferator-activated receptor (PPAR)-gamma 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).


METHODS
AIA 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.


RESULTS
The 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-alpha, IL-1beta 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-gamma and adiponectin in adipose tissue, confirming that they were activating PPAR-gamma in inflammatory conditions, although an increase in fat mass percentage was observed for the most anti-arthritic dose.


CONCLUSIONS
These 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-gamma.
Koufany
Meriem
M
Laboratoire de Physiopathologie et Pharmacologie Articulaires (LPPA), UMR 7561 CNRS-Nancy Université, avenue de la forêt de Haye, BP 184, 54505 Vandoeuvre-lès-Nancy, France. meriem.koufany@medecine.uhp-nancy.fr
Moulin
David
D
Bianchi
Arnaud
A
Muresan
Mikhaela
M
Sebillaud
Sylvie
S
Netter
Patrick
P
Weryha
Georges
G
Jouzeau
Jean-Yves
JY
D052242:Adiponectin / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000150:complications* / Q000453:epidemiology / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000209:etiology* / Q000517:prevention & control*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000503:physiopathology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006614:Hindlimb; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015994:Incidence; D008297:Male; D047495:PPAR gamma / Q000235:genetics; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D000077154:Rosiglitazone; D013583:Synovial Membrane / Q000378:metabolism; D013585:Synovitis / Q000473:pathology; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
D052242:Adiponectin; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D016207:Cytokines; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D016222:Fibroblast Growth Factor 2; D000077205:Pioglitazone